The primary goal of my research is to advance our understanding of the molecular and cellular mechanisms underlying cognition and cognitive disorders. Regulation of synaptic protein synthesis has emerged as a key control point in the consolidation of synaptic plasticity and memory. Recent evidence has implicated inappropriate or excessive synaptic protein synthesis in the pathogenesis of cognitive impairment and autism. For example, the gene products inactivated in tuberous sclerosis complex and fragile X syndrome function as translational repressors. We recently proposed that loss of the normal constraints on synaptic protein synthesis may promote abnormal synaptic connectivity, compromising the performance of neuronal networks mediating cognition, and leading to the development of cognitive impairment and autism. The broad, long-term goals of this application are to understand the role of translational repression by microRNAs in synaptic plasticity, synaptic connectivity and behaviors relevant to autism. MicroRNAs comprise a large family of endogenous 20-23 nucleotide noncoding RNAs that repress protein synthesis by binding to complementary sequences in target mRNAs. MicroRNAs have been implicated in brain development and neuronal survival, but little is known about their roles in synaptic processes or behavior. Intriguingly, the fragile X mental retardation protein (FMRP) interacts physically and genetically with the molecular machinery mediating translational repression by microRNAs. In addition, reduced microRNA expression has been associated with human autistic disorders. Based on these observations, we hypothesize that microRNAs regulate protein synthesis-dependent synaptic plasticity and memory, and that loss of microRNA-mediated translational repression may lead to excessive synaptic protein synthesis, altered synaptic connectivity and autistic behavioral phenotypes. We have recently generated conditional knockout mice in which microRNA expression is partially or completely inactivated in the postnatal forebrain. These microRNA-deficient mice appear grossly normal and display no evidence of neurodegeneration at 2-3 months of age. We propose to analyze these microRNA-deficient mice in parallel with FMRP-deficient mice for behavioral deficits relevant to autism (Aim 1), impairments in protein synthesis-dependent synaptic plasticity and memory (Aim 2), and abnormalities in synaptic connectivity (Aim 3). In the latter Aim, we propose a novel use of "Brainbow" mice to visualize the impact of loss of microRNA or FMRP expression on excitatory synaptic connections. Accomplishment of these Aims should offer new insights into microRNA function and autism pathogenesis. The proposed studies are complementary to and closely integrated with my NIMH-funded R01. The detailed career development plan includes key collaborations and acquisition of enhanced multidisciplinary research skills. The salary support provided by the K02 award will be instrumental in allowing me to focus on research and career development activities without excessive clinical responsibilities.
The proposed project has direct relevance to the brain mechanisms responsible for normal cognition and behavior as well as cognitive and behavioral disorders. The molecular pathways to be investigated have been implicated in the pathogenesis of autism and other mental disorders. Accomplishment of the proposed goals will increase our understanding of the molecular and synaptic defects responsible for these disorders, and possibly identify new therapeutic targets or strategies.