Loss of inhibitory neuron AMPA receptors contributes to ataxia and epilepsy in stargazer mice.
Loss of inhibitory neuron AMPA receptors contributes to ataxia and epilepsy in stargazer mice.
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DOI：
10.1523/jneurosci.2732-08.2008
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发表时间：
2008-10-15
期刊：
影响因子：
--
通讯作者：
Nicoll RA
中科院分区：
文献类型：
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作者：
Menuz K;Nicoll RA
Stargazer小鼠的特征是共济失调和癫痫发作，这类似于人类的失神癫痫。Stargazin是stargazer小鼠中缺乏的蛋白质，可促进神经元AMPA受体（AMPAR）的表达和功能。然而，目前尚不清楚兴奋性AMPAR表达的减少如何产生stargazer癫痫发作，因为癫痫发作通常是由神经元兴奋性增加引起的。此外，虽然观星者共济失调已被归因于小脑颗粒细胞的AMPAR丢失，但其他小脑神经元尚未被检查。为了研究AMPAR功能障碍在这些行为表型中的作用，使用电生理记录来探测相关脑区域中的AMPAR调节。我们发现，小脑浦肯野细胞和抑制性丘脑网状核神经元都强烈降低了stargazer小鼠的突触AMPAR功能。总之，我们的数据表明，在多个神经元群体中受损的AMPAR调节可能有助于在stargazer小鼠中观察到的失神癫痫发作和共济失调的行为表型，并意味着对人类遗传疾病的理解将需要了解突变的基因及其精确的细胞表达模式。
Stargazer mice are characterized by ataxia and seizures, which resemble the human disorder absence epilepsy. Stargazin, the protein absent in stargazer mice, promotes the expression and function of neuronal AMPA receptors (AMPARs). However, it is unclear how decreased expression of excitatory AMPARs generates stargazer seizures, given that seizures often result from increased neuronal excitability. Additionally, although stargazer ataxia has been attributed to loss of AMPARs from cerebellar granule cells, other cerebellar neurons have not been examined. To examine the role of AMPAR dysfunction in these behavioral phenotypes, electrophysiological recordings were used to probe AMPAR regulation in relevant brain regions. We found that both cerebellar Purkinje cells and inhibitory thalamic reticular nucleus neurons have strongly reduced synaptic AMPAR function in stargazer mice. Together, our data suggest that impaired AMPAR regulation in multiple neuron populations may contribute to the behavioral phenotypes of absence seizures and ataxia seen in stargazer mice and imply that an understanding of human genetic disorders will require knowledge of both the genes that are mutated as well as their precise cellular expression pattern.