Low-Level Inhibition of GABAergic Synapses Enhances Gene Expressions Crucial for Neuronal Plasticity in the Hippocampus After Ischemic Stroke

• Published in: Journal of stroke and cerebrovascular diseases Vol. 29; no. 12; p. 105316
• Main Authors: Okamura, Misato, Inoue, Takahiro, Takamatsu, Yasuyuki, Maejima, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2020
• Subjects: Animals; Bicuculline - pharmacology; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Disease Models, Animal; Disks Large Homolog 4 Protein - genetics; Disks Large Homolog 4 Protein - metabolism; GABA; GABA-A Receptor Antagonists - pharmacology; GABAergic Neurons - drug effects; GABAergic Neurons - metabolism; GABAergic Neurons - pathology; Gene Expression Regulation; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Hippocampus - physiopathology; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - genetics; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - physiopathology; Male; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural Inhibition - drug effects; Neuronal Plasticity - drug effects; Neurotrophin; Rats, Sprague-Dawley; Receptor, trkB - genetics; Receptor, trkB - metabolism; Receptors, Growth Factor - genetics; Receptors, Growth Factor - metabolism; Stroke; Synaptic Transmission - drug effects; Synaptophysin - genetics; Synaptophysin - metabolism; Neurotrophin; GABA; Stroke; Hippocampus
• ISSN: 1052-3057; 1532-8511
• DOI: 10.1016/j.jstrokecerebrovasdis.2020.105316

•Ischemic stroke increases the expression of BDNF receptor in the hippocampus.•Inhibition of GABAergic synapses increases hippocampal synaptophysin after stroke.•Inhibition of GABAergic synapses tends to increases hippocampal BDNF after stroke.•Inhibition of GABAergic synapses modulates the expression ratio of BDNF receptors. Pharmacological inhibition of GABAergic synapses could represent a potent neuromodulation strategy to activate hippocampal neurons and increase neurotrophic factor gene expression, thus exerting a beneficial effect on post-stroke cognitive impairment (PSCI). The objective of this study was to assess the effects of low-level inhibition of GABAergic synapses on hippocampal gene expressions related to neuroplasticity using the middle cerebral artery occlusion surgery (MCAO) ischemic stroke rat model. The animals were randomly assigned to three experimental groups—(1) a sham operated group (SHAM), (2) a control group (CON), and (3) a bicuculline group (BIC). MCAO was performed in the CON and BIC groups. A non-epileptic dose of bicuculline (0.25 mg/kg) was intraperitoneally administered every day for two weeks, starting three days after surgery, to the rats in the BIC group. The mRNA expression of brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), in relation to neurotrophic intracellular signal, p75, in relation to apoptosis, and synaptophysin (SYP) and PSD-95, synaptic markers, were assessed in the hippocampus ipsilateral to the ischemic site. MCAO increased the gene expression of TrkB. Furthermore, MCAO plus bicuculline administration increased the expression ratio of TrkB to p75 and SYP gene expression. Therefore, this study showed that administration of bicuculline after stroke beneficially modulated the expression of crucial genes for neuroplasticity, including BDNF receptors and SYP, in the ipsilateral hippocampus, suggesting that low-level inhibition of GABAergic synapses could lead to beneficial neuromodulation in the hippocampus after stroke.