GABAergic interneurons in a Disc1-Mouse model for depression - Influence on neuronal network activity in the prefrontal cortex and behaviour

抑郁症影响患者的生活质量。它的特点是各种症状，包括绝望、动机降低和快感缺乏。脑节律异常被认为是导致精神疾病的潜在病理生理机制。事实上，抑郁症患者表现出紊乱的快速伽玛（30-100赫兹）活动模式。然而，潜在的网络缺陷在很大程度上仍然是未知的。在我们最近发表的工作中，我们在最近工程的转基因小鼠模型的内侧前额叶皮层（mPFC）中解决了这个问题，在该模型中，截断的Disc1（精神分裂症-1；Disc1）基因被表达，从而再现了一种最受支持的潜在抑郁症的候选基因突变。Disc1小鼠表现出明显的抑郁相关行为缺陷，如在悬尾（TST）和强迫游泳测试中冻结增强。通过使用系统生物学方法，我们最近发现Disc1小鼠前额皮质的mPFC中的伽马同步明显减少。这种减少与表达小白蛋白（PV）的gaba能抑制细胞（PVIs）数量减少、输出突触突触传递减少约60%、PVIs上的兴奋驱动减少以及它们在mPFC中的连通性增加三倍相关。尽管有这些令人印象深刻的变化，但mPFC中PVI功能的改变与抑郁相关行为之间的因果关系只是假设，而没有显示出来。此外，目前尚不清楚PVI输入和输出功能的变化如何影响神经元群的活动。在拟议的研究中，我们的目标是通过结合体内电生理和光生理研究与病毒工具和行为分析来解决这个基本问题。(1)我们的目标是通过单单元记录来了解行为小鼠在快速网络振荡期间单个PVIs和主细胞（pc）的时间活动模式。(2)我们的目标是在头部固定的小鼠体内进行全细胞记录，以确定mPFC细胞突触兴奋性和抑制性输入的时间和强度。(3)我们将研究PVI活动的光生理操作是否可以挽救mPFC中的伽马能量和行为。(4)我们的目的是研究Disc1在PVIs中的表达是否足以降低伽马功率并诱导抑郁相关行为。通过这种多学科的方法，我们相信可以提供关于PVIs在抑郁症相关行为出现中的作用的新信息，从而可能揭示新的治疗靶点，以支持改善患有这种疾病的个体的生活状况。

Depression affect life quality of the effected individuals. It is characterized by various symptoms including hopelessness, reduced motivation and anhedonia. Abnormal brain rhythms are considered as potential pathophysiological mechanisms causing mental disease. Indeed, individuals with depression show disturbed fast gamma (30-100 Hz) activity patterns. The underlying network defects remained, however, largely unknown. In our recently published work we addressed this question in the medial prefrontal cortex (mPFC) of the recently engineered transgenic mouse model, in which a truncated Disc1 (Disrupted-in-Schizophrenia-1; Disc1) gene was expressed, thereby reproducing one of the best supported candidate gene mutations underlying depression. Disc1 mice exhibit marked depression-related behavioural deficits such as enhanced freezing in the tail-suspension (TST) and forced swim test. By using a systems-biological approach we recently showed that gamma synchrony in the mPFC of Disc1 mice is markedly reduced in the prefrontal cortex. This reduction was correlated with a diminished number of parvalbumin (PV)-expressing GABAergic inhibitory cells (PVIs), a ~60% reduced synaptic transmission at their output synapses, reduced excitatory drive onto PVIs and a threefold increase in their connectivity in the mPFC. In spite of these impressive changes, a causal relationship between altered PVI function in the mPFC and depression-related behaviour was only assumed but not shown. Moreover, it remained unclear how changes in PVI input and output function may influence neuronal population activity. In the proposed study we aim to address this fundamental question by combining in vivo electrophysiological and optophysiological investigations with viral tools and behavioural analysis. (1) We aim to understand the temporal activity patterns of individual PVIs and principal cells (PCs) during fast network oscillations in behaving mice using single unit recordings. (2) We aim to perform in vivo whole-cell recordings in head-fixed mice to identify the timing and strength of synaptic excitatory and inhibitory inputs in mPFC cells. (3) We will examine whether optophysiological manipulation of PVI activity may rescue gamma power in the mPFC and behaviour. (4) We aim to examine whether Disc1 expression in PVIs is sufficient to reduce gamma power and to induce depression-related behaviour. With this multidisciplinary approach we believe to provide new information on the role of PVIs in the emergence of depression-related behaviour and thereby may reveal new targets for therapeutic treatments to support improvement of the life situation of individuals suffering from this illness.