TY - JOUR
T1 - Loss of EPAC2 alters dendritic spine morphology and inhibitory synapse density
AU - Jones, Kelly A.
AU - Sumiya, Michiko
AU - Woolfrey, Kevin M.
AU - Srivastava, Deepak P.
AU - Penzes, Peter
N1 - Funding Information:
This work was supported by NIH grants R01MH071316 and R01MH097216 to P.P.; and NRSA USA Ruth L. Kirschstein Award F31MH085362 to K. A. J..; and grants from the Medical Research Council UK, MR/L021064/1, Royal Society UK (Grant RG130856), and the Brain and Behavior Foundation (formally National Alliance for Research on Schizophrenia and Depression (NARSAD); Grant No. 25957), awarded to D.P.S.
Funding Information:
This work was supported by NIH grants R01MH071316 and R01MH097216 to P.P.; and NRSA USA Ruth L. Kirschstein Award F31MH085362 to K. A. J..; and grants from the Medical Research Council UK , MR/L021064/1 , Royal Society UK (Grant RG130856 ), and the Brain and Behavior Foundation (formally National Alliance for Research on Schizophrenia and Depression (NARSAD); Grant No. 25957 ), awarded to D.P.S.
Publisher Copyright:
© 2019 The Authors
PY - 2019/7
Y1 - 2019/7
N2 - 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.
AB - 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.
KW - Autism spectrum disorders
KW - Dendritic arborization
KW - Dendritic spines
KW - EPAC2
KW - Excitatory and inhibitory balance
KW - Synaptic plasticity
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U2 - 10.1016/j.mcn.2019.05.001
DO - 10.1016/j.mcn.2019.05.001
M3 - Article
C2 - 31059774
AN - SCOPUS:85065651873
VL - 98
SP - 19
EP - 31
JO - Molecular and Cellular Neurosciences
JF - Molecular and Cellular Neurosciences
SN - 1044-7431
ER -