Wu Nan, Sun Tao, Wu Xin, Chen Hongguang, Zhang Zhen
Department of Neurosurgery, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin, China.
Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, China.
Front Behav Neurosci. 2023 Jan 4;16:1042227. doi: 10.3389/fnbeh.2022.1042227. eCollection 2022.
Stimulation of gamma-aminobutyric acid (GABA) activity through GABA receptor agonists is the basic mechanism of many anticonvulsant drugs. Nevertheless, many of these GABergic drugs have adverse cognitive effects. We previously found that GABAB receptors (GABARs) in the insula regulate operant associative memory in healthy rats. The present study aimed at investigating the effects of GABAR modulation in the insula on operant associative memory in epileptic rats, along with the underlying mechanisms.
The lithium-pilocarpine model of temporal lobe epilepsy (TLE) was established in male Sprague-Dawley rats. A 22-gauge stainless-steel guide cannula was surgically implanted into the granular insula cortex of the epileptic rats. Baclofen (125 ng/μl, 1 μl), CGP35348 (12.5 μg/μl, 1 μl), or saline (1 μl) was slowly infused through the guide cannula. The Intellicage automated behavioral testing system was used to evaluate operant associative memory of the epileptic rats, including non-spatial operant tasks (basic nosepoke learning and skilled nosepoke learning) and spatial operant tasks (chamber position learning). The expression of the GABAR subunits GB1 and GB2 in the insula was examined by immunofluorescence and Western blotting.
The Intellicage tests demonstrated that baclofen significantly impaired basic nosepoke learning, skilled nosepoke learning and chamber position learning of the epileptic rats, while CGP35348 boosted these functions. Immunofluorescence staining revealed that GB1 and GB2 were expressed in the insula of the epileptic rats, and Western blotting analysis showed that baclofen enhanced while CGP35348 inhibited the expression of these subunits.
GABARs in the insula bidirectionally regulate both spatial and non-spatial operant associative memory of epileptic rats. Effects of GABARs on cognition should be taken into account when evaluating new possible treatments for people with epilepsy.
通过γ-氨基丁酸（GABA）受体激动剂刺激GABA活性是许多抗惊厥药物的基本作用机制。然而，许多这类GABA能药物具有不良的认知效应。我们之前发现，岛叶中的GABAB受体（GABARs）调节健康大鼠的操作性联合记忆。本研究旨在探讨岛叶中GABAR调节对癫痫大鼠操作性联合记忆的影响及其潜在机制。
在雄性Sprague-Dawley大鼠中建立颞叶癫痫（TLE）的锂-匹罗卡品模型。将一根22号不锈钢引导套管手术植入癫痫大鼠的颗粒状岛叶皮质。通过引导套管缓慢注入巴氯芬（125 ng/μl，1 μl）、CGP35348（12.5 μg/μl，1 μl）或生理盐水（1 μl）。使用智能笼自动行为测试系统评估癫痫大鼠的操作性联合记忆，包括非空间操作性任务（基本鼻触学习和熟练鼻触学习）和空间操作性任务（箱室位置学习）。通过免疫荧光和蛋白质印迹法检测岛叶中GABAR亚基GB1和GB2的表达。
智能笼测试表明，巴氯芬显著损害癫痫大鼠的基本鼻触学习、熟练鼻触学习和箱室位置学习，而CGP35348增强了这些功能。免疫荧光染色显示GB1和GB2在癫痫大鼠的岛叶中表达，蛋白质印迹分析表明巴氯芬增强而CGP35348抑制这些亚基的表达。
岛叶中的GABAR双向调节癫痫大鼠的空间和非空间操作性联合记忆。在评估癫痫患者新的可能治疗方法时，应考虑GABAR对认知的影响。
