Programmes in Brain and Behaviour Research Institute, Hospital for Sick Children, Toronto, ON, Canada.
Neuroscience. 2010 Apr 28;167(1):154-62. doi: 10.1016/j.neuroscience.2010.01.042. Epub 2010 Jan 29.
Heterozygous mutations in ClC-2 have been associated in rare cases with increased susceptibility to generalized, idiopathic epilepsy. Initially, it was hypothesized that mutations in ClC-2 may be associated with epilepsy due to a direct role for ClC-2 in the modification of hippocampal neuronal excitability. However, the absence of an overt seizure-susceptibility phenotype in young ClC-2 knockout (KO) mice rendered this hypothesis- implausible. A recent study of older ClC-2 KO mice (>6 months) revealed abnormalities in the myelin of central axons and a subtle defect in the neuronal function in the central auditory pathway. These findings prompted us to re-examine hippocampal neuron morphology and excitability in older ClC-2 KO mice. Interestingly, electrocorticographic recordings obtained in older mice revealed spontaneous interictal spikes which are a marker of perturbed hippocampal neurotransmission with a resultant increase in excitation. This electrophysiological defect was associated with astrocyte activation and evidence of neuronal degeneration in the CA3 region of the hippocampus of these older mice. Together, these findings raise the possibility that ClC-2 expression plays a subtle neuroprotective role in the aging hippocampus.
ClC-2 的杂合突变与罕见的全身性特发性癫痫易感性增加有关。最初，人们假设 ClC-2 中的突变可能与癫痫有关，因为 ClC-2 直接参与调节海马神经元兴奋性。然而，年轻的 ClC-2 敲除（KO）小鼠没有明显的癫痫易感性表型，这使得这一假设变得不可信。最近一项针对老年 ClC-2 KO 小鼠（>6 个月）的研究发现，中枢轴突髓鞘异常，中枢听觉通路中的神经元功能存在细微缺陷。这些发现促使我们重新检查老年 ClC-2 KO 小鼠的海马神经元形态和兴奋性。有趣的是，在老年小鼠中获得的皮层电图记录显示自发性发作间期棘波，这是海马神经传递紊乱的标志，导致兴奋增加。这种电生理缺陷与星形胶质细胞激活和这些老年小鼠海马 CA3 区神经元变性的证据有关。这些发现表明，ClC-2 的表达在衰老的海马体中发挥微妙的神经保护作用。
