Rapid synthesis of the X-linked mental retardation protein OPHN1 mediates mGluR-dependent LTD through interaction with the endocytic machinery.
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.
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
Nael
N
Nadif Kasri
Akiko
A
Nakano-Kobayashi
Linda
L
Van Aelst
D000818:Animals; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D003712:Dendrites / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000096:biosynthesis*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C529605:OPHN1 protein, rat; D018094:Receptors, Metabotropic Glutamate