NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse

Abstract

Neuropsychiatric developmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, are typically characterized by alterations in social behavior and have been linked to aberrant dendritic spine and synapse development. Here we show, using genetically engineered mice, that the Cdc42 GTPase-activating multiadaptor protein, NOMA-GAP, regulates autism-like social behavior in the mouse, as well as dendritic spine and synapse development. Surprisingly, we were unable to restore spine morphology or autism-associated social behavior in NOMA-GAP-deficient animals by Cre-mediated deletion of Cdc42 alone. Spine morphology can be restored in vivo by re-expression of wild-type NOMA-GAP or a mutant of NOMA-GAP that lacks the RhoGAP domain, suggesting that other signaling functions are involved. Indeed, we show that NOMA-GAP directly interacts with several MAGUK (membrane-associated guanylate kinase) proteins, and that this modulates NOMA-GAP activity toward Cdc42. Moreover, we demonstrate that NOMA-GAP is a major regulator of PSD-95 in the neocortex. Loss of NOMA-GAP leads to strong upregulation of serine 295 phosphorylation of PSD-95 and moreover to its subcellular mislocalization. This is associated with marked loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and defective synaptic transmission, thereby providing a molecular basis for autism-like social behavior in the absence of NOMA-GAP.

Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

“…Consistent with this, M4 was enriched for genes with fetal-specific expression ( Fig. S2C), and its hub genes included DOK4, ARHGAP33, and TRIO, which are involved in axon and dendrite morphogenesis (49)(50)(51). LoF DNMs in ASD were also over-represented in M6, with common variants nominally enriched.…”

Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 Copy Number Variant–Mediated Risk for Neuropsychiatric Disorders

“…M4 was enriched for neuronal markers, peaked in expression during midfetal development, and was involved in neuron differentiation and projection development ( Figure 3D-F). Consistent with this, M4 was enriched for genes with fetal-specific expression ( Figure S3D in Supplement 1), and its hub genes included DOK4, ARHGAP33, and TRIO, which are involved in axon and dendrite morphogenesis (49)(50)(51). LOF DNMs in ASD were also overrepresented in M6, which showed maximal expression during fetal development but was not enriched for genes expressed in any specific developmental stage ( Figure S3F in Supplement 1).…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…In these mice, the trafficking and surface expression of the BDNF receptor TrkB are impaired, resulting in a deficit in spine and synapse formation 287 . The second study shows that Arhgap33 -/-mice also present morphological variations of their dendritic spines, with a longer length of the spine neck without modification of the head width and a decrease in the density of synapses containing PSD-95 286 .…”

“…Although ARHGAP33 has not been genetically linked to ASD, its genetic ablation in mice results in major deficits in social behavior, a typical autistic trait 286 . Moreover, ARHGAP33 regulates several neuronal morphogenesis mechanisms that are closely related to ASD cellular phenotypes.…”

“…Co-immunoprecipitations performed on cortical lysates of wildtype mice have revealed the interaction of ARHGAP33 with the scaffolding protein PSD-95. ARHGAP33 regulates the phosphorylation and localization of PSD-95, in association with a loss of AMPA receptors at the synaptic membrane 286 . The recruitment of AMPA receptors at the synapse leads to the strengthening and the maturation of spines via the regulation of signaling pathways that modulate the actin cytoskeleton 290 .…”