Undermind Research Topic: I want to find studies on small molecules similar to DDL-920 that increase γ-oscillations in the brain and enhance memory and cognition.

Research topic

I want to find studies on small molecules similar to DDL-920 that increase γ-oscillations in the brain and enhance memory and cognition.

Report

Two studies directly show that the small molecule DDL-920 increases γ-oscillations and enhances memory and cognition in Alzheimer's disease model mice [1, 2].

Details:

DDL-920:
- Reference [1]: Describes DDL-920 as a brain-permeable small molecule acting as a selective negative allosteric modulator (NAM) of γ-aminobutyric acid type A receptors (GABA_A) assembled from α1β2δ subunits. DDL-920 significantly enhances γ-oscillations (30-120 Hz) and improves cognition/memory in Alzheimer's disease (AD) model mice, suggesting its therapeutic potential for AD.
- Reference [2]: Further confirms the findings of [1]. Using anatomical, electrophysiological (both in vitro and in vivo), and behavioral methods, this study shows that DDL-920 increases γ-oscillations and improves memory/cognition in AD model mice. It emphasizes the molecule's brain permeability and selective negative allosteric modulation of GABA_A receptors.
Related Studies on γ-Oscillations:
- Reference [3]: Examines small molecules (EX15 and RE01) that modulate Kv3.1/Kv3.2 potassium channels, increasing γ-oscillations by restoring FSN (fast-spiking interneurons) activity, crucial for network stability. This study validates the potential of γ-oscillation enhancement for rescuing cognitive impairment in AD models.
- Reference [8]: Investigates TrpV1 receptor agonist, capsaicin, which rescues Aβ-induced impairment in neuronal function and network γ-oscillations. This study highlights the restorative role of γ-oscillations in cognitive contexts, albeit with a different target than DDL-920.
Additional Related Mechanisms:
- AMPA Receptor Modulators:
  - Several papers [4, 5, 6] discuss the cognitive enhancement potentials of AMPA receptor modulators (e.g., CX614, S 18986). These modulators potentiate synaptic transmission and increase BDNF expression, which is associated with improved learning and memory. Although γ-oscillations are not always directly discussed, the enhancement of synaptic plasticity and LTP is relevant.
- Other Mechanisms:
  - Reference [7]: Shows dopamine D4 receptor agonist (PD168077) enhancing γ-oscillations in aged mice.
  - Reference [15]: Discusses PDE inhibitors like rolipram, which enhance memory via the cAMP pathway. These pathways are indirectly related to γ-oscillations but crucial for cognitive enhancement.

Conclusion:

Research specifically on DDL-920 shows that it enhances γ-oscillations and improves memory and cognition in Alzheimer's disease model mice [1, 2]. Other studies demonstrate the potential of small molecules targeting different pathways, such as potassium channels (ex. EX15, RE01), AMPA receptors, and dopamine receptors, to enhance γ-oscillations and cognitive functions, highlighting a broader interest in targeting γ-oscillations for cognitive therapies [3, 4, 5, 7, 8]. The consistent finding across related studies supports further exploration of such small molecules in cognitive enhancement and neurological disease contexts.

References

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Last 2 years

> 1 citation per year

> 5 citations per year

Topic Match

Cit./Year

Year

Paper

Paper Relevance Summary

100.0%

0.9

2023

[1] A therapeutic small molecule lead enhances γ-oscillations and improves cognition/memory in Alzheimer’s disease model mice Xiaofei Wei, ..., and Istvan Mody bioRxiv 2023 - 1 citations - Show abstract - Cite 100.0% topic match

Provides evidence that DDL-920 enhances γ-oscillations and cognition/memory. Demonstrates DDL-920’s efficacy in a mouse model of Alzheimer's disease by acting as a selective negative allosteric modulator of GABA_A receptors. Focuses specifically on a brain-permeable small molecule relevant for enhancing cognitive functions through increased γ-oscillations, aligning precisely with the desired topic.

100.0%

0.0

2024

[2] A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer's disease model mice. Xiaofei Wei, ..., and Istvan Mody Proceedings of the National Academy of Sciences of the United States of America 2024 - 0 citations - Show abstract - Cite 100.0% topic match

Shows DDL-920 enhances γ-oscillations and cognition/memory in AD model mice. Uses anatomical, electrophysiological, and behavioral methods to demonstrate DDL-920's effects. Acts as a negative allosteric modulator of GABA_A receptors, primarily α1β2δ subunits.

100.0%

6.5

2020

[3] Modulation of Kv3.1/Kv3.2 promotes gamma oscillations by rescuing Aβ‐induced desynchronization of fast‐spiking interneuron firing in an AD mouse model in vitro Y. Andrade-Talavera, ..., and A. Fisahn The Journal of Physiology 2020 - 29 citations - Show abstract - Cite - PDF 100.0% topic match

Shows modulation of Kv3.1/3.2 channels increases γ-oscillations. EX15 and RE01 enhance FSN activity, counteracting Aβ-induced γ-oscillation disruption. Relevance: Demonstrates small molecules improving cognition via γ-oscillations in an AD model.

99.7%

0.3

2000

[4] Positive modulators of the AMPA receptor S. Grove, ..., and Ming-Qiang Zhang Expert Opinion on Therapeutic Patents 2000 - 8 citations - Show abstract - Cite 99.7% topic match

Provides an overview of positive modulators of the AMPA receptor. Details structural classes of compounds that enhance AMPA-receptor mediated synaptic transmission. Discusses potential cognitive benefits, including CX516, which may enhance γ-oscillations and cognitive functions.

98.2%

13.3

2009

[5] Positive AMPA Receptor Modulation Rapidly Stimulates BDNF Release and Increases Dendritic mRNA Translation Hussam Jourdi, ..., and M. Baudry The Journal of Neuroscience 2009 - 205 citations - Show abstract - Cite - PDF Abstract: Brain-derived neurotrophic factor (BDNF) stimulates local dendritic mRNA translation and is involved in formation and consolidation of memory. 2H,3H,6aH-pyrrolidino[2″,1″-3′,2′]1,3-oxazino[6′,5′-5,4]-benzo[e]1,4-dioxan-10-one (CX614), one of the best-studied positive AMPA receptor modulators (also known as ampakines), increases BDNF mRNA and protein and facilitates long-term potentiation (LTP) induction. Several other ampakines also improve performance in various behavioral and learning tasks. Since local dendritic protein synthesis has been implicated in LTP stabilization and in memory consolidation, this study investigated whether CX614 could influence synaptic plasticity by upregulating dendritic protein translation. CX614 treatment of primary neuronal cultures and acute hippocampal slices rapidly activated the translation machinery and increased local dendritic protein synthesis. CX614-induced activation of translation was blocked by K252a [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester], CNQX, APV, and TTX, and was inhibited in the presence of an extracellular BDNF scavenger, TrkB-Fc. The acute effect of CX614 on translation was mediated by increased BDNF release as demonstrated with a BDNF scavenging assay using TrkB-Fc during CX614 treatment of cultured primary neurons and was blocked by nifedipine, ryanodine, and lack of extracellular Ca2+ in acute hippocampal slices. Finally, CX614, like BDNF, rapidly increased dendritic translation of an exogenous translation reporter. Together, our results demonstrate that positive modulation of AMPA receptors rapidly stimulates dendritic translation, an effect mediated by BDNF secretion and TrkB receptor activation. They also suggest that increased BDNF secretion and stimulation of local protein synthesis contribute to the effects of ampakines on synaptic plasticity. 98.2% topic match

Shows CX614, an AMPA receptor modulator, increases BDNF and enhances LTP. CX614 stimulates local dendritic mRNA translation, important for memory formation and consolidation. Relates to cognitive enhancement via BDNF, but not directly γ-oscillations; moderately relevant.

95.5%

10.6

2004

[6] AMPA receptor potentiators for the treatment of CNS disorders. M. O'Neill, ..., and E. Nisenbaum Current drug targets. CNS and neurological disorders 2004 - 218 citations - Show abstract - Cite Abstract: Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMPA receptor potentiators have been reported. Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin expression. Therefore, these AMPA receptor potentiators offer an exciting new class of drugs with potential for treating (1) cognitive impairment associated with Alzheimer's disease and schizophrenia, (2) depression, (3) slowing the progression and potentially enhancing recovery from Parkinson's disease. 95.5% topic match

Shows the efficacy of AMPA receptor potentiators in cognitive enhancement. Details several classes, such as benzylpiperidines, that improve cognitive function and increase hippocampal activity. Highlights AMPA receptor modulators' ability to upregulate BDNF expression, linking to γ-oscillations and synaptic plasticity.

92.1%

0.4

2022

[7] Activation of Dopamine 4 Receptor Subtype Enhances Gamma Oscillations in Hippocampal Slices of Aged Mice Yuan Wang, ..., and C. Lu Frontiers in Aging Neuroscience 2022 - 1 citations - Show abstract - Cite - PDF 92.1% topic match

Shows that D4 receptor activation enhances γ-oscillations in aged mice. Demonstrates that the D4R agonist PD168077 can restore γ power diminished by aging. Focuses on dopamine modulation, not small-molecule drugs specifically like DDL-920 or direct cognitive enhancement studies.

92.0%

10.1

2018

[8] TrpV1 receptor activation rescues neuronal function and network gamma oscillations from Aβ-induced impairment in mouse hippocampus in vitro H. Balleza-Tapia, ..., and A. Fisahn eLife 2018 - 62 citations - Show abstract - Cite 92.0% topic match

Shows TrpV1 receptor activation rescues gamma oscillations impaired by Aβ. Capsaicin, a TrpV1 agonist, reverses Aβ-induced gamma oscillation degradation and memory impairment in mouse hippocampus. Relevant for γ-oscillation restoration and cognitive enhancement, but not specifically testing small molecules similar to DDL-920.

91.1%

2.2

2007

[9] AMPA receptor potentiators as cognitive enhancers. M. O'Neill and S. Dix IDrugs : the investigational drugs journal 2007 - 39 citations - Show abstract - Cite 91.1% topic match

Shows potential of AMPA receptor potentiators as cognitive enhancers. Explores AMPA receptor allosteric modulators in enhancing glutamatergic transmission and LTP related to memory formation. Some relevance: Focus on cognitive enhancement, but γ-oscillations not specifically discussed.

90.9%

3.5

1996

[10] Effects of a memory-enhancing drug on DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor currents and synaptic transmission in hippocampus. A. Arai, ..., and Gary Lynch The Journal of pharmacology and experimental therapeutics 1996 - 99 citations - Show abstract - Cite 90.9% topic match

Shows effect of BDP-12 on synaptic transmission. BDP-12 enhances glutamatergic responses and AMPA receptor currents in hippocampal neurons, aiding memory encoding. No specific mention of γ-oscillations or direct cognitive enhancement, relevant if focusing on synaptic modulation mechanisms.

87.1%

0.3

2022

[11] The role of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type receptor modulators in object recognition memory reconsolidation Xin-Yi Man, ..., and Zhi-Yong Xiao NeuroReport 2022 - 1 citations - Show abstract - Cite 87.1% topic match

Investigates AMPA receptor modulators' role in memory reconsolidation. Shows CX546 has no effect while 10-mg/kg NBQX impairs object recognition memory reconsolidation in mice. Discusses AMPA receptor's influence on long-term memory but does not address γ-oscillations specifically.

86.3%

5.1

2007

[12] AMPA receptor potentiators: application for depression and Parkinson's disease. M. O'Neill and J. Witkin Current drug targets 2007 - 90 citations - Show abstract - Cite 86.3% topic match

Shows potential of AMPA receptor potentiators in cognitive enhancement. Expands on how AMPA receptor modulators like CX-516 enhance memory by modulating synaptic plasticity. Somewhat related: Does not specifically discuss γ-oscillations or molecules similar to DDL-920.

76.4%

0.0

2016

[13] (chronic recording/synaptic responses/spatial mazes/olfactory learning) U. Staubli, ..., and Gary Lynchi Journal Not Provided 2016 - 0 citations - Show abstract - Cite 76.4% topic match

Shows a benzamide drug facilitating AMPA receptor synaptic responses and enhancing memory. The compound enhances memory in rats, demonstrated via odor discrimination, water maze, and radial maze tests. Relevance is due to synaptic modulation and memory enhancement, but it doesn't specify effects on γ-oscillations.

73.9%

10.2

2007

[14] Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior. A. Arai and Markus Kessler Current drug targets 2007 - 180 citations - Show abstract - Cite 73.9% topic match

Investigates AMPA receptor modulators (ampakines) and their effects on cognition. Describes how ampakines increase synaptic responses, long-term potentiation, and enhance learning and memory in behavioral tests. Highlights potential relevance due to ampakines' role in synaptic modulation, but does not directly address γ-oscillations.

73.8%

6.3

2005

[15] Phosphodiesterase inhibitors for cognitive enhancement. G. Rose, ..., and A. Tehim Current pharmaceutical design 2005 - 121 citations - Show abstract - Cite 73.8% topic match

Shows that PDE4 inhibitors have positive effects on learning and memory. Describes how rolipram prolongs cAMP signals improving cognitive functions in animal models. Relevance: Focuses on cognitive enhancement via PDE inhibition, does not specifically address γ-oscillations.

72.2%

0.0

2005

[16] UC Irvine UC Irvine Previously Published Works Title Facilitation of glutamate receptors enhances memory U. Staubli, ..., and G. Lynch Journal Not Provided 2005 - 0 citations - Show abstract - Cite Abstract: A benzamide drug that crosses the bloodbrain barrier and facilitates DL-a-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic responses was tested for its effects on memory in three behavioral tasks. The compound reversibly increased the amplitude and prolonged the duration of field excitatory postsynaptic potentials in hippocampal slices and produced comparable effects in the dentate gyrus in situ after intraperitoneal iDjections. Rats in jected with the drug 30 min prior to being given a suboptimal number of training trials in a two-odor discrimination task were more likely than controls to select the correct odor in a retention test carried out 96 hr later. Evidence for improved memory was also obtained in a water maze task in which rats were given only four trials to find a submerged platform in the presence of spatial cues; animals injected with the drug 30 min before the training session were significantly faster than vehicle-inJected controls in returning to the platform location when tested 24 hr after training. Finally, the drug produced positive effects in a radial maze test of short-term memory. Well trained rats were allowed to retrieve rewards from four arms of an eight-arm maze and then tested for reentry errors 8 hr later. The number of such errors was substantially reduced on days in which the animals were inJected with the drug before initial learning. These results indicate that a drug that facilitates glutamatergic transmission enhances the encoding of memory across tasks involving different sensory cues and performance requirements. This may reflect an action on the cellular mechanisms responsible for producing synaptic changes since facilitation of AMPA receptors promotes the induction of the long-term potentiation effect. Recent work indicates that facilitation of DL-a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (glutamate) receptor-mediated transmission in slices of hippocampus reduces the amount of afferent stimulation needed to induce a maximal degree of long-term potentiation (LTP) without changing the LTP "ceiling" itself (1). Because there is evidence implicating LTP as a substrate for certain types of memory (2), it is possible that drugs that produce such effects in brain will reduce the amount of training needed for the formation of robust memory. The experiments reported here tested this idea by using a drug that crosses the bloodbrain barrier and enhances synaptic responses in freely moving animals. The carbonic anhydrase inhibitor cyclothiazide and the nootropic compound aniracetam enhance excitatory transmission in vitro by prolonging the open time of glutamate (AMPA) receptors (3-6). Cyclothiazide probably does not cross the blood-brain barrier (7) and aniracetam is rapidly metabolized in peripheral tissues to anisoyl -y-aminobutyric acid (GABA) (8), which we have found to have little effect on The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. glutamatergic transmission. Accordingly, we synthesized a series of compounds that lack the labile imide function of aniracetam and tested their effects first with in vitro slices and then in brain after peripheral administration. Three separate structural modifications yielded a drug [1-(1,3-benzodioxol5-ylcarbonyl)piperidine] with the requisite pharmacological characteristics. This compound was used in three behavioral paradigms and found to substantially improve memory encoding in each case. These results may be of significance for efforts to develop therapeutics directed at memory disorders. MATERIALS AND METHODS Slices of hippocampus were prepared and maintained in an interface chamber using conventional methods. Field excitatory postsynaptic potentials (EPSPs) were recorded in the stratum radiatum of region CAlb and elicited by single stimulation pulses delivered once per 20 sec to a bipolar electrode positioned in the Schaffer commissural projections. Measures of the slope, amplitude, and duration of the responses were collected from digitized records. Chronic stimulation electrodes were implanted in the perforant path and chronic recording electrodes were placed in the hilus of deeply anesthetized male rats (Long-Evans; 250 g). The final positions of the electrodes were determined by physiological criteria; i.e., the production of a large, shortlatency field EPSP with minimal stimulation currents. The electrodes were then attached to a head connector, which was permanently affixed to the skull. One week later the rats were acclimated to a chronic recording cage and to the attachment of a recording lead to the head connector. Recordings were collected for 2-3 days before the start of experimental sessions to ensure the stability of the stimulation-recording arrangements (see ref. 9 for a more complete description). For drug testing, the rats were placed in the cage and 60-90 min of baseline recording was conducted; in most cases, the animals were then injected with vehicle (cyclodextrin) and then 30-45 min later with vehicle plus the experimental benzamide compound (120 mg/kg). Recordings were then continued for 2-3 hr. Seven rats were used, most of which were tested twice with the drug. The behavioral equipment and paradigms used in the studies are described below; different groups of adult male rats were used in the separate experiments. 72.2% topic match

Shows that a benzamide drug enhances memory via AMPA receptor facilitation. The drug improves memory performance in multiple behavioral tasks by increasing synaptic responses in hippocampal neurons. Relevance to γ-oscillations not addressed; focuses on AMPA receptor-mediated synaptic modulation.

69.2%

0.0

2005

[17] Facilitation of glutamate receptors enhances memory recording/synaptic responses/spatial U. Staubli, ..., and G. Lynch Journal Not Provided 2005 - 0 citations - Show abstract - Cite 69.2% topic match

Shows enhancement of memory through AMPA receptor modulation. Benzamide drug increases fEPSPs in hippocampus and improves performance in various memory tasks in rats. Focuses on AMPA receptor-mediated synaptic responses rather than specifically on γ-oscillations.

56.5%

11.2

1994

[18] Facilitation of glutamate receptors enhances memory. U. Staubli, ..., and G. Lynch Proceedings of the National Academy of Sciences of the United States of America 1994 - 345 citations - Show abstract - Cite - PDF 56.5% topic match

Paper shows: Facilitates AMPA receptors to enhance memory. Details: Benzamide compound enhances synaptic responses and improves performance in odor discrimination, water maze, and radial maze memory tasks. Relevance: Focuses on AMPA receptor facilitation, potentially related to γ-oscillations but does not explicitly address γ-oscillations or synaptic modulation similar to DDL-920.

30.6%

10.6

2020

[19] GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer’s Disease Models Jesse E. Hanson, ..., and J. Palop Cell reports 2020 - 53 citations - Show abstract - Cite - PDF 30.6% topic match

18.5%

2.2

2010

[20] DRUG FOCUS: S 18986: A Positive Allosteric Modulator of AMPA‐Type Glutamate Receptors Pharmacological Profile of a Novel Cognitive Enhancer K. Bernard, ..., and P. Morain CNS Neuroscience & Therapeutics 2010 - 31 citations - Show abstract - Cite - PDF 18.5% topic match

Shows that S 18986 is a positive allosteric modulator of AMPA receptors. Demonstrates increased induction and maintenance of LTP in the hippocampus. Does not specifically mention γ-oscillations or direct enhancement of memory and cognition related to γ-oscillations.

15.8%

2.5

1999

[21] Cognition-enhancing drugs increase stimulated hippocampal theta rhythm amplitude in the urethane-anesthetized rat. G. Kinney, ..., and V. Gribkoff The Journal of pharmacology and experimental therapeutics 1999 - 63 citations - Show abstract - Cite 15.8% topic match

Shows relationship between cognition-enhancing drugs and hippocampal theta rhythms. Evaluates effects of piracetam, apamin, and donepezil on hippocampal theta rhythms in urethane-anesthetized rats. Focuses on theta rhythms, not γ-oscillations; relevance to γ-oscillation enhancement is not directly addressed.

15.2%

3.8

2016

[22] Optogenetic Stimulation of Prefrontal Glutamatergic Neurons Enhances Recognition Memory Abigail Benn, ..., and E. Robinson The Journal of Neuroscience 2016 - 33 citations - Show abstract - Cite - PDF 15.2% topic match

Provides insights into enhancing memory via glutamatergic neuronal activity. Demonstrates improved recognition memory by boosting EPSP amplitude using optogenetics and drug treatments.

14.0%

9.1

2021

[23] Induction of specific brain oscillations may restore neural circuits and be used for the treatment of Alzheimer's disease D. Chan, ..., and L. Tsai Journal of Internal Medicine 2021 - 32 citations - Show abstract - Cite - PDF 14.0% topic match

Shows γ-oscillation induction improves cognition in Alzheimer's mouse models. Details audiovisual sensory stimulation at 40 Hz reducing AD pathology and enhancing behavioral performance. Focuses on non-pharmacological neuromodulation, not on small molecules; relevance might be limited.

12.9%

12.1

2011

[24] Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice J. Braudeau, ..., and M. Potier Journal of Psychopharmacology (Oxford, England) 2011 - 163 citations - Show abstract - Cite - PDF 12.9% topic match

12.4%

0.0

2022

[25] Role of Pharmacological Modulation of Tonic Inhibition in Hippocampal Sharp Wave Ripples Amplitude and Place Cell Firing Dynamics Marcia H Ratner, ..., and D. Farb The FASEB Journal 2022 - 0 citations - Show abstract - Cite 12.4% topic match

11.7%

1.8

2014

[26] Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice Julie Vignisse, ..., and T. Strekalova European Neuropsychopharmacology 2014 - 20 citations - Show abstract - Cite 11.7% topic match

11.6%

0.0

2014

[27] AMPA Receptor Modulation for Enhancing Plasticity and Treating Neuropathology C. Gall and G. Lynch Journal Not Provided 2014 - 0 citations - Show abstract - Cite 11.6% topic match

11.1%

1.4

2005

[28] Positive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Modulators Have Different Impact on Synaptic Transmission in the Thalamus and Hippocampus Yan Xia, ..., and A. Arai Journal of Pharmacology and Experimental Therapeutics 2005 - 27 citations - Show abstract - Cite 11.1% topic match

10.9%

0.1

1991

[29] Synaptic Plasticity and Memory Formation G. Lynch https://doi.org/10.21236/ada376184 1991 - 4 citations - Show abstract - Cite 10.9% topic match

10.6%

5.3

1994

[30] Centrally active modulators of glutamate receptors facilitate the induction of long-term potentiation in vivo. U. Staubli, ..., and G. Lynch Proceedings of the National Academy of Sciences of the United States of America 1994 - 161 citations - Show abstract - Cite - PDF 10.6% topic match

10.4%

0.1

2008

[31] The quest for treatment of cognitive impairment: AMPA and mGlu5 receptor modulators Miao-Kun Sun Expert Opinion on Therapeutic Patents 2008 - 1 citations - Show abstract - Cite 10.4% topic match

10.0%

2.0

1996

[32] Psychological effects of a drug that facilitates brain AMPA receptors Gary Lynch, ..., and R. Schehr International Clinical Psychopharmacology 1996 - 58 citations - Show abstract - Cite 10.0% topic match

9.6%

0.5

2005

[33] Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex. D. Ling and L. Benardo Cerebral cortex 2005 - 9 citations - Show abstract - Cite - PDF Abstract: It is widely believed that nootropic (cognition-enhancing) agents produce their therapeutic effects by augmenting excitatory synaptic transmission in cortical circuits, primarily through positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs). However, GABA-mediated inhibition is also critical for cognition, and enhanced GABA function may be likewise therapeutic for cognitive disorders. Could nootropics act through such a mechanism as well? To address this question, we examined the effects of nootropic agents on excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded from layer V pyramidal cells in acute slices of somatosensory cortex. Aniracetam, a positive modulator of AMPA/kainate receptors, increased the peak amplitude of evoked EPSCs and the amplitude and duration of polysynaptic fast IPSCs, manifested as a greater total charge carried by IPSCs. As a result, the EPSC/IPSC ratio of total charge was decreased, representing a shift in the excitation-inhibition balance that favors inhibition. Aniracetam did not affect the magnitude of either monosynaptic IPSCs (mono-IPSCs) recorded in the presence of excitatory amino acid receptor antagonists, or miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin. However, the duration of both mono-IPSCs and mIPSCs was prolonged, suggesting that aniracetam also directly modulates GABAergic transmission. Cyclothiazide, a preferential modulator of AMPAR function, enhanced the magnitude and duration of polysynaptic IPSCs, similar to aniracetam, but did not affect mono-IPSCs. Concanavalin A, a kainate receptor modulator, had little effect on EPSCs or IPSCs, suggesting there was no contribution from kainate receptor activity. These findings indicate that AMPAR modulators strengthen inhibition in neocortical pyramidal cells, most likely by altering the kinetics of AMPARs on synaptically connected interneurons and possibly by modulating GABA(A) receptor responses in pyramidal cells. This suggests that the therapeutic actions of nootropic agents may be partly mediated through enhanced cortical GABAergic inhibition, and not solely through the direct modification of excitation, as previously thought. 9.6% topic match

9.2%

1.0

2008

[34] The AMPA modulator S 18986 improves declarative and working memory performances in aged mice A. Marighetto, ..., and P. Morain Behavioural Pharmacology 2008 - 16 citations - Show abstract - Cite 9.2% topic match

9.1%

3.5

2016

[35] Energy and Potassium Ion Homeostasis during Gamma Oscillations O. Kann, ..., and Justus Schneider Frontiers in Molecular Neuroscience 2016 - 30 citations - Show abstract - Cite - PDF Abstract: Fast neuronal network oscillations in the gamma frequency band (30–100 Hz) occur in various cortex regions, require timed synaptic excitation and inhibition with glutamate and GABA, respectively, and are associated with higher brain functions such as sensory perception, attentional selection and memory formation. However, little is known about energy and ion homeostasis during the gamma oscillation. Recent studies addressed this topic in slices of the rodent hippocampus using cholinergic and glutamatergic receptor models of gamma oscillations (GAM). Methods with high spatial and temporal resolution were applied in vitro, such as electrophysiological recordings of local field potential (LFP) and extracellular potassium concentration ([K+]o), live-cell fluorescence imaging of nicotinamide adenine dinucleotide (phosphate) and flavin adenine dinucleotide [NAD(P)H and FAD, respectively] (cellular redox state), and monitoring of the interstitial partial oxygen pressure (pO2) in depth profiles with microsensor electrodes, including mathematical modeling. The main findings are: (i) GAM are associated with high oxygen consumption rate and significant changes in the cellular redox state, indicating rapid adaptations in glycolysis and oxidative phosphorylation; (ii) GAM are accompanied by fluctuating elevations in [K+]o of less than 0.5 mmol/L from baseline, likely reflecting effective K+-uptake mechanisms of neuron and astrocyte compartments; and (iii) GAM are exquisitely sensitive to metabolic stress induced by lowering oxygen availability or by pharmacological inhibition of the mitochondrial respiratory chain. These findings reflect precise cellular adaptations to maintain adenosine-5′-triphosphate (ATP), ion and neurotransmitter homeostasis and thus neural excitability and synaptic signaling during GAM. Conversely, the exquisite sensitivity of GAM to metabolic stress might significantly contribute the exceptional vulnerability of higher brain functions in brain disease. 9.1% topic match

8.8%

0.0

2004

[36] [Allosteric modulators of AMPA type glutamate receptors a novel gubclass of physiologically active substances]. K. S. Raevskiǐ and K. O. Eremin Biomeditsinskaia khimiia 2004 - 1 citations - Show abstract - Cite 8.8% topic match

8.6%

13.8

2021

[37] Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer’s Disease Patients A. Cimenser, ..., and M. Hajós Frontiers in Systems Neuroscience 2021 - 45 citations - Show abstract - Cite - PDF Abstract: Pathological proteins contributing to Alzheimer’s disease (AD) are known to disrupt normal neuronal functions in the brain, leading to unbalanced neuronal excitatory-inhibitory tone, distorted neuronal synchrony, and network oscillations. However, it has been proposed that abnormalities in neuronal activity directly contribute to the pathogenesis of the disease, and in fact it has been demonstrated that induction of synchronized 40 Hz gamma oscillation of neuronal networks by sensory stimulation reverses AD-related pathological markers in transgenic mice carrying AD-related human pathological genes. Based on these findings, the current study evaluated whether non-invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for AD patients. Patients with mild to moderate AD (n = 22) were randomized to active treatment group (n = 14; gamma sensory stimulation therapy) or to sham group (n = 8). Participants in the active treatment group received precisely timed, 40 Hz visual and auditory stimulations during eye-closed condition to induce cortical 40 Hz steady-state oscillations in 1-h daily sessions over a 6-month period. Participants in the sham group were exposed to similar sensory stimulation designed to not evoke cortical 40 Hz steady-state oscillations that are observed in the active treatment patients. During the trial, nighttime activities of the patients were monitored with continuous actigraphy recordings, and their functional abilities were measured by Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) scale. Results of this study demonstrated that 1-h daily therapy was well tolerated throughout the 6-month treatment period by all subjects. Patients receiving gamma sensory stimulation showed significantly reduced nighttime active periods, in contrast, to deterioration in sleep quality in sham group patients. Patients in the sham group also showed the expected, significant decline in ADCS-ADL scores, whereas patients in the gamma sensory stimulation group fully maintained their functional abilities over the 6-month period. These findings confirm the safe application of 40 Hz sensory stimulation in AD patients and demonstrate a high adherence to daily treatment. Furthermore, this is the first time that beneficial clinical effects of the therapy are reported, justifying expanded and longer trials to explore additional clinical benefits and disease-modifying properties of gamma sensory stimulation therapy. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT03556280. 8.6% topic match

8.5%

0.7

2022

[38] [Ampakines - a promising approach to neuroprotection]. A. V. Kiselev, ..., and S. Kotov Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova 2022 - 2 citations - Show abstract - Cite 8.5% topic match

8.3%

0.0

2021

[39] Effects of gamma sensory stimulation on cognitive function in Alzheimer’s disease patients A. Cimenser, ..., and M. Hajós Alzheimer's & Dementia 2021 - 0 citations - Show abstract - Cite - PDF 8.3% topic match

8.1%

0.0

2009

[40] Ampakines cause sustained increases in BDNF signaling at excitatory synapses without changes in AMPA receptor subunit expression J. Lauterborn, ..., and C. Gall Journal Not Provided 2009 - 0 citations - Show abstract - Cite 8.1% topic match

8.0%

0.5

2022

[41] R-carvedilol, a potential new therapy for Alzheimer’s disease Jinjing Yao and S. Chen Frontiers in Pharmacology 2022 - 1 citations - Show abstract - Cite - PDF 8.0% topic match

7.9%

1.5

2000

[42] Therapeutic potential of positive AMPA receptor modulators in the treatment of neurological disease Kelvin A. Yamada Expert Opinion on Investigational Drugs 2000 - 37 citations - Show abstract - Cite 7.9% topic match

7.3%

0.5

2001

[43] Effect of FK960, a putative cognitive enhancer, on synaptic transmission in CA1 neurons of rat hippocampus. J. Hodgkiss and J. Kelly The Journal of pharmacology and experimental therapeutics 2001 - 12 citations - Show abstract - Cite 7.3% topic match

7.3%

0.0

2023

[44] 40Hz Auditory Entrainment Promotes Synchronization Between Frontal and Parietal Regions of the Brain Mojtaba Lahijanian and Hamid Aghajan 2023 31st International Conference on Electrical Engineering (ICEE) 2023 - 0 citations - Show abstract - Cite 7.3% topic match

7.2%

4.6

2011

[45] Chronic Treatment with a Promnesiant GABA-A α5-Selective Inverse Agonist Increases Immediate Early Genes Expression during Memory Processing in Mice and Rectifies Their Expression Levels in a Down Syndrome Mouse Model J. Braudeau, ..., and M. Potier Advances in Pharmacological Sciences 2011 - 61 citations - Show abstract - Cite - PDF 7.2% topic match

7.2%

0.4

2002

[46] Site-Selective N-Methyl-d-Aspartate and α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionate Antagonists Produce Distinct Effects in Rats Performing Complex Discriminations C. Willmore, ..., and P. Beardsley Neurobiology of Learning and Memory 2002 - 9 citations - Show abstract - Cite 7.2% topic match

7.1%

1.4

2024

[47] EEG biomarkers of α5-GABA positive allosteric modulators in rodents F. Mazza, ..., and Etay Hay bioRxiv 2024 - 1 citations - Show abstract - Cite - PDF 7.1% topic match

6.8%

4.9

2006

[48] LY404187: a novel positive allosteric modulator of AMPA receptors. J. Quirk and E. Nisenbaum CNS drug reviews 2006 - 90 citations - Show abstract - Cite - PDF Abstract: LY404187 is a selective, potent and centrally active positive allosteric modulator of AMPA receptors. LY404187 preferentially acts at recombinant human homomeric GluR2 and GluR4 versus GluR1 and GluR3 AMPA receptors. In addition, LY404187 potentiates the flip splice variant of these AMPA receptors to a greater degree than the flop splice variant. In both recombinant and native AMPA receptors, potentiation by LY404187 displays a unique time-dependent growth that appears to involve a suppression of the desensitization process of these ion channels. LY404187 has been shown to enhance glutamatergic synaptic transmission both in vitro and in vivo. This augmentation of synaptic activity is due to the direct potentiation of AMPA receptor function, as well as an indirect recruitment of voltage-dependent NMDA receptor activity. Enhanced calcium influx through NMDA receptors is known to be a critical step in initiating long-term modifications in synaptic function (e.g., long-term potentiation, LTP). These modifications in synaptic function may be substrates for certain forms of memory encoding. Consistent with a recruitment of NMDA receptor activity, LY404187 has been shown to enhance performance in animal models of cognitive function requiring different mnemonic processes. These data suggest that AMPA receptor potentiators may be therapeutically beneficial for treating cognitive deficits in a variety of disorders, particularly those that are associated with reduced glutamatergic signaling such as schizophrenia. In addition, LY404187 has been demonstrated to be efficacious in animal models of behavioral despair that possess considerable predictive validity for antidepressant activity. Although the therapeutic efficacy of AMPA receptor potentiators in these and other diseases will ultimately be determined in the clinic, evidence suggests that the benefit of these compounds will be mediated by multiple mechanisms of action. These mechanisms include direct enhancement of AMPA receptor function, secondary mobilization of intracellular signaling cascades, and prolonged modulation of gene expression. 6.8% topic match

6.7%

0.0

2016

[49] CHAPTER 14:Development of AMPA Receptor Modulators as Cognition Enhancers C. Jamieson and Emma L. Duffy https://doi.org/10.1039/9781782629276-00310 2016 - 0 citations - Show abstract - Cite 6.7% topic match

6.4%

1.2

2024

[50] A Focused Review of Gamma Neuromodulation as a Therapeutic Target in Alzheimer’s Spectrum Disorders I-Wei Shu, ..., and Fiza Singh Journal of psychiatry and brain science 2024 - 1 citations - Show abstract - Cite 6.4% topic match

6.4%

3.1

1995

[51] Facilitation of olfactory learning by a modulator of AMPA receptors John Larson, ..., and G. Lynch Journal of Neuroscience 1995 - 91 citations - Show abstract - Cite - PDF Abstract: The effects of a benzoyl-piperidine drug (BDP) that facilitates AMPA receptor-mediated synaptic responses were tested on the acquisition and retention of long-term memory at dosages that had no detectable effects on a variety of performance measures. BDP-12 produced a dose-dependent suppression of exploratory activity in rats with statistically reliable effects occurring at 50 mg/kg (i.p.). The drug had no effects on balance beam performance at 30 mg/kg but at 45 mg/kg reduced the number of crossings made within a session; it did not, however, affect the time required to perform a traversal. The performance of well-trained rats presented with a familiar pair of odors (correct and incorrect) was not not detectably altered by BDP-12 at 30 mg/kg; however, the number of correct responses made in a five-trial test was reduced at 45 mg/kg. These results indicate that the AMPA receptor modulator at 30 mg/kg has little influence on arousal, motivation, sensori-motor processing, and attention; higher dosages cause a depression of learned and unlearned prepotent responses. The effects of the lower concentration were tested on two-odor discrimination learning in rats that had extensive training on the task. The animals (n = 20) were given three or five acquisition trials with novel odor pairs immediately after an injection of drug or vehicle and then tested 1–3 d later for retention in five unrewarded probe trials. Retention performance was not significantly better than chance 52.6 +/- 4.5% correct) for odors learned on vehicle injection days but was well above chance for odors learned on drug injection days (70.6 +/- 4.2% correct). Within-subject comparisons confirmed the memory enhancing effect of BDP-12 (p < 0.01). Analyses of performance during five training trials indicated that the rats made more correct responses on days on which they were given the drug than on days on which they were injected with vehicle (p < 0.02). Within-subject differences in acquisition were correlated with differences in retention (r = 0.70). There were no evident effects of the drug on response latencies during acquisition. These results suggest that AMPA receptor modulators reduce the amount of training needed for the formation of long-term memory and do so at dosages which have little effect on variables that secondarily influence acquisition. Possible reasons for this selectivity are discussed. 6.4% topic match

6.3%

0.1

2007

[52] Novel dipyrazoles acting as glutamate modulators P. Francotte, ..., and B. Pirotte Expert Opinion on Therapeutic Patents 2007 - 1 citations - Show abstract - Cite 6.3% topic match

6.2%

0.0

2010

[53] Adenosinergic modulation of hippocampal gamma oscillations : from single cell to whole animal A. Pietersen Journal Not Provided 2010 - 0 citations - Show abstract - Cite 6.2% topic match

6.0%

1.3

2014

[54] Aminostyrylbenzofuran Directly Reduces Oligomeric Amyloid-β and Reverses Cognitive Deficits in Alzheimer Transgenic Mice Sang-Hyun Lee, ..., and Y. Ahn PLoS ONE 2014 - 14 citations - Show abstract - Cite - PDF 6.0% topic match

5.9%

3.4

1993

[55] A drug that facilitates glutamatergic transmission reduces exploratory activity and improves performance in a learning‐dependent task R. Granger, ..., and G. Lynch Synapse 1993 - 106 citations - Show abstract - Cite 5.9% topic match

5.7%

11.2

2005

[56] Mechanism of Positive Allosteric Modulators Acting on AMPA Receptors Rongsheng Jin, ..., and K. Partin The Journal of Neuroscience 2005 - 215 citations - Show abstract - Cite - PDF 5.7% topic match

5.5%

0.5

2023

[57] Oligomeric β-Amyloid Suppresses Hippocampal γ-Oscillations through Activation of the mTOR/S6K1 Pathway Ya-li Wang, ..., and C. Lu Aging and Disease 2023 - 1 citations - Show abstract - Cite - PDF 5.5% topic match

5.5%

0.0

2022

[58] Integrating music‐based interventions with gamma‐frequency stimulation for Subjective Cognitive Decline and Mild Cognitive Impairment Parker Tichko, ..., and P. Loui Alzheimer's & Dementia 2022 - 0 citations - Show abstract - Cite 5.5% topic match

5.2%

1.3

2004

[59] The AMPA Receptor Potentiator LY404187 Increases Cerebral Glucose Utilization and c-fos Expression in the Rat Jill H. Fowler, ..., and J. Mcculloch Journal of Cerebral Blood Flow & Metabolism 2004 - 26 citations - Show abstract - Cite - PDF 5.2% topic match

5.1%

7.9

1997

[60] Enhancement by an Ampakine of Memory Encoding in Humans M. Ingvar, ..., and G. Lynch Experimental Neurology 1997 - 217 citations - Show abstract - Cite 5.1% topic match

4.7%

1.4

2006

[61] In search of novel AMPA potentiators. P. Francotte, ..., and B. Pirotte Recent patents on CNS drug discovery 2006 - 25 citations - Show abstract - Cite 4.7% topic match

4.7%

2.9

1998

[62] Modulating Excitatory Synaptic Neurotransmission: Potential Treatment for Neurological Disease? Kelvin A. Yamada Neurobiology of Disease 1998 - 76 citations - Show abstract - Cite 4.7% topic match

4.7%

107.6

2006

[63] Neural Synchrony in Brain Disorders: Relevance for Cognitive Dysfunctions and Pathophysiology P. Uhlhaas and W. Singer Neuron 2006 - 1961 citations - Show abstract - Cite - PDF 4.7% topic match

4.7%

6.9

2008

[64] The expression of GABAAβ subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells M. Herd, ..., and D. Belelli The Journal of Physiology 2008 - 116 citations - Show abstract - Cite Abstract: The subunit composition of GABAA receptors influences their biophysical and pharmacological properties, dictates neuronal location and the interaction with associated proteins, and markedly influences the impact of intracellular biochemistry. The focus has been on α and γ subunits, with little attention given to β subunits. Dentate gyrus granule cells (DGGCs) express all three β subunit isoforms and exhibit both synaptic and extrasynaptic receptors that mediate ‘phasic’ and ‘tonic’ transmission, respectively. To investigate the subcellular distribution of the β subunits we have utilized the patch‐clamp technique to compare the properties of ‘tonic’ and miniature inhibitory postsynaptic currents (mIPSCs) recorded from DGGCs of hippocampal slices of P20–26 wild‐type (WT), β2−/−, β2N265S (etomidate‐insensitive), α1−/− and δ−/− mice. Deletion of either the β2 or the δ subunit produced a significant reduction of the tonic current and attenuated the increase of this current induced by the δ subunit‐preferring agonist 4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol (THIP). By contrast, mIPSCs were not influenced by deletion of these genes. Enhancement of the tonic current by the β2/3 subunit‐selective agent etomidate was significantly reduced for DGGCs derived from β2N265S mice, whereas this manipulation had no effect on the prolongation of mIPSCs produced by this anaesthetic. Collectively, these observations, together with previous studies on α4−/− mice, identify a population of extrasynaptic α4β2δ receptors, whereas synaptic GABAA receptors appear to primarily incorporate the β3 subunit. A component of the tonic current is diazepam sensitive and is mediated by extrasynaptic receptors incorporating α5 and γ2 subunits. Deletion of the β2 subunit had no effect on the diazepam‐induced current and therefore these extrasynaptic receptors do not contain this subunit. The unambiguous identification of these distinct pools of synaptic and extrasynaptic GABAA receptors should aid our understanding of how they act in harmony, to regulate hippocampal signalling in health and disease. 4.7% topic match

4.6%

4.3

2013

[65] Altered gamma oscillations during pregnancy through loss of δ subunit-containing GABAA receptors on parvalbumin interneurons Isabella Ferando and I. Módy Frontiers in Neural Circuits 2013 - 49 citations - Show abstract - Cite - PDF 4.6% topic match

4.6%

0.0

2021

[66] Randomized controlled trial of gamma sensory stimulation treatment maintains functional ability and decreases sleep fragmentation in Alzheimer’s disease patients A. Cimenser, ..., and M. Hajós Alzheimer's & Dementia 2021 - 0 citations - Show abstract - Cite 4.6% topic match

4.1%

4.4

2020

[67] Long‐lasting correction of in vivo LTP and cognitive deficits of mice modelling Down syndrome with an α5‐selective GABAA inverse agonist A. Duchon, ..., and M. Potier British Journal of Pharmacology 2020 - 22 citations - Show abstract - Cite - PDF 4.1% topic match

4.0%

77.2

2019

[68] Multi-sensory Gamma Stimulation Ameliorates Alzheimer’s-Associated Pathology and Improves Cognition Anthony J. Martorell, ..., and L. Tsai Cell 2019 - 443 citations - Show abstract - Cite - PDF 4.0% topic match

3.9%

0.0

2022

[69] Gamma‐Frequency Sensory Stimulation is Safe and Well‐Tolerated Treatment Option for Patients with Alzheimer’s Disease M. Hajós, ..., and Z. Malchano Alzheimer's & Dementia 2022 - 0 citations - Show abstract - Cite 3.9% topic match

3.5%

5.3

2021

[70] Mutual Interactions between Brain States and Alzheimer’s Disease Pathology: A Focus on Gamma and Slow Oscillations Nicole Byron, ..., and S. Sakata Biology 2021 - 18 citations - Show abstract - Cite - PDF Abstract: Simple Summary Electrical activity in the brain dynamically changes throughout the day. Abnormalities in brain activity have been associated with various brain disorders, including Alzheimer’s disease (AD). While brain disorders stem from complex pathological processes, resulting in abnormalities in neural activity and cognitive deficits, recent studies have demonstrated that controlling brain activity can modify disease pathologies as well as cognitive functions. In particular, studies in mouse models of AD have provided promising results regarding the amelioration of AD pathology by invasive and non-invasive brain stimulations. In this review article, by focusing on AD, we provide an overview of this emerging field. We summarise how brain activity changes in humans and mouse models, and how different artificial manipulations of brain activity can modify AD pathology. Although further investigations are essential, this research direction will provide insight into non-pharmacological intervention strategies for dementia. Abstract Brain state varies from moment to moment. While brain state can be defined by ongoing neuronal population activity, such as neuronal oscillations, this is tightly coupled with certain behavioural or vigilant states. In recent decades, abnormalities in brain state have been recognised as biomarkers of various brain diseases and disorders. Intriguingly, accumulating evidence also demonstrates mutual interactions between brain states and disease pathologies: while abnormalities in brain state arise during disease progression, manipulations of brain state can modify disease pathology, suggesting a therapeutic potential. In this review, by focusing on Alzheimer’s disease (AD), the most common form of dementia, we provide an overview of how brain states change in AD patients and mouse models, and how controlling brain states can modify AD pathology. Specifically, we summarise the relationship between AD and changes in gamma and slow oscillations. As pathological changes in these oscillations correlate with AD pathology, manipulations of either gamma or slow oscillations can modify AD pathology in mouse models. We argue that neuromodulation approaches to target brain states are a promising non-pharmacological intervention for neurodegenerative diseases. 3.5% topic match

3.3%

0.5

1996

[71] Remembrance of odors past: enhancement by central facilitation of AMPA receptors. U. Staubli, ..., and Fangbo Xu Behavioral neuroscience 1996 - 13 citations - Show abstract - Cite 3.3% topic match

3.2%

9.1

2007

[72] Elicited hippocampal theta rhythm: a screen for anxiolytic and procognitive drugs through changes in hippocampal function? N. McNaughton, ..., and M. Hajós Behavioural Pharmacology 2007 - 157 citations - Show abstract - Cite 3.2% topic match

3.1%

0.7

2020

[73] Entrainment of gamma oscillations by auditory chirp stimulation in Alzheimer’s disease patients Mohammad Javad Sedghizadeh, ..., and Z. Vahabi Alzheimer's & Dementia 2020 - 3 citations - Show abstract - Cite - PDF 3.1% topic match

2.9%

102.3

2013

[74] The Theta-Gamma Neural Code J. Lisman and O. Jensen Neuron 2013 - 1204 citations - Show abstract - Cite - PDF 2.9% topic match

2.8%

1.5

1996

[75] Effects of a centrally active benzoylpyrrolidine drug on AMPA receptor kinetics. A. Arai, ..., and G. Lynch Neuroscience 1996 - 43 citations - Show abstract - Cite 2.8% topic match

2.4%

5.5

2009

[76] Altered markers of tonic inhibition in the dorsolateral prefrontal cortex of subjects with schizophrenia. Jon W. Johnson and S. Sesack The American journal of psychiatry 2009 - 86 citations - Show abstract - Cite - PDF Abstract: OBJECTIVE Cognitive impairments in schizophrenia are associated with lower expression of markers of gamma-aminobutyric acid (GABA) synthesis in the prefrontal cortex. The effects of GABA are mediated by GABA(A) receptors that mediate either phasic or tonic inhibition. The authors assessed the expression of GABA(A) receptor alpha4 and delta subunits, which coassemble to form receptors mediating tonic inhibition, in schizophrenia. METHOD The authors used in situ hybridization to quantify expression patterns of GABA(A) receptor alpha4 and delta subunits in prefrontal cortex from 23 matched pairs of schizophrenia and comparison subjects. RESULTS Levels of delta mRNA were significantly lower in schizophrenia subjects regardless of medication use, whereas alpha4 mRNA levels were lower only in subjects with schizophrenia receiving certain medications at the time of death. To understand the nature of this unexpected dissociation between alpha4 and delta subunit expression in schizophrenia, the authors used similar methods to quantify alpha4 and delta mRNA levels in multiple animal models. During postnatal development of monkey prefrontal cortex, levels of alpha4 mRNA decreased, whereas delta mRNA levels increased. In addition, delta mRNA levels, but not alpha4 mRNA levels, were lower in the medial frontal cortex of mice with a genetic deletion of the GABA(A) receptor alpha1 subunit, and neither delta nor alpha4 mRNA levels were altered in rodent models of altered excitatory neurotransmission. CONCLUSIONS Since GABA(A) receptor alpha1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can coassemble with delta subunits to form functional GABA(A) receptors, lower delta mRNA levels in schizophrenia might reflect a reduced number of alpha(1)beta(x)delta GABA(A) receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia. 2.4% topic match

2.3%

3.0

1997

[77] AMPA Receptor Facilitation Accelerates Fear Learning without Altering the Level of Conditioned Fear Acquired M. T. Rogan, ..., and Joseph E LeDoux The Journal of Neuroscience 1997 - 82 citations - Show abstract - Cite - PDF 2.3% topic match

2.2%

2.7

2005

[78] AMPA receptor potentiators as novel antidepressants. A. Alt, ..., and D. Bleakman Current pharmaceutical design 2005 - 53 citations - Show abstract - Cite 2.2% topic match

1.9%

3.0

2020

[79] Relevance of transgenic mouse models for Alzheimer's disease. Leon M. Tai, ..., and S. Brady Progress in molecular biology and translational science 2020 - 13 citations - Show abstract - Cite 1.9% topic match

1.9%

46.5

2019

[80] Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection Chinnakkaruppan Adaikkan, ..., and L. Tsai Neuron 2019 - 259 citations - Show abstract - Cite - PDF 1.9% topic match

1.9%

4.6

1982

[81] Physiological testing of the elite athlete W. Ross, ..., and J. McDougall Journal Not Provided 1982 - 199 citations - Show abstract - Cite 1.9% topic match

1.7%

82.7

2016

[82] Gamma frequency entrainment attenuates amyloid load and modifies microglia Hannah F. Iaccarino, ..., and L. Tsai Nature 2016 - 667 citations - Show abstract - Cite 1.7% topic match

1.6%

0.0

2023

[83] Sensory‐Evoked 40Hz Gamma Oscillation: A Feasible and Promising Treatment Option for Alzheimer’s Disease Mihály Hajós, ..., and Zach Malchano Alzheimer's & Dementia 2023 - 0 citations - Show abstract - Cite - PDF 1.6% topic match

1.6%

0.2

1998

[84] Drugs that increase intelligence?: Application for childhood cognitive impairment G. Capone Mental Retardation and Developmental Disabilities Research Reviews 1998 - 5 citations - Show abstract - Cite Abstract: Due in part to the favorable demographics of Alzheimer's disease in the general population, pharmaceutical companies worldwide are aggressively pursuing the research and development of cognitive-enhancing drugs. There have been two rather noteworthy successes in recent years as both tacrine and donepezil have received FDA approval as useful pharmacologic treatment for Alzheimer's disease. Given what is now known regarding the critical periods for synaptic development and the organization of large-scale neuronal circuits in the developing cerebral cortex, it appears that there may exist a window of opportunity during which specifically targeted, pharmacologic intervention could exert a significantly favorable biologic effect during development. Pharmacologic agents that increase the brain's responsiveness to activity-dependent plasticity may be of particular therapeutic benefit to children with some forms of mental retardation. Currently available medications designed for use in adults with dementia have targeted cholinergic neurotransmission and to a lesser degree glutamatergic neurotransmission, both of which play important roles in learning, memory, and developmental organization of the brain. The “cholinergic hypothesis” of memory dysfunction has done much to focus research efforts on cholinergic strategies for the enhancement of learning and memory. Medications that affect cholinergic neurotransmission include acetylcholine precursors, acetylcholinesterase inhibitors, and muscarinic agonists. Drugs targeting the glutamatergic system are among the most novel modalities in treating disorders of memory and learning. These drugs have grown in proportion to advancements in our understanding of the physiologic and pathologic effects of this important excitatory amino acid neurotransmitter. The most important class of medications that affect glutamatergic neurotransmission include nootropics (ampakines) and glycinergic compounds. The rationale for using drugs that act on the glutamatergic system during critical periods for neuronal organization depends, in part, on the degree to which abnormal dendritic spine morphology and/or function associated with some forms of mental retardation is mediated by dysfunctional glutamatergic neurotransmission. It also depends to what degree spine morphology and/or function can be modified in these conditions. MRDD Research Reviews 1998;4:36–49. © 1998 Wiley-Liss, Inc. 1.6% topic match

1.4%

47.8

2008

[85] Dynamic cross-frequency couplings of local field potential oscillations in rat striatum and hippocampus during performance of a T-maze task A. Tort, ..., and N. Kopell Proceedings of the National Academy of Sciences 2008 - 765 citations - Show abstract - Cite 1.4% topic match

1.3%

1.6

2024

[86] Evaluating the Neuroprotective Potential of Novel Benzodioxole Derivatives in Parkinson's Disease via AMPA Receptor Modulation. M. Hawash, ..., and Mohammad Bdair ACS chemical neuroscience 2024 - 1 citations - Show abstract - Cite 1.3% topic match

1.3%

0.0

1986

[87] [New aspects of the neurophysiological mechanism of the action of nootropic preparations]. T. Voronina and S. Krapivin Biulleten' eksperimental'noi biologii i meditsiny 1986 - 0 citations - Show abstract - Cite 1.3% topic match

1.2%

1.2

2024

[88] Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer’s disease Mihály Hajós, ..., and Zach Malchano Frontiers in Neurology 2024 - 1 citations - Show abstract - Cite - PDF Abstract: Background Alzheimer’s Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito’s Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito’s medical device (CogTx-001) in participants with mild to moderate AD. Methods The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Results Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85–90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Conclusion Our results demonstrate that 1-h daily treatment with Cognito’s Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280. 1.2% topic match

1.1%

0.6

2020

[89] Brain gamma rhythm and potential treatment of neurodegenerative disease Jianhua Zhao, ..., and Chengbiao Lu Journal of Neurorestoratology 2020 - 3 citations - Show abstract - Cite - PDF 1.1% topic match

1.0%

8.7

2011

[90] The likelihood of cognitive enhancement G. Lynch, ..., and C. Gall Pharmacology Biochemistry and Behavior 2011 - 117 citations - Show abstract - Cite - PDF 1.0% topic match

0.9%

0.0

2020

[91] Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage T. Prévot, ..., and E. Sibille bioRxiv 2020 - 0 citations - Show abstract - Cite - PDF Abstract: Over the last 15 years, worldwide life expectancy increased by 5 years jumping from 66 years to 71 years. With progress in science, medicine, and care we tend to live longer. Such extended life expectancy is still associated with age-related changes, including in the brain. The aging brain goes through various changes that can be called morphomolecular senescence. Overall, the brain volume changes, neuronal activity is modified and plasticity of the cells diminishes, sometimes leading to neuronal atrophy and death. Altogether, these changes contribute to the emergence of cognitive decline that still does not have an efficient treatment available. Many studies in the context of cognitive decline focused on pathological aging, targeting β-amyloid in Alzheimer’s disease, for example. However, β-amyloid plaques are also present in healthy adults and treatments targeting plaques have failed to improve cognitive functions. In order to improve the quality of life of aging population, it is crucial to focus on the development of novel therapies targeting different systems altered during aging, such as the GABAergic system. In previous studies, it has been shown that positive allosteric modulators (PAM) acting at the α5-containing GABA-A receptors improve cognitive performances, and that these α5-GABA-A receptors are implicated in dendritic growth of pyramidal neurons. Here, we hypothesized that targeting the α5-GABA-A receptors could contribute to the reduction of cognitive decline, directly through activity of the receptors, and indirectly by increasing neuronal morphology. Using primary neuronal culture and chronic treatment in mice, we demonstrated that an α5-PAM increased dendritic length, spine count and spine density in brain regions involved in cognitive processes (prefrontal cortex and hippocampus). We also confirmed the procognitive efficacy of the α5-PAM and showed that the washout period diminishes the precognitive effects without altering the effect on neuronal morphology. Future studies will be needed to investigate what downstream mechanisms responsible for the neurotrophic effect of the α5-PAM. 0.9% topic match

0.8%

13.5

2021

[92] Gamma Oscillations in Alzheimer’s Disease and Their Potential Therapeutic Role Artemis Traikapi and N. Konstantinou Frontiers in Systems Neuroscience 2021 - 41 citations - Show abstract - Cite - PDF 0.8% topic match

0.8%

0.0

1986

[93] New aspects of the neurophysiological mechanism of the action of nootropic preparations Voronina Ta and Krapivin Sv Bulletin of Experimental Biology and Medicine 1986 - 1 citations - Show abstract - Cite 0.8% topic match

0.7%

2.4

2018

[94] GABA beyond the synapse: defining the subtype‐specific pharmacodynamics of non‐synaptic GABAA receptors A. Lagrange, ..., and R. Macdonald The Journal of Physiology 2018 - 15 citations - Show abstract - Cite - PDF 0.7% topic match

0.6%

4.1

2023

[95] Gamma sensory entrainment for cognitive improvement in neurodegenerative diseases: opportunities and challenges ahead Prangya Parimita Sahu and Philip Tseng Frontiers in Integrative Neuroscience 2023 - 7 citations - Show abstract - Cite - PDF 0.6% topic match

0.6%

1.3

2021

[96] Gamma frequency sensory stimulation prevents brain atrophy, improves sleep and memory in probable mild Alzheimer’s patients D. Chan, ..., and L. Tsai Alzheimer's & Dementia 2021 - 4 citations - Show abstract - Cite 0.6% topic match

0.5%

8.9

2022

[97] An update on the use of gamma (multi)sensory stimulation for Alzheimer’s disease treatment Valerio Manippa, ..., and G. Logroscino Frontiers in Aging Neuroscience 2022 - 18 citations - Show abstract - Cite - PDF 0.5% topic match

0.4%

0.0

2022

[98] Sensory stimulation improves daily functions in Alzheimer’s disease A. Cimenser, ..., and M. Hajós Alzheimer's & Dementia 2022 - 0 citations - Show abstract - Cite 0.4% topic match

0.4%

0.0

2020

[99] SOUND OF SILENCE Clare Wilson The Last Seat in the House 2020 - 0 citations - Show abstract - Cite 0.4% topic match

0.3%

55.6

2009

[100] Theta–gamma coupling increases during the learning of item–context associations A. Tort, ..., and H. Eichenbaum Proceedings of the National Academy of Sciences 2009 - 837 citations - Show abstract - Cite - PDF 0.3% topic match

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