BACKGROUND Platelet-activating factor acetylhydrolase 1B1 (LIS1), a critical mediator of neuronal migration in developing brain, is expressed throughout life. However, relatively little is known about LIS1 function in the mature brain. We previously demonstrated that LIS1 involvement in the formation and turnover of synaptic protrusions and synapses of young brain after neuronal migration is complete. Here we examine the requirement for LIS1 to maintain hippocampal circuit function in adulthood. METHODS Effects of conditional Lis1 inactivation in excitatory pyramidal neurons, starting in juvenile mouse brain, were probed using high-resolution approaches combining mouse genetics, designer receptor exclusively activated by designer drug technology to specifically manipulate CA1 pyramidal neuron excitatory activity, electrophysiology, hippocampus-selective behavioral testing, and magnetic resonance imaging tractography to examine the connectivity of LIS1-deficient neurons. RESULTS We found progressive excitatory and inhibitory postsynaptic dysfunction as soon as 10 days after conditional inactivation of Lis1 targeting CA1 pyramidal neurons. Surprisingly, by postnatal day 60 it also caused CA1 histological disorganization, with a selective decline in parvalbumin-expressing interneurons and further reduction in inhibitory neurotransmission. Accompanying these changes were behavioral and cognitive deficits that could be rescued by either designer receptor exclusively activated by designer drug-directed specific increases in CA1 excitatory transmission or pharmacological enhancement of gamma-aminobutyric acid transmission. Lagging behind electrophysiological changes was a progressive, selective decline in neural connectivity, affecting hippocampal efferent pathways documented by magnetic resonance imaging tractography. CONCLUSIONS LIS1 supports synaptic function and plasticity of mature CA1 neurons. Postjuvenile loss of LIS1 disrupts the structure and cellular composition of the hippocampus, its connectivity with other brain regions, and cognition dependent on hippocampal circuits.

中文翻译：

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成熟的海马神经元需要 LIS1 来实现突触完整性：对认知的影响

背景血小板激活因子乙酰水解酶 1B1 (LIS1) 是发育中大脑中神经元迁移的关键介质，在整个生命过程中都有表达。然而，对于成熟大脑中的 LIS1 功能知之甚少。我们之前已经证明，LIS1 在神经元迁移完成后参与了年轻大脑突触突起和突触的形成和更新。在这里，我们研究了 LIS1 在成年期维持海马回路功能的要求。方法 使用高分辨率方法结合小鼠遗传学、由设计药物技术专门激活的设计受体以特异性操纵 CA1 锥体神经元兴奋性活动、电生理学、海马选择性行为测试和磁共振成像束成像检查 LIS1 缺陷神经元的连通性。结果 我们发现在针对 CA1 锥体神经元的 Lis1 条件失活后 10 天，我们发现进行性兴奋性和抑制性突触后功能障碍。令人惊讶的是，到出生后第 60 天，它还导致 CA1 组织学紊乱，表达小白蛋白的中间神经元选择性下降，抑制性神经传递进一步减少。伴随这些变化的是行为和认知缺陷，这些缺陷可以通过由设计者药物导向的 CA1 兴奋性传递的特异性增加或 γ-氨基丁酸传递的药理学增强专门激活的设计者受体来挽救。滞后于电生理变化的是神经连接性的渐进性、选择性下降，影响了磁共振成像束成像记录的海马传出通路。结论 LIS1 支持成熟 CA1 神经元的突触功能和可塑性。LIS1 的幼年后丢失会破坏海马的结构和细胞组成、其与其他大脑区域的连接以及依赖于海马回路的认知。