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

J Stroke Cerebrovasc Dis. 2020 Dec;29(12):105316. doi: 10.1016/j.jstrokecerebrovasdis.2020.105316. Epub 2020 Sep 28.


Objective: 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.

Methods: 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.

Results: MCAO increased the gene expression of TrkB. Furthermore, MCAO plus bicuculline administration increased the expression ratio of TrkB to p75 and SYP gene expression.

Conclusion: 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.

Keywords: GABA; Hippocampus; Neurotrophin; Stroke.

MeSH terms

  • 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-A Receptor Antagonists / pharmacology*
  • GABAergic Neurons / drug effects*
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / pathology
  • Gene Expression Regulation
  • 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*
  • Rats, Sprague-Dawley
  • Receptor, trkB / genetics
  • Receptor, trkB / metabolism
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / metabolism
  • Synaptic Transmission / drug effects*
  • Synaptophysin / genetics
  • Synaptophysin / metabolism


  • Bdnf protein, rat
  • Brain-Derived Neurotrophic Factor
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • GABA-A Receptor Antagonists
  • Nerve Tissue Proteins
  • Receptors, Growth Factor
  • Synaptophysin
  • Syp protein, rat
  • Ngfr protein, rat
  • Ntrk2 protein, rat
  • Receptor, trkB
  • Bicuculline