Dickerson Linda W, Bonthius Daniel J, Schutte Brian C, Yang Baoli, Barna Thomas J, Bailey Melissa C, Nehrke Keith, Williamson Roger A, Lamb Fred S
Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
Brain Res. 2002 Dec 27;958(2):227-50. doi: 10.1016/s0006-8993(02)03519-9.
Mice lacking ClC-3 chloride channels, encoded by the Clcn3 gene, undergo neurodegeneration of the hippocampal formation and retina [Neuron, 29 (2001) 185-196; Genes Cells, 7 (2002) 597-605]. We independently created a mouse lacking the Clcn3 gene which demonstrated similar central nervous system abnormalities, including early postnatal degeneration of retinal photoreceptors. However, we observed a characteristic spatial-temporal sequence of hippocampal neurodegeneration that differs from the pattern previously reported. Anterior-to-posterior degeneration and astrogliosis of the dentate gyrus and hippocampus progressed over months. Sequential loss of hippocampal neuronal subpopulations began in the dentate gyrus and progressed to CA3, followed by CA1 neurons. Projection neurons of the entorhinal cortex degenerated, secondary to the loss of their synaptic targets within the hippocampal formation. Other characteristics of the Clcn3(-/-) mice included an abnormal gait, kyphosis, and absence of hindlimb escape extension upon tail elevation. Spontaneous seizures were observed in four adult Clcn3(-/-) mice, and one mouse died during the event. We hypothesized that neuronal injury may be related to recurrent seizures. Clcn3(-/-) mice had normal serum electrolytes and pH, and exhibited neither hyperglycemia nor rebound hypoglycemia following a glucose load. They displayed a greatly reduced susceptibility to pentylenetetrazole-induced seizures and an abnormally prolonged sedation to benzodiazepines. There was no change in vulnerability to kainic acid-induced seizures. Immunostaining revealed a progressive loss of GABA synthesizing cells in the dentate gyrus. The death of these cells was preceded by increased GABA(A) receptor immunoreactivity. These data suggest that GABA(A) inhibitory neurotransmission is altered in Clcn3(-/-) mice. The increase in GABA(A) receptor density may represent a compensatory response either to chronic excessive excitatory stimuli or reduced inhibitory input from local GABAergic interneurons within the dentate gyrus.
由Clcn3基因编码的ClC - 3氯通道缺失的小鼠会发生海马结构和视网膜的神经退行性变[《神经元》，29(2001)185 - 196；《基因与细胞》，7(2002)597 - 605]。我们独立培育出了一种缺失Clcn3基因的小鼠，它表现出类似的中枢神经系统异常，包括出生后早期视网膜光感受器的退化。然而，我们观察到海马神经退行性变具有独特的时空序列，与先前报道的模式不同。齿状回和海马从前往后的退化以及星形胶质细胞增生持续了数月。海马神经元亚群的相继丧失始于齿状回，然后发展到CA3，接着是CA1神经元。内嗅皮质的投射神经元退化，继发于其在海马结构中突触靶点的丧失。Clcn3(-/-)小鼠的其他特征包括步态异常、脊柱后凸以及提起尾巴时后肢无逃逸伸展。在4只成年Clcn3(-/-)小鼠中观察到自发性癫痫发作，其中1只小鼠在发作期间死亡。我们推测神经元损伤可能与反复癫痫发作有关。Clcn3(-/-)小鼠血清电解质和pH值正常，葡萄糖负荷后既无高血糖也无反弹性低血糖。它们对戊四氮诱导的癫痫发作敏感性大大降低，对苯二氮䓬类药物的镇静作用异常延长。对 kainic 酸诱导的癫痫发作的易感性没有变化。免疫染色显示齿状回中GABA合成细胞逐渐丧失。这些细胞死亡之前，GABA(A)受体免疫反应性增加。这些数据表明Clcn3(-/-)小鼠中GABA(A)抑制性神经传递发生了改变。GABA(A)受体密度的增加可能代表对慢性过度兴奋性刺激或齿状回内局部GABA能中间神经元抑制性输入减少的一种代偿反应。
