From Hyposociability to Hypersociability-The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior.
From Hyposociability to Hypersociability-The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior.
复制标题
DOI：
10.3389/fnbeh.2021.618397
复制
发表时间：
2021
影响因子：
3
通讯作者：
Mack NR
中科院分区：
文献类型：
--
作者：
Gao WJ;Mack NR
异常的社会行为，包括社交能力不足和社交能力过度，经常在神经发育障碍（例如自闭症谱系障碍）中观察到。然而，与这两种不同的社会行为异常相关的机制仍然未知。突触后密度蛋白 95 (PSD-95) 是兴奋性突触中高度丰富的支架蛋白，通过与 NMDA 和 AMPA 受体结合，是突触成熟的重要调节因子。 DLG4 基因编码 PSD-95，它是超社交行为的风险基因。有趣的是，PSD-95 基因敲除小鼠在青春期表现出社交能力不足，但在成年期表现出社交能力强。青少年社交能力下降伴随着内侧前额叶皮层 (mPFC) 的 NMDAR 功能亢进，mPFC 是控制社交能力的社交脑的重要部分。 mPFC 发育的成熟被推迟到年轻人。然而，PSD-95 缺陷如何影响 mPFC 的功能成熟及其与其他社会大脑区域的联系仍然未知。尤其未知的是，PSD-95 敲除如何在青少年到成人的发展过程中驱动社会行为从低社交性转变为高社交性。我们提出了一种依赖于 NMDAR 的从社交能力低下到高度社交能力的发育转换。 PSD-95 缺陷会在发育过程中以年龄和通路特异性的方式破坏 NMDAR 介导的 mPFC 和社交脑的突触连接。通过利用 PSD-95 缺陷小鼠，可以在同一模型中研究导致社交性低下和过度社交的机制。这将使我们能够评估 mPFC 的本地和远程连接，并研究它们如何参与社会行为的明显损伤以及这些连接的变化如何随着时间的推移而成熟。
Abnormal social behavior, including both hypo- and hypersociability, is often observed in neurodevelopmental disorders such as autism spectrum disorders. However, the mechanisms associated with these two distinct social behavior abnormalities remain unknown. Postsynaptic density protein-95 (PSD-95) is a highly abundant scaffolding protein in the excitatory synapses and an essential regulator of synaptic maturation by binding to NMDA and AMPA receptors. The DLG4 gene encodes PSD-95, and it is a risk gene for hypersocial behavior. Interestingly, PSD-95 knockout mice exhibit hyposociability during adolescence but hypersociability in adulthood. The adolescent hyposociability is accompanied with an NMDAR hyperfunction in the medial prefrontal cortex (mPFC), an essential part of the social brain for control of sociability. The maturation of mPFC development is delayed until young adults. However, how PSD-95 deficiency affects the functional maturation of mPFC and its connection with other social brain regions remains uncharacterized. It is especially unknown how PSD-95 knockout drives the switch of social behavior from hypo- to hyper-sociability during adolescent-to-adult development. We propose an NMDAR-dependent developmental switch of hypo- to hyper-sociability. PSD-95 deficiency disrupts NMDAR-mediated synaptic connectivity of mPFC and social brain during development in an age- and pathway-specific manner. By utilizing the PSD-95 deficiency mouse, the mechanisms contributing to both hypo- and hyper-sociability can be studied in the same model. This will allow us to assess both local and long-range connectivity of mPFC and examine how they are involved in the distinct impairments in social behavior and how changes in these connections may mature over time.
登录
查看更多内容
影响因子：
5.7
作者：
Buchmann A;Dentico D;Peterson MJ;Riedner BA;Sarasso S;Massimini M;Tononi G;Ferrarelli F
通讯作者：
Ferrarelli F
DOI：
10.1073/pnas.0811025106
发表时间：
2008-12-30
影响因子：
11.1
作者：
Elias, G. M.;Elias, L. A. B.;Nicoll, R. A.
通讯作者：
Nicoll, R. A.
影响因子：
16.2
作者：
Elias, Guillermo M.;Funke, Lars;Nicoll, Roger A.
通讯作者：
Nicoll, Roger A.
影响因子：
25
作者：
Barak, Boaz;Zhang, Zicong;Feng, Guoping
通讯作者：
Feng, Guoping
DOI：
10.1073/pnas.1517045112
发表时间：
2015-12-15
影响因子：
11.1
作者：
Chen, Xiaobing;Levy, Jonathan M.;Reese, Thomas S.
通讯作者：
Reese, Thomas S.