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首页> 外文期刊>Neuron >Excitatory/Inhibitory Synaptic Imbalance Leads to Hippocampal Hyperexcitability in Mouse Models of Tuberous Sclerosis
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Excitatory/Inhibitory Synaptic Imbalance Leads to Hippocampal Hyperexcitability in Mouse Models of Tuberous Sclerosis

机译：兴奋/抑制性突触失衡导致结节性硬化小鼠模型中的海马超兴奋性

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Neural circuits are regulated by activity-dependent feedback systems that tightly control network excitability and which are thought to be crucial for proper brain development. Defects in the ability to establish and maintain network homeostasis may be central to the pathogenesis of neurodevelopmental disorders. Here, we examine the function of the tuberous sclerosis complex (TSC)-mTOR signaling pathway, a common target of mutations associated with epilepsy and autism spectrum disorder, in regulating activity-dependent processes in the mouse hippocampus. We find that the TSC-mTOR pathway is a central component of a positive feedback loop that promotes network activity by repressing inhibitory synapses onto excitatory neurons. In Tsc1 KO neurons, weakened inhibition caused by deregulated mTOR alters the balance of excitatory and inhibitory synaptic transmission, leading to hippocampal hyperexcitability. These findings identify the TSC-mTOR pathway as a regulator of neural network activity and have implications for the neurological dysfunction in disorders exhibiting deregulated mTOR signaling.
机译：神经回路由与活动有关的反馈系统调节，该系统严格控制网络的兴奋性，被认为对大脑的正常发育至关重要。建立和维持网络稳态能力的缺陷可能是神经发育障碍发病机制的关键。在这里，我们检查了结节性硬化症复合体（TSC）-mTOR信号通路的功能，该通路是与癫痫和自闭症谱系障碍相关的常见突变靶标，在调节小鼠海马中的活动依赖性过程中发挥作用。我们发现，TSC-mTOR通路是正反馈回路的主要组成部分，它通过抑制抑制性突触对兴奋性神经元的表达来促进网络活动。在Tsc1 KO神经元中，由mTOR失调引起的抑制作用减弱会改变兴奋性和抑制性突触传递的平衡，导致海马超兴奋性。这些发现确定了TSC-mTOR通路是神经网络活动的调节剂，并且对表现出失调的mTOR信号的疾病中的神经功能障碍具有影响。

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