Because several neurological and neurodevelopmental disorders are associated with disruptions in dendritic morphology, it is crucial to understand the molecular mechanisms that regulate the process of active maintenance of dendritic arbors. After development, neurons must actively maintain each of these dendritic arbors to sustain their specific connectivity. Neurons in the mammalian cortex exhibit two distinct dendritic arbors: apical dendrites, which extend far from the cell body, and basal dendrites, which elaborate locally around the cell body.
These findings define a role for Epac2 in enabling crosstalk between Ras and Rap signaling in maintaining basal dendrite complexity, and exemplify how rare coding variants, in addition to their disease relevance, can provide insight into cellular mechanisms relevant for brain connectivity.Ī fundamental feature of a neuron is the morphology of its dendrites, which are the processes that receive and integrate synaptic signals from other neurons. Finally, we observed that components of the Ras/Epac2/Rap pathway exhibited differential abundance in the basal versus apical dendritic compartments. This mutation disrupted Epac2's interaction with Ras, and inhibition of Ras selectively interfered with basal dendrite maintenance. Overexpression of an Epac2 rare coding variant, found in human subjects diagnosed with autism, also impaired basal dendritic morphology. We found that in vivo Epac2 knockdown in layer 2/3 cortical neurons via in utero electroporation reduced basal dendritic architecture, and that Epac2 knockdown in mature cortical neurons in vitro mimicked this effect. Epac2 is a guanine nucleotide exchange factor (GEF) for the Ras-like small GTPase Rap, and it is highly enriched in the adult mouse brain.
Here we identified a role for the Ras/Epac2 pathway in maintaining basal dendrite complexity of cortical neurons. While apical and basal dendritic compartments of pyramidal neurons are functionally specialized and differentially regulated, little is known about mechanisms that selectively maintain basal dendrites. The architecture of dendritic arbors determines circuit connectivity, receptive fields, and computational properties of neurons, and dendritic structure is impaired in several psychiatric disorders.
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