Ipsilesional Hippocampal Gaba is elevated and correlates with cognitive impairment and maladaptive neurogenesis after cortical stroke in mice

Abstract

Cognitive dysfunction is a frequent stroke sequela but its pathogenesis and treatment remain unresolved. Involvement of aberrant hippocampal neurogenesis and maladaptive circuitry remodelling has been proposed but their mechanisms are unknown. Our aim was to evaluate potential underlying molecular/cellular events implicated. Stroke was induced by permanent occlusion of the middle cerebral artery (MCAO) in 2-month-old C57BL/6 male mice. Hippocampal metabolites/neurotransmitters were analysed longitudinally by magnetic resonance spectroscopy (MRS). Cognitive function was evaluated with the contextual fear conditioning test. Microglia, astrocytes, neuroblasts and interneurons were analysed by immunofluorescence. Approximately 50% of mice exhibited progressive post-MCAO cognitive impairment. Notably, immature hippocampal neurons in the impaired group displayed more severe aberrant phenotypes than those from the non-impaired group. Using MRS, significant bilateral changes in hippocampal metabolites such as or N-acetylaspartic acid (NAA) were found that correlated, respectively, with numbers of glia and immature neuroblasts in the ischemic group. Importantly, some metabolites were specifically altered in the ipsilateral hippocampus suggesting its involvement in aberrant neurogenesis and remodelling processes. Specifically, MCAO animals with higher hippocampal GABA levels displayed worse cognitive outcome. Implication of GABA in this setting was supported by the amelioration of ischemia-induced memory deficits and aberrant hippocampal neurogenesis after blocking pharmacologically GABAergic neurotransmission. These data suggest that GABA exerts its detrimental effect, at least partly, by affecting morphology and integration of newborn neurons into the hippocampal circuits. Hippocampal GABAergic neurotransmission could be considered a novel diagnostic and therapeutic target for post-stroke cognitive impairment.