Cases of nonspecific X-linked mental retardation (MRX) in humans have been attributed to mutations in 11 different genes. Three of these genes code for molecules that interact with the Rho signalling pathway, which is known to regulate the actin cytoskeleton. So, how might Rho pathway dysfunction lead to the cognitive deficits that are associated with MRX? In a new study reported in Nature Neuroscience, Govek and colleagues provide some answers to this question.

In one family, MRX was found to be associated with a mutation in the gene that encodes a Rho-GTPase activating protein called oligophrenin-1 (OPHN-1). Govek et al. showed that in the rat brain, puncta of oligophrenin-1 were present at both presynaptic and postsynaptic sites, perhaps indicating a role in synaptic development and/or function. In the postsynaptic compartment, the protein was co-localized with F-actin, which is a key component of the dendritic spine cytoskeleton.

The authors used two approaches — antisense RNA and RNA interference — to knock down Ophn-1 gene function in hippocampal slices from rats at postnatal day 4. They found that the mean dendritic spine length was significantly reduced on neurons that had been transfected with an Ophn-1 antisense construct or small interfering RNAs. This knock-down phenotype could be mimicked by overexpression of RhoA, but not by overexpression of the other Rho family members Rac1 and Cdc42. In addition, the Ophn-1 knock-down phenotype was rescued by inhibiting Rho-kinase, a downstream target of RhoA that was previously shown to be involved in neurite retraction.

These findings indicate that Ophn-1 normally maintains dendritic spine length by negatively regulating the RhoA/Rho-kinase signalling pathway. Govek et al. also showed that Ophn-1 contains a binding site for Homer, an adaptor protein that provides a link between glutamate receptor activation and cytoskeletal rearrangements. Therefore, Ophn-1 might be part of a pathway that stabilizes spines in response to synaptic activity. This points towards a model for MRX, in which the defects in spine morphogenesis and stabilization that result from loss of Ophn-1 function impair the brain's capacity for synaptic plasticity, which in turn leads to deficits in learning and memory.