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CHOP-Mediated Disruption of Hippocampal Synaptic Plasticity and Neuronal Activity Contributes to Chronic Pain-Related

Qingsheng Meng1, Songxue Su1, Lei Lei2,3

  • 1Department of Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.

CNS Neuroscience & Therapeutics
|January 16, 2025
PubMed

Insights

Chronic constrictive nerve injury causes endoplasmic reticulum stress and C/EBP homologous protein (CHOP) upregulation, leading to chronic pain and cognitive deficits. Reducing CHOP and ER stress improves synaptic plasticity and neuronal activity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pathology

Background:

  • Endoplasmic reticulum (ER) stress and subsequent protein homeostasis disruption are implicated in neurodegenerative diseases.
  • C/EBP homologous protein (CHOP) is a key biomarker for the unfolded protein response (UPR).

Purpose of the Study:

  • To investigate the role of CHOP in chronic pain and cognitive impairment following chronic constrictive nerve injury (CCI).
  • To assess CHOP as a biomarker for UPR in the context of CCI-induced neurological deficits.

Main Methods:

  • Morris water maze and fear conditioning tests assessed memory. ER stress markers, including CHOP, were quantified.
  • Apoptosis was measured using TUNEL and cleaved caspase-3. Synaptic plasticity was evaluated via Golgi-Cox staining and long-term potentiation (LTP).
  • Neuronal activity was monitored using immunofluorescence and fiber photometry. CHOP was knocked down using LV-Ddit3-shRNAs, and ER stress was alleviated with 4-phenylbutyric acid (4-PBA).

Main Results:

  • CCI induced persistent pain and cognitive deficits, accompanied by ER dilation, CHOP upregulation, reduced dendritic spine density, and impaired LTP in the dorsal CA1 (dCA1) region.
  • CaMKIIα/c-Fos co-localization and CaMKIIα-mediated calcium signaling were reduced post-CCI. CaMKIIα activation mitigated cognitive impairments.
  • CHOP knockdown and 4-PBA treatment improved synaptic plasticity, neuronal activity, and cognitive function in CCI mice.

Conclusions:

  • CCI-induced CHOP upregulation in the dCA1 region impairs synaptic plasticity and neuronal activity.
  • This impairment contributes to cognitive deficits associated with chronic pain.
Abstract

Keywords:
CHOPchronic paincognitive impairmentneuronal activitysynaptic plasticity

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