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The molecular mechanisms that promote excitatorysynapse development havebeen extensively studied.However, the molecular events preventingprecociousexcitatory synapse development so thatsynapses form atthe correct time and place areless well understood. Here, we report thefunctionalcharacterization of ARHGAP12, a previously uncharacterizedRhoGTPase-activating protein (RhoGAP)in the brain. ARHGAP12is specificallyexpressed inthe CA1 region of the hippocampus, whereit localizesto the postsynaptic compartment of excitatorysynapses.ARHGAP12 negatively controls spinesize via its RhoGAPactivity and promotes, byinteractingwith CIP4,postsynaptic AMPAreceptor endocytosis. Arhgap12 knockdown results in precocious maturationof excitatory synapses, as indicated by a reduction in the proportion ofsilent synapses. Collectively, our data show that ARHGAP12 is a synapticRhoGAP that regulates excitatory synaptic structure and function duringdevelopment.

Contains fulltext : 166988.pdf (Publisher’s version ) (Open Access) The human brain is one of the most complex and fascinating organs, which governs fundamental processes including learning and memory. It is now widely believed that synaptic plasticity, the ability of the brain to modify the efficacy of neuronal communication in response to experience, is the cellular basis of learning and memory. The dynamic modification of neuronal communication can be achieved by the structural regulation of spines, small actin enriched protrusions on dendrites, as well as the functional regulation via remodeling neurotransmitter receptors such as glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPArs). Evidence suggests that impairments in spine structure and synaptic strength during development contribute to numerous neurological diseases including autism spectrum disorders (ASD) and intellectual disability (ID). To understand how the normal brain regulates cognition and how neurodevelopmental disorders may occur, mechanistic insights into the regulation of structural and functional plasticity are required. Rho subfamily of GTP-binding proteins, key regulators of actin cytoskeleton dynamics, has been found to play critical roles in synapse formation, maturation and maintenance. With the main focus on the genes that are involved in Rho GTPase signaling pathways, the research reported in the thesis reveals the roles of several previously uncharacterized genes, most of which are linked to ID, in neuronal development at the synaptic level. These results enrich our understanding of cellular and molecular mechanisms underlying learning and memory, and shed light on novel and effective therapies for neurological disorders including ID. Radboud University, 20 maart 2017 Promotor : Bokhoven, H. van Co-promotor : Nadif Kasri, N.