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）代表通常在儿童早期或青春期诊断的神经发育障碍的子集。它们具有很高的遗传性，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。ARHGAP 46（也称为GMIP）是含有RhoGAP的多接头信号蛋白的ARHGAP家族的成员，其变体与各种神经精神疾病有关，包括ASD，精神分裂症和MDD。然而，ARHGAP 46在大脑中的功能尚不清楚。我们的初步数据表明ARHGAP 46参与了新皮层的发育，特别是树突发育和成熟的调节。大脑新皮层处理更高级的大脑功能，如决策和随意运动。新皮层的兴奋性锥体神经元具有高度精细的树突树，其中包含用于信息获取的专门位点，树突棘。树突树及其棘的成熟缺陷损害大脑连接和信息处理，并且通常在大量神经精神疾病中观察到。在这个项目中，我们将研究ARHGAP 46在大脑发育过程中的细胞和分子作用，以及ARHGAP 46干扰对大脑功能和动物行为的影响。我们已经为此目的产生了一种新的动物模型，并将结合联合收割机的实时成像和生物化学分析ARHGAP 46缺陷的原代皮层神经元与在体内修饰的信号通路在发育中的小鼠新皮层，以解决ARHGAP 46在新皮层发育过程中的作用。由于ARHGAP 46的信号传导作用相对未知，我们对内源性ARHGAP 46蛋白复合物进行了IP质谱分析，以鉴定ARHGAP 46的新候选效应物。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表征。此外，我们将结合联合收割机这些细胞和分子的方法与形态学和电生理学的方法，以及与评估神经精神疾病相关的改变条件ARHGAP 46缺陷小鼠的行为，以了解ARHGAP 46调节途径如何有助于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.