Role of the neuropsychiatric disorder-associated gene, ARHGAP46 in the development and function of the neocortex

神经精神障碍，如重度抑郁症（MDD）、双相情感障碍（BP）、精神分裂症和自闭症谱系障碍（ASD），是神经发育障碍的一个子集，通常在儿童早期或青春期被诊断出来。它们表现出高遗传性，此外，全基因组关联研究表明，它们具有共同的遗传决定因素。ARHGAP46（也称为GMIP）是含有rhogap的多接头信号蛋白的ARHGAP家族成员，其变异与各种神经精神疾病有关，包括ASD、精神分裂症和重度抑郁症。然而，ARHGAP46在大脑中的功能尚不清楚。我们的初步数据表明，ARHGAP46参与了新皮层的发育，特别是对树突发育和成熟的调节。大脑新皮层负责处理高级大脑功能，如决策和自主运动。新皮质的兴奋性锥体神经元拥有高度复杂的树突树，其中包含专门的信息获取位点，即树突棘。树突树及其棘的成熟缺陷损害了大脑的连通性和信息处理，并且在许多神经精神疾病中都很常见。在这个项目中，我们将研究ARHGAP46在大脑发育过程中的细胞和分子作用，以及ARHGAP46紊乱对大脑功能和动物行为的影响。为此，我们建立了一种新的动物模型，并将结合ARHGAP46缺陷的初级皮质神经元的活体成像和生化分析，以及发育中的小鼠新皮层信号通路的体内修饰，来解决ARHGAP46在新皮层发育中的作用。由于ARHGAP46的信号作用相对未知，我们对内源性ARHGAP46蛋白复合物进行了IP质谱分析，以鉴定新的候选ARHGAP46效应物。这些新的相互作用对新皮层发育的意义也将在这里进一步描述。此外，我们将把这些细胞和分子方法与形态计量学和电生理学方法结合起来，并与评估条件arhgap46缺陷小鼠的行为中与神经精神疾病相关的改变相结合，以了解arhgap46调节通路如何促进神经精神疾病的病理。

Neuropsychiatric disorders such as major depressive disorder (MDD), bipolar disorder (BP), schizophrenia and autism spectrum disorders (ASD) represent a subset of neurodevelopmental disorders that are typically diagnosed in early childhood or adolescence. They show high heritability and, furthermore, genome-wide association studies have shown that they share common genetic determinants. Variants in ARHGAP46 (also called GMIP), a member of the ARHGAP family of RhoGAP-containing multiadaptor signalling proteins, have been linked to various neuropsychiatric disorders including ASD, schizophrenia and MDD. The function of ARHGAP46 in the brain, however, is not known. Our preliminary data indicate involvement of ARHGAP46 in the development of the neocortex, specifically in the regulation of dendritic development and maturation. The cerebral neocortex processes higher brain functions such as decision-making and voluntary movement. The excitatory pyramidal neurons of the neocortex, possess highly elaborated dendritic trees containing specialized sites for information acquisition, the dendritic spines. Defects in the maturation of the dendritic tree and its spines impairs cerebral connectivity and the processing of information, and are commonly observed in a wide number of neuropsychiatric disorders. In this project we will investigate both the cellular and molecular roles of ARHGAP46 during cerebral development as well as the consequences of disturbance of ARHGAP46 for cerebral function and for animal behaviour. We have generated a new animal model for this purpose and will combine live-imaging and biochemical analysis of ARHGAP46-deficient primary cortical neurons with the in vivo modification of signalling pathways in the developing murine neocortex to address the role of ARHGAP46 during neocortical development. Since the signalling roles of ARHGAP46 are relatively unknown, we have carried out IP mass spectrometric analysis of endogenous ARHGAP46 protein complexes to identify novel candidate effectors of ARHGAP46. The significance of these novel interactions for neocortical development will also be further characterised here. Moreover, we will combine these cellular and molecular approaches with morphometric and electrophysiological approaches, as well as with the assessment of neuropsychiatric disease-relevant alterations in the behaviour of conditional ARHGAP46-deficient mice to understand how ARHGAP46-regulated pathways contribute to the pathology of neuropsychiatric disorders.