Activation of GABA_A receptors enhances the behavioral recovery but not axonal sprouting in ischemic rats

Article type: Research Article

Authors: Wang, Huibin^a | Cheng, Xi^a | Yu, Hang^b | Zhang, Xiuchun^a | Guan, Meiting^a | Zhao, Lanqing^a | Liu, Yang^b | Linag, Yifan^a | Luo, Yujia^a | Zhao, Chuansheng^{a; *}

Affiliations: [a] Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China | [b] The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong Province, China | [c] Key Laboratory of Immunodermatology, Ministry of Health, Shenyang, Liaoning Province, China

Correspondence: [*] Corresponding author: Chuansheng ZHAO, No. 155, North Nanjing Street, Heping District, Shenyang,110001, Liaoning, PR China. Tel.: +86 24 83283026; Fax: +86 24 83282315; E-mail: cszhao@mail.cmu.edu.cn.

Abstract: Background:GABAA receptors modulate the behavioral recovery encountered in both experimental animals and patients with ischemic injury, possibly through promoting structural plasticity. We hypothesized that activation of GABAA receptors would regulate axonal growth, which in turn would improve the behavioral recovery in ischemic rats. Objective:To investigate the effects of muscimol on axonal growth, synaptic plasticity and behavioral performance in rats after a focal ischemia induced by endothelin-1 (ET-1). Methods:Focal ischemic infarct was induced by ET-1. The rats were randomly divided into 3 groups: sham-operated group, ischemic group, ischemic+muscimol group. The muscimol infusion into contralateral cortex started on post-operative day 7 continuing until day 21. Biotinylated dextran amine was injected on post-operative day 14 into the contralesional motor cortex to trace the crossing corticospinal tract fibers. The expression levels of growth inhibitors, Nogo receptor, NogoA, RhoA, and Rho-associated kinase were measured in the peri-infarct cortex. The expressions of vGlut-1 and postsynaptic density-95 were measured by immunohistochemistry and Western blot in the denervated spinal cord. The behavioral recovery was evaluated by sensorimotor tests on post-operative days 32–34. Results:Treatment with the specific GABAA receptors agonist, muscimol, did not increase axonal growth into the denervated hemispheres and spinal cord after stroke. However, the activation of GABAA receptors partially improved the rats’ behavioral performance after the ET-1-induced stroke. Conclusions:Our study revealed that infusion of muscimol into the contralateral motor cortex during the repair stage could partially improve the behavioral performances without promoting axonal growth from uninjured hemisphere motor cortex to the denervated striatum and spinal cord, nor did it prevent the expression of axonal growth inhibitors in peri-lesioned cortex. More detailed studies will be required to clarify the role of GABAA Rs in regulating the behavioral recovery after a stroke.

Keywords: Muscimol, GABA_A receptors, axonal growth, stroke, behavioral recovery

DOI: 10.3233/RNN-180827

Journal: Restorative Neurology and Neuroscience, vol. 37, no. 4, pp. 315-331, 2019