Loss of EPAC2 alters dendritic spine morphology and inhibitory synapse density
| Autor: | Michiko Sumiya, Kelly A. Jones, Deepak Srivastava, Peter Penzes, Kevin M. Woolfrey |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Dendritic spine EPAC2 Vesicular Inhibitory Amino Acid Transport Proteins Dendritic Spines Vesicular glutamate transporter 1 AMPA receptor Inhibitory postsynaptic potential Gyrus Cinguli Article Dendritic spines Synaptic plasticity Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Dendritic arborization Animals Guanine Nucleotide Exchange Factors Small GTPase Receptors AMPA Molecular Biology Cells Cultured biology Excitatory Postsynaptic Potentials Cell Biology Autism spectrum disorders Cadherins Cell biology Mice Inbred C57BL 030104 developmental biology Inhibitory Postsynaptic Potentials Synapses Excitatory postsynaptic potential biology.protein Guanine nucleotide exchange factor 030217 neurology & neurosurgery Excitatory and inhibitory balance |
| Zdroj: | Jones, K A, Sumiya, M, Woolfrey, K M, Srivastava, D P & Penzes, P 2019, ' Loss of EPAC2 alters dendritic spine morphology and inhibitory synapse density ', Molecular and Cellular Neuroscience, vol. 98, pp. 19-31 . https://doi.org/10.1016/j.mcn.2019.05.001 Molecular and Cellular Neurosciences |
| Popis: | 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 expression of vesicular GABA transporter (VGAT) but not vesicular glutamate transporter 1 (VGluT1), indicating an altered ratio of excitatory and inhibitory synapses 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 loss of EPAC2 enhances the stability of excitatory synapses and increases the number of inhibitory inputs. Highlights • EPAC2 is required for cAMP-dependent spine remodeling. • Loss of EPAC2 results in over-stabilized excitatory synapses. • Loss of EPAC2 results in an increase in inhibitory input onto neurons. • EPAC2 is required for correct dendritic arborization and spine formation in vivo. |
| Databáze: | OpenAIRE |
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