You are currently viewing the abstract.
View Full TextLog in to view the full text
AAAS login provides access to Science for AAAS members, and access to other journals in the Science family to users who have purchased individual subscriptions.
More options
Download and print this article for your personal scholarly, research, and educational use.
Buy a single issue of Science for just $15 USD.
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.
Abstract
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.
This is an article distributed under the terms of the Science Journals Default License.
