Disruption of SynGAP–dopamine D1 receptor complexes alters actin and microtubule dynamics and impairs GABAergic interneuron migration

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Science Signaling  06 Aug 2019:
Vol. 12, Issue 593, eaau9122
DOI: 10.1126/scisignal.aau9122

SynGAP1 in neurodevelopment

Disruptions in dopamine signaling and mutations in SYNGAP1 are individually associated with various neurological disorders, particularly those associated with aberrant neuronal activity in response to the neurotransmitter GABA, including epilepsy, schizophrenia, and autism. Su et al. found that the dopamine receptor D1R and SynGAP (synaptic GTPase–activating protein) formed a complex in response to extracellular dopamine. Experiments with an engineered interfering peptide revealed that this complex promoted dopamine-induced migration of GABAergic interneurons during embryonic and early postnatal development in mice. This physiological role appeared to be specific to GABAergic but not glutamatergic interneurons, although D1R and SynGAP form complexes in both neuron types. These findings may provide insights into various neurodevelopmental and connectivity disorders.


Disruption of γ-aminobutyric acid (GABA)–ergic interneuron migration is implicated in various neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. The dopamine D1 receptor (D1R) promotes GABAergic interneuron migration, which is disrupted in various neurological disorders, some of which are also associated with mutations in the gene encoding synaptic Ras–guanosine triphosphatase–activating protein (SynGAP). Here, we explored the mechanisms underlying these associations and their possible connection. In prenatal mouse brain tissue, we found a previously unknown interaction between the D1R and SynGAP. This D1R-SynGAP interaction facilitated D1R localization to the plasma membrane and promoted D1R-mediated downstream signaling pathways, including phosphorylation of protein kinase A and p38 mitogen-activated protein kinase. These effects were blocked by a peptide (TAT-D1Rpep) that disrupted the D1R-SynGAP interaction. Furthermore, disrupting this complex in mice during embryonic development resulted in pronounced and selective deficits in the tangential migration of GABAergic interneurons, possibly due to altered actin and microtubule dynamics. Our results provide insights into the molecular mechanisms regulating interneuron development and suggest that disruption of the D1R-SynGAP interaction may underlie SYNGAP1 mutation–related neurodevelopmental disorders.

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