An Autism-Associated Variant of Epac2 Reveals a Role for Ras/Epac2 Signaling in Controlling Basal Dendrite Maintenance in Mice

Deepak P Srivastava,Theron A Russell,Kelly A Jones,Hyerin Lee,David L Wokosin,Marina V Yasvoina,Katharine R Smith,Peter Penzes,Gordon M G Shepherd,Charles T Anderson,Kevin M Woolfrey,P Hande Ozdinler,Matthias Landgraf

doi:10.1371/journal.pbio.1001350

Deepak P Srivastava, Theron A Russell + Show 11 more

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https://doi.org/10.1371/journal.pbio.1001350

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Abstract

Author SummaryA fundamental feature of a neuron is the morphology of its dendrites, which are the processes that receive and integrate synaptic signals from other neurons. 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. After development, neurons must actively maintain each of these dendritic arbors to sustain their specific connectivity. 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. We find that disruption of a particular molecular pathway, the Ras-Epac2 pathway, can result in dramatic simplification of basal, but not apical, dendritic arbors in both cultured neurons and in the intact mouse brain. We show that a mutant form of Epac2, identified in patients with autism, also impairs basal dendrite maintenance and disrupts its interaction with Ras. Our findings suggest that specific molecular pathways can regulate distinct dendritic regions, and that disease-related mutations can inform our understanding of the molecules that regulate important biological processes.

Highlights

Dendritic structure is critical for neuronal function, as the size and shape of the dendritic arbor defines the neuron’s receptive field [1]
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
We find that disruption of a particular molecular pathway, the RasEpac2 pathway, can result in dramatic simplification of basal, but not apical, dendritic arbors in both cultured neurons and in the intact mouse brain

Summary

Introduction

Dendritic structure is critical for neuronal function, as the size and shape of the dendritic arbor defines the neuron’s receptive field [1]. Generating and maintaining proper arborization is crucial for neural circuit function [2]. The importance of maintaining dendritic arborization is illustrated by observations of loss of dendritic complexity in patients with neuropsychiatric disorders. The maintenance of dendritic arbor complexity for extended periods of time during development and into adulthood is likely to be crucial for the preservation of functional circuitry and connectivity relevant for learning and complex behaviors. An increasing body of evidence suggests that the apical versus basal regions of the dendritic arbor are functionally specialized.

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