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

• Applicant: Professorin Dr. Marta de Rocha Rosário
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 527322213

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.

• DFG Programme: Research Grants