University of California, San Diego (UCSD)

The Molecular Basis of Human Mental Retardation

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The objective of the proposed research is to gain an understanding of cellular and molecular defects that cause non-syndromic mental retardation (NSMR), a neurological disorder that affects 2 – 3 % of children and young adults. NSMR is thought to be a result of alterations in molecular pathways underlying neuronal processes involved in cognitive function. It is not fully understood which molecular pathways are critical. Recently, eleven X-linked genes have been found to be mutated in NSMR families. Several of these genes encode proteins involved in Rho GTPase signaling and possibly mediate the organization of the neuronal actin cytoskeleton, which is thought to play a key role in growth cone guidance, formation of functional synapses, and synaptic plasticity.

We plan to study the normal function of three genes, as well as the defects caused by mutations in these genes, with the emphasis on the possible link to impaired cognitive function. By generating conditional knockout mice, we will evaluate the function of these genes and their role in experience-mediated synaptic changes and cognitive function in mice.

This study will combine a genetic approach: in vivo anatomical and morphological studies, in vitro primary cell culture approaches, and behavioral studies. The proposed research will help elucidate the etiology of NSMR and hopefully lead to improved treatments. In addition, by using Cre-LoxP strategy that provides temporal control over targeted genes, we will address the question whether NSMR is a developmental or ongoing disorder of neuronal function.