title: SRGAP2 and Its Human-Specific Paralog Co-Regulate the Development of Excitatory and Inhibitory Synapses.
abstract: The proper function of neural circuits requires spatially and temporally balanced development of excitatory and inhibitory synapses. However, the molecular mechanisms coordinating excitatory and inhibitory synaptogenesis remain unknown. Here we demonstrate that SRGAP2A and its human-specific paralog SRGAP2C co-regulate the development of excitatory and inhibitory synapses in cortical pyramidal neurons in vivo. SRGAP2A promotes synaptic maturation, and ultimately the synaptic accumulation of AMPA and GABAA receptors, by interacting with key components of both excitatory and inhibitory postsynaptic scaffolds, Homer and Gephyrin. Furthermore, SRGAP2A limits the density of both types of synapses via its Rac1-GAP activity. SRGAP2C inhibits all identified functions of SRGAP2A, protracting the maturation and increasing the density of excitatory and inhibitory synapses. Our results uncover a molecular mechanism coordinating critical features of synaptic development and suggest that human-specific duplication of SRGAP2 might have contributed to the emergence of unique traits of human neurons while preserving the excitation/inhibition balance.
authors.affiliation: Institut de Biologie de l'Ecole Normale Supérieure (IBENS), CNRS, Inserm, Ecole Normale Supérieure, PSL Research University, F-75005 Paris, France.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fossati
authors.affiliation: Institut de Biologie de l'Ecole Normale Supérieure (IBENS), CNRS, Inserm, Ecole Normale Supérieure, PSL Research University, F-75005 Paris, France.
authors.forename: Rocco
authors.initials: R
authors.lastname: Pizzarelli
authors.affiliation: Department of Neuroscience, Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, NY 10032, USA.
authors.forename: Ewoud R
authors.initials: ER
authors.lastname: Schmidt
authors.affiliation: Department of Neuroscience, Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, NY 10032, USA.
authors.forename: Justine V
authors.initials: JV
authors.lastname: Kupferman
authors.affiliation: Institut de Biologie de l'Ecole Normale Supérieure (IBENS), CNRS, Inserm, Ecole Normale Supérieure, PSL Research University, F-75005 Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Stroebel
authors.affiliation: Department of Neuroscience, Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, NY 10032, USA. Electronic address: fp2304@cumc.columbia.edu.
authors.forename: Franck
authors.initials: F
authors.lastname: Polleux
authors.affiliation: Institut de Biologie de l'Ecole Normale Supérieure (IBENS), CNRS, Inserm, Ecole Normale Supérieure, PSL Research University, F-75005 Paris, France. Electronic address: cecile.charrier@ens.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Charrier
mesh_terms: D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D009433:Neural Inhibition / Q000502:physiology*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D011963:Receptors, GABA-A / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D020690:GTPase-Activating Proteins; D011963:Receptors, GABA-A; C501995:SRGAP2 protein, human