ONO-8590580, a Novel GABAAα5 Negative Allosteric Modulator Enhances Long-Term Potentiation and Improves Cognitive Deficits in Preclinical Models

Although the role of CCR5 in immunity and in HIV infection has been studied widely, its role in neuronal plasticity, learning and memory is not understood. Here, we report that decreasing the function of CCR5 increases MAPK/CREB signaling, long-term potentiation (LTP), and hippocampus-dependent memory in mice, while neuronal CCR5 overexpression caused memory deficits. Decreasing CCR5 function in mouse barrel cortex also resulted in enhanced spike timing dependent plasticity and consequently, dramatically accelerated experience-dependent plasticity. These results suggest that CCR5 is a powerful suppressor for plasticity and memory, and CCR5 over-activation by viral proteins may contribute to HIV-associated cognitive deficits. Consistent with this hypothesis, the HIV V3 peptide caused LTP, signaling and memory deficits that were prevented by Ccr5 knockout or knockdown. Overall, our results demonstrate that CCR5 plays an important role in neuroplasticity, learning and memory, and indicate that CCR5 has a role in the cognitive deficits caused by HIV.

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The AMPA receptor positive allosteric modulator S 47445 rescues in vivo CA3-CA1 long-term potentiation and structural synaptic changes in old mice

Neuropharmacology ◽

10.1016/j.neuropharm.2017.06.009 ◽

2017 ◽

Vol 123 ◽

pp. 395-409 ◽

Cited By ~ 8

Author(s):

Albert Giralt ◽

María Ángeles Gómez-Climent ◽

Rafael Alcalá ◽

Sylvie Bretin ◽

Daniel Bertrand ◽

...

Keyword(s):

Ampa Receptor ◽

Long Term Potentiation ◽

Allosteric Modulator ◽

Positive Allosteric Modulator ◽

Term Potentiation ◽

Synaptic Changes ◽

Old Mice

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Amyloid Beta-Related Alterations to Glutamate Signaling Dynamics During Alzheimer’s Disease Progression

ASN NEURO ◽

10.1177/1759091419855541 ◽

2019 ◽

Vol 11 ◽

pp. 175909141985554 ◽

Cited By ~ 16

Author(s):

Caleigh A. Findley ◽

Andrzej Bartke ◽

Kevin N. Hascup ◽

Erin R. Hascup

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Progression ◽

Amyloid Beta ◽

Cognitive Deficits ◽

Senile Plaques ◽

Neuronal Loss ◽

Long Term Potentiation ◽

Term Potentiation

Alzheimer’s disease (AD) ranks sixth on the Centers for Disease Control and Prevention Top 10 Leading Causes of Death list for 2016, and the Alzheimer’s Association attributes 60% to 80% of dementia cases as AD related. AD pathology hallmarks include accumulation of senile plaques and neurofibrillary tangles; however, evidence supports that soluble amyloid beta (Aβ), rather than insoluble plaques, may instigate synaptic failure. Soluble Aβ accumulation results in depression of long-term potentiation leading to cognitive deficits commonly characterized in AD. The mechanisms through which Aβ incites cognitive decline have been extensively explored, with a growing body of evidence pointing to modulation of the glutamatergic system. The period of glutamatergic hypoactivation observed alongside long-term potentiation depression and cognitive deficits in later disease stages may be the consequence of a preceding period of increased glutamatergic activity. This review will explore the Aβ-related changes to the tripartite glutamate synapse resulting in altered cell signaling throughout disease progression, ultimately culminating in oxidative stress, synaptic dysfunction, and neuronal loss.

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Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the β-amyloid precursor protein

Neuroscience ◽

10.1016/s0306-4522(98)00410-2 ◽

1999 ◽

Vol 90 (1) ◽

pp. 1-13 ◽

Cited By ~ 204

Author(s):

G.R Dawson ◽

G.R Seabrook ◽

H Zheng ◽

D.W Smith ◽

S Graham ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Cognitive Deficits ◽

Long Term Potentiation ◽

Precursor Protein ◽

Marker Density ◽

Age Related ◽

Term Potentiation ◽

Β Amyloid

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rTMS Ameliorates Prenatal Stress–Induced Cognitive Deficits in Male-Offspring Rats Associated With BDNF/TrkB Signaling Pathway

Neurorehabilitation and Neural Repair ◽

10.1177/1545968319834898 ◽

2019 ◽

Vol 33 (4) ◽

pp. 271-283 ◽

Cited By ~ 6

Author(s):

Yingchun Shang ◽

Xin Wang ◽

Fangjuan Li ◽

Tao Yin ◽

Jianhai Zhang ◽

...

Keyword(s):

Synaptic Plasticity ◽

Spatial Cognition ◽

Cognitive Deficits ◽

Prenatal Stress ◽

Long Term Potentiation ◽

Signaling Proteins ◽

Ca1 Region ◽

Hippocampal Synaptic Plasticity ◽

Term Potentiation

Background. Growing evidences suggest that brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) plays a key role in the regulation of hippocampal synaptic plasticity in a prenatal stress (PNS) rat model. Repetitive transcranial magnetic stimulation (rTMS) is currently being acknowledged to affect attention and memory in both preclinical and clinical studies, although the mechanism is still unclear. Objective. The current study aimed to explore whether a whole brain rTMS (5 Hz, 14 days) could ameliorate cognitive dysfunction–induced PNS in male offspring, and examine if the positive effect of rTMS was associated with the BDNF/TrkB signaling in the hippocampus. Methods. The rats were randomly divided into 5 groups: CON, PNS, PNS + rTMS, PNS + rTMS + DMSO (dimethyl sulfoxide), and PNS + rTMS + K252a. Spatial cognition was evaluated by using Morris water maze test. Following behavioral assessment, both paired-pulse facilitation and long-term potentiation were recorded from Schaffer collaterals to CA1 region in the hippocampus. Synaptic, apoptotic, and BDNF/TrkB signaling proteins were measured by Western blot. Results. PNS-exposed offspring exhibited cognitive deficits, long-term potentiation inhibition in the hippocampus, the decrease of synaptic and BDNF/TrkB signaling proteins expression, apoptosis, and reduced number of cells in the CA1 region. Five-hertz rTMS significantly alleviated the PNS-induced abnormalities. However, the effect of rTMS was antagonized by intracerebroventricular infusion of K252a (a TrkB inhibitor). Conclusions. The findings suggest that 5-Hz rTMS significantly improves the impairment of spatial cognition and hippocampal synaptic plasticity, which is possibly associated with the activation of BDNF/TrkB signaling.

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