The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis

Abstract

Of 11 genes involved in nonspecific X-linked mental retardation (MRX), three encode regulators or effectors of the Rho GTPases, suggesting an important role for Rho signaling in cognitive function. It remains unknown, however, how mutations in Rho-linked genes lead to MRX. Here we report that oligophrenin-1, a Rho-GTPase activating protein that is absent in a family affected with MRX, is required for dendritic spine morphogenesis. Using RNA interference and antisense RNA approaches, we show that knock-down of oligophrenin-1 levels in CA1 neurons in rat hippocampal slices significantly decreases spine length. This phenotype can be recapitulated using an activated form of RhoA and rescued by inhibiting Rho-kinase, indicating that reduced oligophrenin-1 levels affect spine length by increasing RhoA and Rho-kinase activities. We further demonstrate an interaction between oligophrenin-1 and the postsynaptic adaptor protein Homer. Our findings provide the first insight into how mutations in a Rho-linked MRX gene may compromise neuronal function.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…In young cultured neurons, oligophrenin1 colocalizes with the actin cytoskeleton in the growing tip of dendrites 257 , and is detected in the axon, dendrites and dendritic spines of mature neurons 258 . In vitro, the use of RNA interference methods has revealed the important role of oligophrenin1 in the regulation of dendrite morphogenesis and the regulation of dendritic spine maturation 258 . Notably, the downregulation of oligophrenin1 expression in rat hippocampal slices leads to a decrease in spine length without affecting spine density 258 .…”

Rho-linked genes and neurological disorders

“…OPHN1 is expressed in multiple tissues with the highest expression in the developing brain, where it is found in neurons of all major regions, including hippocampus, cerebellum and cortex, and is present in axons, dendrites and spines [24,30]. The OPHN1 protein negatively regulates RhoA, Rac1, and Cdc42 in vitro, in non-neuronal and neuronal cells [8,24].…”

“…The OPHN1 protein negatively regulates RhoA, Rac1, and Cdc42 in vitro, in non-neuronal and neuronal cells [8,24]. Significantly, recent studies by Govek et al showed that knock-down of OPHN1 expression in CA1 pyramidal neurons in hippocampal slices results in a significant decrease in dendritic spine length [30]. As spine morphology is ultimately linked to synaptic function [89], such spine morphological changes are likely to compromise synaptic plasticity, and potentially lead to learning and memory deficits.…”

“…As spine morphology is ultimately linked to synaptic function [89], such spine morphological changes are likely to compromise synaptic plasticity, and potentially lead to learning and memory deficits. The above spine length phenotype was mimicked using a constitutive active RhoA (CA-RhoA) mutant and could be largely rescued by inhibiting the RhoA effector, Rho-kinase (Govek et al 2004). Rho-kinase (also called ROK or ROCK) has been well documented to play a key role in RhoA-induced actin reorganization and to mediate at least in part RhoA's effects on spine morphogenesis [69,77].…”

“…Interestingly, OPHN1 has also been found to associate with Homer [30], a postsynaptic adaptor protein that links glutamate receptors, such as type-1 metabotropic glutamate receptors (mGluRs), to multiple intracellular targets [23,85]. Moreover, Homer proteins have been shown to influence dendritic spine morphogenesis and synaptic transmission [26,71,72].…”