The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors.
Oligophrenin-1 (OPHN1) encodes a Rho-GTPase-activating protein (Rho-GAP) whose loss of function has been associated with X-linked mental retardation (MR). The pathophysiological role of OPHN1, however, remains poorly understood. Here we show that OPHN1 through its Rho-GAP activity plays a critical role in the activity-dependent maturation and plasticity of excitatory synapses by controlling their structural and functional stability. Synaptic activity through NMDA receptor activation drives OPHN1 into dendritic spines, where it forms a complex with AMPA receptors, and selectively enhances AMPA-receptor-mediated synaptic transmission and spine size by stabilizing synaptic AMPA receptors. Consequently, decreased or defective OPHN1 signaling prevents glutamatergic synapse maturation and causes loss of synaptic structure, function, and plasticity. These results imply that normal activity-driven glutamatergic synapse development is impaired by perturbation of OPHN1 function. Thus, our findings link genetic deficits in OPHN1 to glutamatergic dysfunction and suggest that defects in early circuitry development are an important contributory factor to this form of MR.
Nadif Kasri
Nael
N
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Nakano-Kobayashi
Akiko
A
Malinow
Roberto
R
Li
Bo
B
Van Aelst
Linda
L
D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D008607:Intellectual Disability / Q000503:physiopathology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*
D003598:Cytoskeletal Proteins; D018690:Excitatory Amino Acid Agonists; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C529605:OPHN1 protein, rat; D018091:Receptors, AMPA; D016202:N-Methylaspartate; C104722:glutamate receptor ionotropic, AMPA 2