Alteration of Neuronal Excitability and Short-Term Synaptic Plasticity in the Prefrontal Cortex of a Mouse Model of Mental Illness
Alteration of Neuronal Excitability and Short-Term Synaptic Plasticity in the Prefrontal Cortex of a Mouse Model of Mental Illness
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DOI：
10.1523/jneurosci.4345-15.2017
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发表时间：
2017-04-12
影响因子：
5.3
通讯作者：
Gogos, Joseph A.
中科院分区：
文献类型：
--
作者：
Crabtree, Gregg W.;Sun, Ziyi;Gogos, Joseph A.
我们使用一种遗传小鼠模型，忠实地再现了与精神分裂症和其他精神疾病密切相关的DISC 1基因改变，研究了这种突变对前额叶皮层的影响。虽然皮质分层，细胞结构和蛋白质组被发现在很大程度上不受影响，mPFC的电生理检查发现神经元的过度兴奋和改变，在短期突触可塑性与增强的神经递质释放一致。II/III层锥体神经元兴奋性的增加伴随着动作电位阈值附近电压激活钾电流的一致降低，以及从浅层到V层的输入的增强募集。从表层产生的V层突触的长期抑制与这些突触处增强的神经递质释放一致。第二/第三层锥体神经元的记录显示，可以解释增强的神经递质释放的动作电位扩大。值得注意的是，我们发现电压依赖性钾通道亚基K（v）1.1的功能表达减少，大大有助于我们观察到的兴奋性和短期可塑性改变。K（v）1.1表达的潜在失调可归因于PFC中的cAMP升高，继发于Disc 1缺乏症中磷酸二酯酶4活性降低，并通过腺苷酸环化酶的药理学阻断来挽救。我们的研究结果表明，Disc 1缺陷对神经回路功能的潜在破坏性影响，部分原因是Kv1.1失调，导致神经元兴奋性增强和短期突触可塑性改变的双重功能障碍。
Using a genetic mouse model that faithfully recapitulates a DISC1 genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V. We further observed reductions in both the paired-pulse ratios and the enhanced short-term depression of layer V synapses arising from superficial layers consistent with enhanced neurotransmitter release at these synapses. Recordings from layer II/III pyramidal neurons revealed action potential widening that could account for enhanced neurotransmitter release. Significantly, we found that reduced functional expression of the voltagedependent potassium channel subunit K(v)1.1 substantially contributes to both the excitability and short-term plasticity alterations that we observed. The underlying dysregulation of K(v)1.1 expression was attributable to cAMP elevations in the PFC secondary to reduced phosphodiesterase 4 activity present in Disc1 deficiency and was rescued by pharmacological blockade of adenylate cyclase. Our results demonstrate a potentially devastating impact of Disc1 deficiency on neural circuit function, partly due to Kv1.1 dysregulation that leads to a dual dysfunction consisting of enhanced neuronal excitability and altered short-term synaptic plasticity.