Ipsilesional Hippocampal GABA Is Elevated and Correlates With Cognitive Impairment and Maladaptive Neurogenesis After Cortical Stroke in Mice

Torres-López C, Cuartero MI, García-Culebras A et al. Stroke. 2023 Oct;54(10):2652-2665. doi: 10.1161/STROKEAHA.123.043516. Epub 2023 Sep 11. PMID: 37694402



BACKGROUND: Cognitive dysfunction is a frequent stroke sequela, but its pathogenesis and treatment remain unresolved. Involvement of aberrant hippocampal neurogenesis and maladaptive circuitry remodeling has been proposed, but their mechanisms are unknown. Our aim was to evaluate potential underlying molecular/cellular events implicated.
METHODS: Stroke was induced by permanent occlusion of the middle cerebral artery occlusion in 2-month-old C57BL/6 male mice. Hippocampal metabolites/neurotransmitters were analyzed longitudinally by in vivo magnetic resonance spectroscopy. Cognitive function was evaluated with the contextual fear conditioning test. Microglia, astrocytes, neuroblasts, interneurons, γ-aminobutyric acid (GABA), and c-fos were analyzed by immunofluorescence.
RESULTS: Approximately 50% of mice exhibited progressive post–middle cerebral artery occlusion cognitive impairment. Notably, immature hippocampal neurons in the impaired group displayed more severe aberrant phenotypes than those from the nonimpaired group. Using magnetic resonance spectroscopy, significant bilateral changes in hippocampal metabolites, such as myo-inositol or N-acetylaspartic acid, 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 hippocampal neurogenesis and remodeling processes. Specifically, middle cerebral artery occlusion 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, an intervention which was ineffective when neurogenesis was inhibited. These data suggest that GABA exerts its detrimental effect, at least partly, by affecting morphology and
integration of newborn neurons into the hippocampal circuits.
CONCLUSIONS: Hippocampal GABAergic neurotransmission could be considered a novel diagnostic and therapeutic target for poststroke cognitive impairment.

Funding: This work was supported by grants from Spanish Ministry of Science and Innovation (MCIN) PID2019-106581RB-I00 (Dr Moro), from Leducq Foundation for Cardiovascular Research TNE-19CVD01 (Drs Moro and Buckwalter) and TNE- 21CVD04 (Drs Moro and Lizasoain), from Instituto de Salud Carlos III (ISCIII) and co-financed by the European Development Regional Fund “A Way to Achieve Europe” PI20/00535 and RICORS (Redes de Investigación Cooperativa Orientadas a Resultados en Salud)-ICTUS RD21/0006/0001 (Dr Lizasoain) and from American Heart Association and Paul Allen Frontiers group 19PABHI34580007 (Dr Buckwalter). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the ISCIII, the MCIN, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S). The microscopy
experiments were performed in the Unidad de Microscopía e Imagen Dinámica, CNIC, ICTS-ReDib (Infraestructura Científica y técnica Singular – Red Distribuida de Imagen Biomédica), cofunded by MCIN/AEI (Agencia Estatal de Investigación)/ 10.13039/501100011033 and FEDER “Una manera de hacer Europa” (no. ICTS-2018-04-CNIC-16). Part of the research work included in this publication has been performed in the ICTS-ReDib infrastructure BioImaC (MCIN).