Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine (JHU SOM), Baltimore, MD 21287.
Department of Psychiatry, JHU SOM, Baltimore, MD 21287.
Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):10479-10484. doi: 10.1073/pnas.1700689114. Epub 2017 Sep 11.
Genome-wide association studies have implicated the locus in bipolar disorder, a major human psychotic illness. encodes ankyrin-G, which organizes the neuronal axon initial segment (AIS). We generated a mouse model with conditional disruption of in pyramidal neurons of the adult forebrain (Ank-G cKO). This resulted in the expected loss of pyramidal neuron AIS voltage-gated sodium and potassium channels. There was also dramatic loss of markers of afferent GABAergic cartridge synapses, resembling the cortical microcircuitry changes in brains from psychotic patients, and suggesting disinhibition. Expression of c-fos was increased in cortical pyramidal neurons, consistent with increased neuronal activity due to disinhibition. The mice showed robust behavioral phenotypes reminiscent of aspects of human mania, ameliorated by antimania drugs lithium and valproate. Repeated social defeat stress resulted in repeated episodes of dramatic behavioral changes from hyperactivity to "depression-like" behavior, suggestive of some aspects of human bipolar disorder. Overall, we suggest that this Ank-G cKO mouse model recapitulates some of the core features of human bipolar disorder and indicates that cortical microcircuitry alterations during adulthood may be involved in pathogenesis. The model may be useful for studying disease pathophysiology and for developing experimental therapeutics.
全基因组关联研究表明， 位点与双相情感障碍有关，这是一种主要的人类精神病。 编码锚蛋白-G，它组织神经元轴突起始段（AIS）。我们生成了一种在成年大脑前脑的锥体神经元中具有条件性破坏 的小鼠模型（Ank-G cKO）。这导致了预期的锥体神经元 AIS 电压门控钠和钾通道的丧失。还出现了 GABA 能传入性突触囊泡标记物的明显丧失，类似于精神病患者大脑中的皮质微电路变化，并提示去抑制。皮质锥体神经元中 c-fos 的表达增加，与去抑制引起的神经元活动增加一致。这些小鼠表现出强烈的行为表型，类似于人类躁狂症的某些方面，抗躁狂药物锂和丙戊酸钠可改善这些表型。反复社会挫败应激导致反复出现从过度活跃到“类似抑郁”行为的剧烈行为变化，提示人类双相情感障碍的某些方面。总的来说，我们认为这种 Ank-G cKO 小鼠模型再现了人类双相情感障碍的一些核心特征，并表明成年期皮质微电路的改变可能与发病机制有关。该模型可能有助于研究疾病的病理生理学和开发实验性治疗方法。
