The Rho-Linked Mental Retardation Protein OPHN1 Controls Synaptic Vesicle Endocytosis via Endophilin A1

Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York, NY 11724, USA.
Current biology: CB (Impact Factor: 9.57). 06/2009; 19(13):1133-9. DOI: 10.1016/j.cub.2009.05.022
Source: PubMed


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.

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Available from: Nael Nadif Kasri, Apr 16, 2014
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    • "Therefore, srGAP3 could play an analogous role in endocytic processes as the BAR domain-containing Rho-GAP protein Oligophrenin1 [66]. Oligophrenin1 has been found to recruit Endophilins via a similar proline-rich motif located in the C-terminal proline-rich region, thereby promoting synaptic vesicle uptake and AMPA receptor internalisation [67] [68]. Here, we provide first evidence that the CTR of srGAP3 might function as an adaptor platform connecting srGAP3 and therefore its targets – like the Robo receptor – to different protein networks, namely the endocytic machinery. "
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    ABSTRACT: The Slit-Robo GTPase-activating protein 3 (srGAP3) has been implicated in different critical aspects of neuronal development. These findings have mainly been based on the characterisation of the three conserved globular N-terminal domains, while the function of the C-terminal region (CTR) is still unknown. We show that this predicted unstructured region acts as an adaptor by binding to the endocytic proteins Amphiphysin, Endophilin-A2, Endophilin-A1, as well as the Ras signalling protein Grb2. All these interactions depend on a single proline-rich motif in the CTR and the Src-homology 3 domains of the binding partners. Via these interactions srGAP3 could link receptor signalling events to the endocytic machinery. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Mar 2015 · FEBS letters
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    • "OPHN1 encodes oligophrenin-1, a protein with a Rho-GAP domain which negatively regulates RhoA, Rac1 and Cdc42 [19], [21]. In addition to the regulation of Rho-family GTPases, oligophrenin-1 regulates the size of the readily releasable pool (RRP) of vesicles in inhibitory synapses [4], possibly through regulation of synaptic vesicle endocytosis [22], [23]. The altered vesicle dynamics prevents synapses from functioning at frequencies within the gamma range [4]. "
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    ABSTRACT: Intellectual disability affects 2-3% of the population; mutations of the X-chromosome are a major cause of moderate to severe cases. The link between the molecular consequences of the mutation and impaired cognitive function remains unclear. Loss of function mutations of oligophrenin-1 (OPHN1) disrupt Rho-GTPase signalling. Here we demonstrate abnormal neurotransmission at CA3 synapses in hippocampal slices from Ophn1-/y mice, resulting from a substantial decrease in the readily releasable pool of vesicles. As a result, synaptic transmission fails at high frequencies required for oscillations associated with cognitive functions. Both spontaneous and KA-induced gamma oscillations were reduced in Ophn1-/y hippocampal slices. Spontaneous oscillations were rapidly rescued by inhibition of the downstream signalling pathway of oligophrenin-1. These findings suggest that the intellectual disability due to mutations of oligophrenin-1 results from a synaptopathy and consequent network malfunction, providing a plausible mechanism for the learning disabilities. Furthermore, they raise the prospect of drug treatments for affected individuals.
    Full-text · Article · May 2014 · PLoS ONE
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    • "Rapid OPHN1 Synthesis Mediates mGluR-LTD Neuron 72, 300–315, October 20, 2011 ª2011 Elsevier Inc. 305 A third class of proteins we found to associate with OPHN1 are members of the endophilin A family, which include endophilin A1, A2, and A3 (Kjaerulff et al., 2011). In previous studies, we and others demonstrated a direct interaction between OPHN1 and endophilin A1 (Endo1) (Khelfaoui et al., 2009; Nakano-Kobayashi et al., 2009), which is predominantly expressed in presynaptic nerve terminals, and showed that this interaction is critical for OPHN1's presynaptic function in synaptic vesicle retrieval (Nakano-Kobayashi et al., 2009). The endophilin A2 (Endo2) and endophilin A3 (Endo3) proteins, on the other hand, are enriched in postsynaptic compartments and have been implicated in the regulation of AMPAR endocytosis in hippocampal neurons (Chowdhury et al., 2006). "
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    ABSTRACT: Activation of group I metabotropic glutamate receptors leads to long-term depression (mGluR-LTD). Alterations in this form of plasticity have been linked to drug addiction and cognitive disorders. A key characteristic of mGluR-LTD is its dependence on rapid protein synthesis; however, the identities of the proteins mediating LTD remain elusive. Here, we identify the X-linked mental retardation protein OPHN1 as a molecule essential for mGluR-LTD in the hippocampus. mGluR-LTD induction elicits rapid dendritic OPHN1 synthesis, which is dependent on mGluR1 activation and independent of fragile X mental retardation protein (FMRP). This response is essential for mGluR-LTD, as acute blockade of OPHN1 synthesis impedes LTD. mGluR-induced OPHN1 mediates LTD and associated persistent decreases in surface AMPARs via interactions with endophilin A2/3. Importantly, this role of OPHN1 is separable from its effects on basal synaptic strength, which require OPHN1's Rho-GAP activity and interaction with Homer1b/c. Thus, our data establish a role for rapid OPHN1 synthesis in mGluR-LTD. VIDEO ABSTRACT:
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