Role of oligophrenin-1 in circuit formation and function in a mouse model of X-linked mental retardation

MR is a complex disease of the central nervous system (CNS) whose etiopathogenesis is still poorly understood. The genetic contribution to the etiology of MR is well established and among the genetic conditions, the most frequent are the X-linked mental retardation (XLMR) forms caused by single gene mutations on chromosome X. Among the X-Linked Mental Retardation (XLMR) genes, Oligophrenin-1 (OPHN1) encodes a synaptic RhoGTPase-activating protein that regulates neuronal morphology, i.e. shape of dendritic spines and outgrowth of axons in the brain. The involvement of OPHN1 in XLMR was established by the identification of mutations within the gene in patients with XLMR. More recent studies reported the presence of OPHN1 mutations in families with mental retardation associated with epilepsy and /or cerebellar hypoplasia. Oligophrenin-1 gene is expressed in brain areas that are characterized by high synaptic plasticity, in particular, the olfactory bulb, the hippocampus and the cerebral cortex. At the cellular level, Oligophrenin-1 is expressed in both glial and neuronal cells where it colocalizes with actin, notably at the tip of growing neurites. The loss of function of OPHN1 is thought to cause abnormalities in neuronal morphology and wiring. These steps are essential for normal function of the CNS. Indeed distortions in neural circuit formation are associated to altered information processing, which is likely to be responsible of the cognitive impairment present in MR. Understanding whether and how OPHN1 deficiency affect neuronal morphology and circuit formation and function is crucial to develop any possible future therapeutic strategies. To accomplish this goal the present project aim to analyze neuronal morphology and wiring in a mouse model of MR due to loss of function of OPHN1. We will also test a novel therapeutic strategy based on inhibition of a RhoGTPase whose activity is potently stimulated by loss of OPHN1.