When NMDA receptors are activated in the synapse, the team found that OPHN1 is recruited to dendritic spines, where it locally regulates the actin cytoskeleton -- as it turns out, in proximity to another receptor type in the synapse called AMPA receptors. This finding proved critical in the team's progress in understanding what goes wrong when the OPHN1 gene malfunctions.

Destabilizing AMPA receptors

"If you lose the OPHN1 protein," says Van Aelst, "for example, if you have a mutation in the OPHN1 gene, then the protein becomes non-functional. This, in turn, perturbs the stabilization of the AMPA receptors. And that, we propose, accounts for depressed function of glutamatergic, or excitatory neurons." Below-normal glutamatergic function, specifically observed in these experiments in the rat hippocampus, can in this way be associated with certain pathologies.

There is no question, Van Aelst clarifies, that "defective OPHN1 signaling results in destabilization of synaptic AMPA receptors and dendritic spine structure, leading to impairment in synaptic plasticity and eventually loss of spines and NMDA receptors." This chain of events has been observed definitively in rats.

The impact of OPHN1 signaling anomalies in people, however, is still hypothetical. "Our work suggests a cellular mechanism by which mutations in OPHN1 can contribute to cognitive deficits observed in patients who have the mutations," Van Aelst says.

Future work in Van Aelst's lab will focus on OPHN1's potential role in pathologies in other neuronal pathways, between or within other parts of the brain. The protein is found nearly everywhere, but it is not known if its absence or loss of function causes abnormalities in other parts of the brain.

"The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors," appears in Genes & Development, June 1. The full citation is Nael Nadif Kasri, Akiko Nakano-Kobayashi, Roberto Malinow, Bo Li, and Linda Van Aelst. The article is available online at: genesdev/cgi/doi/10.1101/gad.1783809. Cold Spring Harbor Laboratory (CSHL) is a private, not-for-profit research and education institution at the forefront of efforts in molecular biology and genetics to generate knowledge that will yield better diagnostics and treatments for cancer, neurological diseases and other major causes of human suffering.

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