Altered GABAergic function accompanies hippocampal degeneration in mice lacking ClC-3 voltage-gated chloride channels

被引:94
作者
Dickerson, LW
Bonthius, DJ
Schutte, BC
Yang, BL
Barna, TJ
Bailey, MC
Nehrke, K
Williamson, RA
Lamb, FS
机构
[1] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA
[2] Univ Iowa, Dept Obstet & Gynecol, Iowa City, IA 52242 USA
[3] Univ Iowa, Dept Neurol, Iowa City, IA 52242 USA
[4] Univ Iowa, Dept Anat & Cell Biol, Iowa City, IA USA
[5] Univ Iowa, Cardiovasc Res Ctr, Iowa City, IA USA
[6] Univ Iowa, PhD Program Genet, Iowa City, IA USA
[7] Univ Iowa, PhD Program Neurosci, Iowa City, IA USA
[8] Univ Rochester, Ctr Oral Biol, Rochester, NY USA
关键词
gene targeting; hippocampus; pentylenetetrazole; kainic acid; midazolam; glucose tolerance;
D O I
10.1016/S0006-8993(02)03519-9
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 injure 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 chance 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. (C) 2002 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:227 / 250
页数:24
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