Qi Jin, Kim Minjung, Sanchez Russell, Ziaee Saba M, Kohtz Jhumku D, Koh Sookyong
Neurobiology Program, Stanley Manne Children's Research Institute, Chicago, IL United States of America.
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA United States of America.
PLoS One. 2018 Jan 29;13(1):e0191794. doi: 10.1371/journal.pone.0191794. eCollection 2018.
Reduced gamma-aminobutyric acid (GABA) inhibition has been implicated in both anxiety and epilepsy. GAD65-/- (NOD/LtJ) mice have significantly decreased basal GABA levels in the brain and a lowered threshold for seizure generation. One fifth of GAD65 -/- mice experienced stress-induced seizures upon exposure to an open field at 4 weeks of age. In each successive week until 8 weeks of age, the latency to seizures decreased with prior seizure experience. 100% of GAD65-/- mice exhibited stress-induced seizures by the end of 8 weeks. GAD65-/- mice also exhibited marked impairment in open field exploratory behavior and deficits in spatial learning acquisition on a Barnes maze. Anxiety-like behavior in an open field was observed prior to seizure onset and was predictive of subsequent seizures. Immunohistochemical characterization of interneuron subtypes in GAD65-/- mice showed a selective decrease in GABA and neuropeptide Y (NPY) levels and no change in calbindin (CLB) or calretinin (CLR) immunoreactivity in the hippocampus. Stem cells from the medial ganglionic eminence (MGE) were injected into the hippocampal hilus to restore GABAergic interneurons. One week after transplantation, MGE-transplanted mice demonstrated significant seizure resistance compared to sham surgical controls. The percent area of GFP+ MGE graft in the hippocampus correlated significantly with the increase in seizure latency. Our data indicate that impaired GABAergic neurotransmission can cause anxiety-like behavior and stress-induced seizures that can be rescued by MGE stem cell transplantation.
γ-氨基丁酸（GABA）抑制作用减弱与焦虑和癫痫均有关联。GAD65基因敲除（NOD/LtJ）小鼠脑内的基础GABA水平显著降低，癫痫发作阈值也降低。五分之一的GAD65基因敲除小鼠在4周龄时暴露于旷场后会出现应激诱导的癫痫发作。在8周龄前的每一周，随着先前的癫痫发作经历，癫痫发作的潜伏期会缩短。到8周龄结束时，100%的GAD65基因敲除小鼠都出现了应激诱导的癫痫发作。GAD65基因敲除小鼠在旷场探索行为中也表现出明显受损，在巴恩斯迷宫的空间学习获取方面存在缺陷。在癫痫发作开始前观察到旷场中的焦虑样行为，且该行为可预测随后的癫痫发作。对GAD65基因敲除小鼠中间神经元亚型的免疫组织化学特征分析显示，海马中GABA和神经肽Y（NPY）水平选择性降低，而钙结合蛋白（CLB）或钙视网膜蛋白（CLR）免疫反应性无变化。将来自内侧神经节隆起（MGE）的干细胞注射到海马齿状回以恢复GABA能中间神经元。移植后一周，与假手术对照组相比，接受MGE移植的小鼠表现出显著的癫痫抵抗性。海马中绿色荧光蛋白（GFP）+ MGE移植物的面积百分比与癫痫发作潜伏期的增加显著相关。我们的数据表明，GABA能神经传递受损可导致焦虑样行为和应激诱导的癫痫发作，而MGE干细胞移植可挽救这些症状。
