Reduced Excitability and Increased Neurite Complexity of Cortical Interneurons in a Familial Mouse Model of Amyotrophic Lateral Sclerosis
Reduced Excitability and Increased Neurite Complexity of Cortical Interneurons in a Familial Mouse Model of Amyotrophic Lateral Sclerosis
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DOI：
10.3389/fncel.2018.00328
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发表时间：
2018-09-28
影响因子：
5.3
通讯作者：
Dickson, Tracey C.
中科院分区：
文献类型：
--
作者：
Clark, Rosemary M.;Brizuela, Mariana;Dickson, Tracey C.
皮质中间神经元在调节脑回路中的兴奋-兴奋平衡、过滤突触信息和通过释放GABA指示锥体细胞的活动中起关键作用。在致命的运动神经元（MN）疾病，肌萎缩性侧索硬化症（ALS），兴奋和抑制之间的不平衡是一个早期事件在运动皮层，之前的发展明显的临床症状。患有散发性和家族性疾病的患者表现出皮质抑制减少，包括铜/锌超氧化物歧化酶-1（SOD 1）基因突变的患者。在这项研究中，我们调查了家族性致病hSOD 1-G93 A ALS突变对神经元网络中皮质中间神经元的影响。我们进行了全细胞膜片钳记录和神经生物素示踪GFP阳性的中间神经元在原代皮质培养Gad 67-GFP：：hSOD 1（G93 A）小鼠胚胎。靶向记录显示Gad 67-GFP：：hSOD 1（G93 A）中间神经元的被动特性没有明显差异，然而与Gad 67-GFP：：WT对照相比，峰值外向电流显著减少，细胞的兴奋性降低。与Gad 67-GFP：：WT对照相比，事后神经突重建鉴定出Gad 67-GFP：：hSOD 1（G93 A）中间神经元神经突轴的形态复杂性显著增加。我们的研究结果从SOD 1模型表明，皮层中间神经元的电生理和形态学的改变，可能有助于衰减抑制功能的疾病。确定这些现象是由网络驱动的还是代表中间神经元的内在改变，可能有助于解释ALS中抑制易感性的出现和最终破坏兴奋性。
Cortical interneurons play a crucial role in regulating inhibitory-excitatory balance in brain circuits, filtering synaptic information and dictating the activity of pyramidal cells through the release of GABA. In the fatal motor neuron (MN) disease, amyotrophic lateral sclerosis (ALS), an imbalance between excitation and inhibition is an early event in the motor cortex, preceding the development of overt clinical symptoms. Patients with both sporadic and familial forms of the disease exhibit reduced cortical inhibition, including patients with mutations in the copper/zinc superoxide-dismutase-1 (SOD1) gene. In this study, we investigated the influence of the familial disease-causing hSOD1-G93A ALS mutation on cortical interneurons in neuronal networks. We performed whole-cell patch-clamp recordings and neurobiotin tracing from GFP positive interneurons in primary cortical cultures derived from Gad67-GFP:: hSOD1(G93A) mouse embryos. Targeted recordings revealed no overt differences in the passive properties of Gad67-GFP:: hSOD1(G93A) interneurons, however the peak outward current was significantly diminished and cells were less excitable compared to Gad67-GFP:: WT controls. Post hoc neurite reconstruction identified a significantly increased morphological complexity of the Gad67-GFP:: hSOD1(G93A) interneuron neurite arbor compared to Gad67-GFP:: WT controls. Our results from the SOD1 model suggest that cortical interneurons have electrophysiological and morphological alterations that could contribute to attenuated inhibitory function in the disease. Determining if these phenomena are driven by the network or represent intrinsic alteration of the interneuron may help explain the emergence of inhibitory susceptibility and ultimately disrupted excitability, in ALS.