From Nonsyndromic X-linked Mental Retardation (MRX) diseases to discovery genes for cognitive circuitry in humans

Mental Retardation (MR) is the most frequent cause of serious neurological handicap in children and young adults. It impairs the development and function of the brain causing a damage of learning and social behaviour. Pathologically, the MR disease is commonly associated with abnormalities of dendritic spines, the main sites of the excitatory synapses in the brain. Among the hereditary forms, X-linked non-syndromic mental retardation (MRX) accounts for ~25% of males with mental deficit having developmental onset. X chromosome genes implicated in MR are several and code for proteins implicated in diverse processes such as signalling cascades and transcriptional regulation. Relatively little is known regarding their pathogenetic mechanisms in MRX phenotypes, in particular how it may lead to synaptic plasticity impairment and intellective deficit. Moreover, because cognitive alterations are the only clinical feature ever observed in MRX patients, to focus on these disorders highlights the importance to uncover which molecules are relevant for complex cognition in human. Instead, research into MRX genes has begun to bridge what it is known about the brain design underlying normal and subnormal neural circuitry and our understanding of how genetic and environmental factors shape brain modularity. Herein, we will address what is known about the relationship between mental disorders and homeostatic plasticity and how a MRX disease may be considered a global effect of a specific genetic deficit in a cognitive module. First, we will report on huge genetic heterogeneity of MRX disease and linkage data recapitulating, which human genes can mutate to a MRX phenotype and are required for proper neurological development. As familial and molecular data begin to describe, it has been revealed how these brain defects are conspicuously clustered in defined regions of X chromosome and other disease genes, which control cognitive skills, are still uncovered. Secondly, we will review evidences from a number of MRX genes highlighting the importance to study signalling pathways underlining mental processes. Indeed, the identification of specific cascades and critical timing of developmental events may supply relevant informations for preclinical interventions an early time of brain plasticity. Only a better understanding of the molecular and cellular MRX bases can provide early diagnosis, family planning and also bioassays for potential cognitive-enhancing molecules, which may be useful for other MR forms as well.