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CNS Neuroscience & Therapeutics

CNS Neuroscience & Therapeutics

IF: 4.8
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mGluR5 in Pyramidal Neurons in the Hippocampus Mediates Chronic Stress-Induced Memory Deficits

Published:12 June 2025 DOI: 10.1111/cns.70477
Hong-Cheng Lu, Zhuo-Jun Du, Hao Chen, Ting Guo, Shu-Cai Yang, Xin Li

Abstract

Background

Chronic stress causes variable profiles of physiological deficits, including mood disorders, sleep disorders, and memory deficits. However, the neural mechanisms and potential drug targets of chronic stress-induced memory deficit remain elusive.

Aims

This study aimed to explore the function and regulatory mechanisms of metabotropic glutamate receptor 5 (mGluR5) in chronic stress-induced memory deficit and investigate the potential therapeutic target for stress-related memory deficit.

Methods

Behavioral tests were used to assess the effects of chronic stress on memory. Electrophysiological recordings were conducted to examine the synaptic inputs after chronic stress. RNA sequencing was employed to achieve transcriptional alterations in the hippocampus after stress or mGluR5 knockdown. Enrichment analysis was performed to identify the downstream effector of chronic stress-induced memory deficits.

Results

Chronic restraint stress (CRS) impairs hippocampal-dependent memory and electrophysiological recordings reveal that chronic stress impairs synaptic inputs. Subsequently, we observe that the mGluR5 level declines after CRS, which is an important molecule for learning and memory. mGluR5 knockdown induces memory deficits and impairs synaptic inputs. Enhancement of mGluR5 activity by CDPPB could restore chronic stress-induced memory deficits and rescue impaired synaptic inputs. Furthermore, we identify that pituitary adenylyl cyclase activating peptide (PACAP) is down-regulated after CRS and mGluR5 knockdown. PACAP application could restore the impaired inhibitory synaptic inputs after CRS.

Conclusions

These results illuminate that the mGluR5 mediates chronic stress-induced memory deficits, which may provide promising strategies for treating stress-related memory deficits.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
PACAP38 137061-48-4 C203H331N63O53S1 172 suppliers $161.00-$665.00
PACAP38 137061-48-4 C203H331N63O53S1 172 suppliers $161.00-$665.00
3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide 781652-57-1 C23H16N4O 100 suppliers $74.00-$7394.00
3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide 781652-57-1 C23H16N4O 100 suppliers $74.00-$7394.00

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