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

精神分裂症是一种使人衰弱的精神疾病，影响1%的人口，另外还有2-3%的人。 患上了情感障碍SCZ患者表现出一系列的认知缺陷，包括缺陷的 情景记忆，在精神病发作之前存在，经常在受影响的亲属中表达 个体情景记忆的形成部分取决于主体的空间调谐（位置细胞）活动。 海马体中的细胞在健康的海马体中驱动这种学习能力的生物机制 仍然在很大程度上未知，更不用说他们在精神分裂症中的破坏，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小鼠头固定过程中海马CA 1区的应用 在学习行为过程中，我们最近发现了CA 1在体内生理特性的特定改变， 22q11.2缺失综合征的Df（16）A+/−转基因小鼠模型中的锥体细胞， 遗传风险发展SCZ。Df（16）A+/− CA 1位置细胞表现出长期稳定性降低，背景受损， 相关和缺乏奖励相关的重组。一种新形式的突触可塑性，被称为行为时间- 尺度突触可塑性（BTSP），已被发现驱动在CA 1的空间选择性放电场的快速形成 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+/−中失调， 小鼠因此，我们假设BTSP，一种主要形式的可塑性，驱动位置细胞的招聘过程中， 学习，被SCZ风险突变破坏。这些在神经元群体水平上的发现提供了切入点 用于剖析精神分裂症风险引起的潜在细胞、分子和微电路功能障碍 突变。为了获得这些机制的见解，我们将联合Losonczy实验室的互补专业知识， Gogos实验室在神经精神疾病的病因学有效的遗传小鼠模型中进行多尺度 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解剖 成年小鼠海马CA 1区回路。目的1旨在评估CA 1中突触可塑性的改变 Df（16）A+/−小鼠在情景学习过程中的锥体细胞。目标2涉及解剖抑制微电路 动态在情节学习，而目标3是专注于解剖改变兴奋性和神经调节 在Df（16）A+/−小鼠的情景学习过程中对CA 1的输入动力学。总的来说，目标1-3提供了一个易于处理的 路径到一个更深层次的，机械的理解与校园相关的认知记忆缺陷， 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.