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bioRxiv · 10.1101/526772

Loss of EPAC2 results in altered synaptic composition of dendritic spines and excitatory and inhibitory balance

Jones, K. A.·Sumiya, M.·Woolfrey, K. M.·Srivastava, D. P.·Penzes, P.
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Abstract

EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras) and is highly enriched at synapses. Activation of EPAC2 has been shown to induce dendritic spine shrinkage and increase spine motility, effects that are necessary for synaptic plasticity. These morphological effects are dysregulated by rare mutations of EPAC2 associated with autism spectrum disorders. In addition, EPAC2 destabilizes synapses through the removal of synaptic GluA2/3-containing AMPA receptors. Previous work has shown that Epac2 knockout mice (Epac2-/-) display abnormal social interactions, as well as gross disorganization of the frontal cortex and abnormal spine motility in vivo. In this study we sought to further understand the cellular consequences of knocking out Epac2 on the development of neuronal and synaptic structure and organization of cortical neurons. Using primary cortical neurons generated from Epac2+/+ or Epac2-/- mice, we confirm that EPAC2 is required for cAMP-dependent spine shrinkage. Neurons from Epac2-/- mice also displayed increased synaptic expression of GluA2/3-containing AMPA receptors, as well as of the adhesion protein N-cadherin. Intriguingly, analysis of excitatory and inhibitory synaptic proteins revealed that loss of EPAC2 resulted in altered of expression of vesicular glutamate transporter 1 (VGluT1) and vesicular GABA transporter (VGAT), indicating a potential imbalance in excitatory/inhibitory inputs onto neurons. Finally, examination of cortical neurons located within the anterior cingulate cortex further revealed subtle deficits in the establishment of dendritic arborization in vivo. These data provide evidence that EPAC2 is required for the correct composition of synapses and that loss of this protein could result in an imbalance of excitatory and inhibitory synapses.

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Jones, K. A., Sumiya, M., Woolfrey, K. M., Srivastava, D. P., Penzes, P.. 2019-01-21. Loss of EPAC2 results in altered synaptic composition of dendritic spines and excitatory and inhibitory balance. https://doi.org/10.1101/526772

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