Changes in neural network homeostasis trigger neuropsychiatric symptoms
Changes in neural network homeostasis trigger neuropsychiatric symptoms
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DOI：
10.1172/jci71472
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发表时间：
2014-02-01
影响因子：
15.9
通讯作者：
Meier, Jochen C.
中科院分区：
文献类型：
--
作者：
Winkelmann, Aline;Maggio, Nicola;Meier, Jochen C.
调节突触传递强度和内在神经元兴奋性的机制已得到很好的表征;然而，促进致病性神经网络功能障碍的机制却定义不清。我们产生了具有靶向神经元类型特异性表达甘氨酸神经递质受体（GlyR）功能获得变体的小鼠，该变体在颞叶癫痫患者的脑切除术中发现。在这个小鼠模型中，靶向表达的功能获得性GlyR在末梢的多巴胺能细胞或小清蛋白阳性的中间神经元持续改变神经网络的兴奋性。与海马神经元中功能获得性GlyR表达相关的网络兴奋性增加导致复发性癫痫样放电，这引起认知功能障碍和记忆缺陷，而不影响双向突触可塑性。与此相反，由于小白蛋白阳性中间神经元中GlyR的功能获得性表达导致网络兴奋性降低，导致焦虑表型，但不影响认知表现或辨别性联想记忆。我们的动物模型揭示了神经元类型特异性对认知、辨别性联想记忆的形成和体内情绪行为的影响。此外，我们的数据确定了一个突触前致病的分子机制，损害神经网络兴奋性的稳态调节，并触发神经精神症状。
The mechanisms that regulate the strength of synaptic transmission and intrinsic neuronal excitability are well characterized; however, the mechanisms that promote disease-causing neural network dysfunction are poorly defined. We generated mice with targeted neuron type-specific expression of a gain-of-function variant of the neurotransmitter receptor for glycine (GlyR) that is found in hippocampectomies from patients with temporal lobe epilepsy. In this mouse model, targeted expression of gain-of-function GlyR in terminals of glutamatergic cells or in parvalbumin-positive interneurons persistently altered neural network excitability. The increased network excitability associated with gain-of-function GlyR expression in glutamatergic neurons resulted in recurrent epileptiform discharge, which provoked cognitive dysfunction and memory deficits without affecting bidirectional synaptic plasticity. In contrast, decreased network excitability due to gain-of-function GlyR expression in parvalbumin-positive interneurons resulted in an anxiety phenotype, but did not affect cognitive performance or discriminative associative memory. Our animal model unveils neuron type-specific effects on cognition, formation of discriminative associative memory, and emotional behavior in vivo. Furthermore, our data identify a presynaptic disease-causing molecular mechanism that impairs homeostatic regulation of neural network excitability and triggers neuropsychiatric symptoms.