GABAB receptor antagonist promotes hippocampal neurogenesis and facilitates cognitive function recovery following acute cerebral ischemia in mice

Oumei Cheng,Cheng Chen,Dan Song,Yaohua Chen,Lili Chen

doi:10.1186/s13287-020-02059-x

Abstract

Purpose and backgroundPrevious studies have suggested that promoting endogenous neurogenesis has great significance for the recovery of cognitive dysfunction caused by cerebral ischemia (CI). Pharmacological inhibition of GABAB receptor can enhance neurogenesis in adult healthy and depressed mice. In the study, we intended to investigate the effects of GABAB receptor antagonists on cognitive function and hippocampal neurogenesis in mice following CI.MethodsAdult mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min to induce CI and treated with CGP52432 (antagonist of GABAB receptor, CGP, 10 mg/kg intraperitoneal injection) starting 24 h after CI. The Morris water maze test was performed to test spatial learning and memory at day 28. Immunofluorescence was applied to detect neurogenesis in the DG region at day 14 and 28. In in vitro experiments, cell proliferation was detected by CCK8 and immunofluorescence, and the expression of cAMP/CREB signaling pathway-related proteins was detected by ELISA assay and Western blot.ResultsCGP significantly improved spatial learning and memory disorders caused by CI, and it enhanced the proliferation of neural stem cells (NSCs), the number of immature neurons, and the differentiation from newborn cells to neurons. In vitro experiments further confirmed that CGP dose-dependently enhanced the cell viability of NSCs, and immunofluorescence staining showed that CGP promoted the proliferation of NSCs. In addition, treatment with CGP increased the expression of cAMP, PKA, and pCREB in cultured NSCs.ConclusionInhibition of GABAB receptor can effectively promote hippocampal neurogenesis and improve spatial learning and memory in adult mice following CI.

Highlights

Cerebral ischemia (CI) injury caused spatial learning and memory deficits, possibly due to the death of a large number of hippocampal pyramidal neurons [1,2,3]
We investigated the effects of CGP52432 (GABAB receptor antagonists, CGP) on neurogenesis and cognition in CI models induced by transient bilateral common carotid artery occlusion (BCCAO) for 20 min and conducted in vitro experiments to explore the role of CGP on the proliferation of neural stem cells (NSCs) and related mechanisms
In the present study, we found that CGP treatment had significant effects on improving spatial learning and memory disorders in adult mice subjected to BCCAO

Summary

Introduction

Cerebral ischemia (CI) injury caused spatial learning and memory deficits, possibly due to the death of a large number of hippocampal pyramidal neurons [1,2,3]. On the other hand, accumulating evidence suggested that increasing neurogenesis after CI may contribute to the recovery of cognitive function [4,5,6]. It is meaningful to improve cognitive impairment caused by CI through promoting neurogenesis to supplement lost neurons. Enhancement of signals acting on GABAA receptor showed neuroprotective effects in CI animals [13, 14]. GABAAα5 receptor antagonists administered by oral gavage 72 h after stroke can enhance neural precursor cell proliferation and neuronal differentiation in the ipsilateral subventricular region of mice [15]. Intraperitoneal injection of GABAA receptor inverse agonists on day 7 after stroke increased neuronal proliferation in the peri-infarct zone in rats [16]

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Discussion

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