Synaptic Physiology Laboratory, Department of Physiology and Biophysics, Aarhus University, DK-8000 Aarhus C, Denmark.
Cereb Cortex. 2011 Mar;21(3):625-35. doi: 10.1093/cercor/bhq134. Epub 2010 Jul 19.
Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of the central nervous system. Symptomatic and presymptomatic ALS patients demonstrate cortical hyperexcitability, which raises the possibility that alterations in inhibitory gamma-aminobutyric acid (GABA)ergic system could underlie this dysfunction. Here, we studied the GABAergic system in cortex using patch-clamp recordings in the wobbler mouse, a model of ALS. In layer 5 pyramidal neurons of motor cortex, the frequency of GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents was reduced by 72% in wobbler mice. Also, miniature inhibitory postsynaptic currents recorded under blockade of action potentials were decreased by 64%. Tonic inhibition mediated by extrasynaptic GABA(A) receptors was reduced by 87%. In agreement, we found a decreased density of parvalbumin- and somatostatin-positive inhibitory interneurons and reduced vesicular GABA transporter immunoreactivity in the neuropil. Finally, we observed an increased input resistance and excitability of wobbler excitatory neurons, which could be explained by lack of GABA(A) receptor-mediated influences. In conclusion, we demonstrate decreases in GABAergic inhibition, which might explain the cortical hyperexcitability in wobbler mice.
肌萎缩侧索硬化症（ALS）是一种中枢神经系统进行性退行性疾病。有症状和无症状的 ALS 患者表现出皮质过度兴奋，这表明抑制性γ-氨基丁酸（GABA）能系统的改变可能是这种功能障碍的基础。在这里，我们使用 wobbler 小鼠（ALS 的模型）的膜片钳记录研究了皮质中的 GABA 能系统。在运动皮质的第 5 层锥体神经元中， wobbler 小鼠的 GABA(A) 受体介导的自发性抑制性突触后电流的频率降低了 72%。此外，在阻断动作电位的情况下记录到的微小抑制性突触后电流降低了 64%。由突触外 GABA(A)受体介导的紧张性抑制降低了 87%。一致的是，我们发现神经突中的囊泡 GABA 转运蛋白免疫反应性和表达 parvalbumin 和 somatostatin 的抑制性中间神经元密度降低。最后，我们观察到 wobbler 兴奋性神经元的输入电阻和兴奋性增加，这可以用缺乏 GABA(A) 受体介导的影响来解释。总之，我们证明 GABA 能抑制作用降低，这可能解释了 wobbler 小鼠皮质过度兴奋的原因。
