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

Disc1-小鼠抑郁症模型中的 GABA 能中间神经元 - 对前额皮质神经元网络活动和行为的影响

• 批准号: 218641338
• 负责人: Professorin Dr. Marlene Bartos
• 金额: --
• 依托单位: Lehrstuhl für Physiologie I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/218641338?language=en
• 关键词: GABAergic; interneurons; Disc1; Mouse; model

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.

抑郁症影响受影响个体的生活质量。它的特点是各种症状，包括绝望、动力下降和快感缺乏。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 Hz）活动模式。然而，潜在的网络缺陷仍然很大程度上未知。在我们最近发表的工作中，我们在最近设计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，其中表达了截短的 Disc1 (Disrupted-in-Schizophrenia-1; Disc1) 基因，从而再现了最受支持的抑郁症候选基因突变之一。 Disc1 小鼠表现出明显的与抑郁相关的行为缺陷，例如悬尾（TST）和强迫游泳测试中的增强冻结。通过使用系统生物学方法，我们最近表明，Disc1 小鼠 mPFC 的伽马同步性在前额皮质中显着降低。这种减少与表达小清蛋白 (PV) 的 GABA 能抑制细胞 (PVI) 数量减少、输出突触的突触传递减少约 60%、PVI 兴奋性驱动减少以及 mPFC 中连接性增加三倍相关。尽管发生了这些令人印象深刻的变化，mPFC 中 PVI 功能改变与抑郁相关行为之间的因果关系仅被假设，但并未得到证实。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活动。在拟议的研究中，我们旨在通过将体内电生理学和光生理学研究与病毒工具和行为分析相结合来解决这个基本问题。 (1) 我们的目标是使用单单元记录来了解行为小鼠快速网络振荡期间个体 PVI 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 细胞中突触兴奋和抑制输入的时间和强度。 (3) 我们将研究 PVI 活动的光生理学操作是否可以挽救 mPFC 和行为中的伽马功率。 (4) 我们的目的是检查 PVI 中 Disc1 的表达是否足以降低伽马功率并诱导抑郁相关行为。我们相信，通过这种多学科方法，可以提供关于 PVI 在抑郁相关行为出现中的作用的新信息，从而可能揭示新的治疗目标，以支持改善患有这种疾病的个体的生活状况。

项目成果

Recording Spatially Restricted Oscillations in the Hippocampus of Behaving Mice.

记录行为小鼠海马体的空间受限振荡

• DOI: 10.3791/57714
• 期刊: Journal of visualized experiments : JoVE
• 作者: Sauer JF;Strüber M;Bartos M (
• 通讯作者: Bartos M (

Topographically organized representation of space and context in the medial prefrontal cortex

• DOI: 10.1101/2021.06.04.447085
• 发表时间: 2021-06
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Jonas-Frederic Sauer;Shani Folschweiller;M. Bartos

Enhanced mGlu5 Signaling in Excitatory Neurons Promotes Rapid Antidepressant Effects via AMPA Receptor Activation

• DOI: 10.1016/j.neuron.2019.07.011
• 发表时间: 2019-10-23
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Holz, Amrei;Muelsch, Felix;Serchov, Tsvetan
• 通讯作者: Serchov, Tsvetan