Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, 55812, USA.
Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.
Neuropsychopharmacology. 2020 Jun;45(7):1159-1170. doi: 10.1038/s41386-020-0656-5. Epub 2020 Mar 16.
Autism spectrum disorder (ASD) encompasses wide-ranging neuropsychiatric symptoms with unclear etiology. Although the cerebellum is a key region implicated in ASD, it remains elusive how the cerebellar circuitry is altered and whether the cerebellum can serve as a therapeutic target to rectify the phenotype of idiopathic ASD with polygenic abnormalities. Using a syndromic ASD model, e.g., Black and Tan BRachyury TItpr3/J (BTBR) mice, we revealed that increased excitability of presynaptic interneurons (INs) and decreased intrinsic excitability of postsynaptic Purkinje neurons (PNs) resulted in low PN firing rates in the cerebellum. Knowing that downregulation of Kv1.2 potassium channel in the IN nerve terminals likely augmented their excitability and GABA release, we applied a positive Kv1.2 modulator to mitigate the presynaptic over-inhibition and social impairment of BTBR mice. Selective restoration of the PN activity by a new chemogenetic approach alleviated core ASD-like behaviors of the BTBR strain. These findings highlight complex mechanisms converging onto the cerebellar dysfunction in the phenotypic model and provide effective strategies for potential therapies of ASD.
自闭症谱系障碍（ASD）涵盖了广泛的神经精神症状，其病因尚不清楚。尽管小脑是与 ASD 相关的关键区域，但小脑回路如何改变以及小脑是否可以作为治疗靶点来纠正具有多基因异常的特发性 ASD 的表型仍然难以捉摸。使用综合征 ASD 模型，例如黑棕色 BRachyury TItpr3/J（BTBR）小鼠，我们发现，突触前中间神经元（INs）的兴奋性增加和突触后浦肯野神经元（PNs）的内在兴奋性降低导致小脑内 PN 放电率降低。由于知道 IN 神经末梢中 Kv1.2 钾通道的下调可能会增强它们的兴奋性和 GABA 释放，因此我们应用了一种正性 Kv1.2 调节剂来减轻 BTBR 小鼠的突触前过度抑制和社交障碍。通过一种新的化学遗传学方法选择性地恢复 PN 活性，减轻了 BTBR 菌株的核心 ASD 样行为。这些发现强调了表型模型中小脑功能障碍的复杂机制，并为 ASD 的潜在治疗提供了有效的策略。
