Microcircuit, cellular and molecular dissection of impaired hippocampal function in a mouse model of the 22q11.2 deletion

精神分裂症是一种衰弱的精神疾病，影响1%的人口，另外还有2%-3%的人患有精神分裂症 发展成分裂性情感障碍。SCZ患者表现出包括缺陷在内的一系列认知缺陷 情节记忆，出现在精神病发作之前，经常表现在受影响的亲属身上 个人。情节记忆的形成部分是由主体的空间调谐(位置细胞)活动决定的 海马体中的细胞。驱动健康海马体这种学习能力的生物学机制 仍然在很大程度上是未知的，更不用说它们对精神分裂症的破坏了，在我们的知识中留下了很大的空白 需要解决的问题。在体脑功能成像在头位定位小鼠背海马区CA1区的应用 在学习行为中，我们最近发现了CA1体内生理特性的特殊变化 Df(16)A+/−转基因小鼠模型中的锥体细胞22q11.2缺失综合征，已知的最大 发生SCZ的遗传风险。DF(16)A+/−CA1Place细胞长期稳定性降低，上下文受损- 相关和缺乏与报酬相关的重组。一种新的突触可塑性，称为行为时间- 已发现尺度突触可塑性(BTSP)驱动CA1区空间选择性激发野的快速形成 锥体细胞；值得注意的是，我们的初步研究表明，这种形式的可塑性在DF(16)A+/−中受到失调调节 老鼠。因此，我们假设BTSP，一种主要的可塑性形式，在 学习，会受到SCZ风险突变的干扰。这些在神经元群体水平上的发现提供了切入点 对精神分裂症风险引起的潜在细胞、分子和微电路功能障碍进行剖析 突变。为了获得这些机械洞察，我们将联合Losonczy实验室的互补专业知识和 Gogos实验室在病因学有效的遗传性神经精神障碍小鼠模型上进行多尺度研究 精神分裂症相关记忆缺陷的微电路、细胞和分子病理生理学研究 成年小鼠海马区CA1环路。目的1旨在评估CA1区突触可塑性的改变 DF(16)A+/−小鼠发作性学习中的锥体细胞目标2涉及解剖抑制微电路 间歇性学习中的动力学，而目标3专注于解剖改变的兴奋性和神经调制 DF(16)A+/−小鼠情景学习过程中对CA1的输入动力学总而言之，目标1-3提供了一个容易处理的 通向更深层次、机械性地理解海马区相关认知记忆缺陷的途径 精神分裂症。

Schizophrenia is a debilitating psychiatric disorder that effects 1% of the population, with an additional 2-3% developing a schizoaffective disorder. SCZ patients exhibit a spectrum of cognitive deficits including defective episodic memory, present prior to the onset of psychosis and frequently expressed in relatives of affected individuals. Episodic memory formation is dictated in part by spatially tuned (place cell) activity of principal cells in the hippocampus. The biological mechanisms driving this learning capacity in the healthy hippocampus remain largely unknown, let alone their disruption in schizophrenia, leaving large gaps in our knowledge that need to be addressed. Using in vivo functional imaging in mouse dorsal hippocampal area CA1 during head-fixed during learning behaviors, we recently uncovered specific alterations in in vivo physiological properties of CA1 pyramidal cells in the Df(16)A+/− transgenic mouse model of 22q11.2 deletion syndrome, the largest known genetic risk to develop SCZ. Df(16)A+/− CA1 place cells exhibit reduced long-term stability, impaired context- related and lack of reward-related reorganization. A novel form of synaptic plasticity, termed behavioral time- scale synaptic plasticity (BTSP), has been found to drive rapid formation of spatially selective firing fields in CA1 pyramidal cells; notably, our preliminary studies suggest that this form of plasticity is dysregulated in Df(16)A+/− mice. We thus hypothesize that BTSP, a major form of plasticity that drives place cell-recruitment during learning, is disrupted by SCZ risk mutations. These findings at the neuronal population level provide entry points for dissecting the underlying cellular, molecular and microcircuit dysfunctions caused by schizophrenia risk mutations. To gain these mechanistic insights we will unite the complementary expertise of the Losonczy lab and the Gogos lab in etiologically valid genetic mouse models of neuropsychiatric disorders to carry out multiscale dissection of microcircuit, cellular and molecular pathophysiology of schizophrenia-related memory deficits in the adult mouse hippocampal CA1 circuitry. Aim 1 is aimed at assessing altered synaptic plasticity in CA1 pyramidal cells during episodic learning in Df(16)A+/− mice. Aim 2 deals with dissecting inhibitory microcircuit dynamics during episodic learning, while Aim 3 is focused at dissecting altered excitatory and neuromodulatory input dynamics to CA1 during episodic learning in Df(16)A+/− mice. Taken together, Aims 1-3 provide a tractable path to a deeper, mechanistic understanding of hippocampus-related cognitive memory deficits in schizophrenia.