The Rho-linked mental retardation protein OPHN1 controls synaptic vesicle endocytosis via endophilin A1.

Journal article

Neurons transmit information at chemical synapses by releasing neurotransmitters that are stored in synaptic vesicles (SVs) at the presynaptic site. After release, these vesicles need to be efficiently retrieved in order to maintain synaptic transmission. In concurrence, malfunctions in SV recycling have been associated with cognitive disorders. Oligophrenin-1 (OPHN1) encodes a Rho-GTPase-activating protein (Rho-GAP) whose loss of function causes X-linked mental retardation. OPHN1 is highly expressed in the brain and present both pre- and postsynaptically in neurons. Previous studies report that postsynaptic OPHN1 is important for dendritic spine morphogenesis, but its function at the presynaptic site remains largely unexplored. Here, we present evidence that reduced or defective OPHN1 signaling impairs SV cycling at hippocampal synapses. In particular, we show that OPHN1 knockdown affects the kinetic efficiency of endocytosis. We further demonstrate that OPHN1 forms a complex with endophilin A1, a protein implicated in membrane curvature generation during SV endocytosis and, importantly, that OPHN1's interaction with endophilin A1 and its Rho-GAP activity are important for its function in SV endocytosis. Our findings suggest that defects in efficient SV retrieval may contribute to the pathogenesis of OPHN1-linked cognitive impairment.

Authors: Nakano-Kobayashi, A; Kasri, N; Newey, S; Van Aelst, L

• Publication status: Published
• Journal: Current biology : CB
• Volume: 19
• Issue: 13
• Pages: 1133-1139
• Publication date: 2009-07-01
• DOI: 10.1016/j.cub.2009.05.022
• EISSN: 1879-0445
• ISSN: 0960-9822
• Language: English
• Keywords: RNA Interference; GTPase-Activating Proteins; Synaptic Transmission; Animals; Adaptor Proteins, Signal Transducing; Hippocampus; Nuclear Proteins; Endocytosis; Cytoskeletal Proteins; Fluorescent Dyes; Recombinant Fusion Proteins; Gene Knockdown Techniques; Synaptic Vesicles; Signal Transduction; Mice; Neurons