The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors

Abstract

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 activitydependent 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.[Keywords: Rho GTPase-activating protein; Oligophrenin-1; glutamatergic function; AMPA receptor; actin cytoskeleton; mental retardation] Supplemental material is available at http://www.genesdev.org.

A circadian clock in hippocampus is regulated by interaction between oligophrenin-1 and Rev-erbα

“…Again, this may not have functional significance, but could be an epiphenomenon arising from interaction between 'synaptic' oligophrenin-1 and 'nuclear' Rev-erbα. It is known that the oligophrenin-1 localization to dentritic spines is driven by synaptic activity where it complexes with, stabilizes, and selectively activates AMPA receptors 39 .…”

Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway

“…First, based on previous reports demonstrating that mutations in the Ophn1 gene were associated with alterations in a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidreceptor (AMPAR) trafficking [13,14], a process which depends on AMPAR phosphorylation [23], we tested the phosphorylation state of AMPARs in Ophn1 þ/y and Ophn1 2/y brain extracts using specific antibodies against phosphorylated forms of AMPARs [24] (see electronic supplementary material, figure S1c). We first observed that, even though the total amount of the AMPAR subunits GluA1 and GluA2 was similar in both genotypes (data not shown), PKA-mediated phosphorylation of AMPARs was higher in Ophn1 2/y brains, when compared with WT animals.…”

“…In hippocampal slice preparations, acute downregulation of ophn1 expression using siRNA approaches leads to alterations in the density and morphology of postsynaptic spine density along with changes in AMPARs mobility and deficits in postsynaptic LTP [14]. Consistent with these results and with the fact that dendritic spine morphology is affected in several genetic mouse models for X-linked intellectual disabilities (ID), including Il1rapl1 and Ophn1 [9,54], this suggests an important role for deficits in postsynaptic function and plasticity in the pathophysiology of X-linked ID.…”

The Guanine Nucleotide Exchange Factor (GEF) Asef2 Promotes Dendritic Spine Formation via Rac Activation and Spinophilin-dependent Targeting

“…tual disorders (25)(26)(27). Therefore, these studies highlight the importance of GEFs and GAPs in regulating spine and synapse function and point to a need to investigate the contribution of other GEFs and GAPs to these processes.…”