This is an NIH Independent Scientist Award, which is designed to foster the development of outstanding scientists and enable them to expand their potential to make significant contributions to their field of research. The primary goal of this research is to advance understanding of the molecular and cellular mechanisms underlying cognition and cognitive disorders. Recent evidence has implicated inappropriate or excessive synaptic protein synthesis in the pathogenesis of cognitive impairment and autism. The broad, long-term goals of this project 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. 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, microRNAs may regulate protein synthesis-dependent synaptic plasticity and memory, and loss of microRNA-mediated translational repression may lead to excessive synaptic protein synthesis, altered synaptic connectivity and autistic behavioral phenotypes. Conditional knockout mice in which microRNA expression is partially or completely inactivated in the postnatal forebrain will be analyzed in parallel with FMRP-deficient mice for behavioral deficits relevant to autism, impairments in protein synthesis-dependent synaptic plasticity and memory, and abnormalities in synaptic connectivity. Accomplishment of the proposed goals will increase understanding of the molecular and synaptic defects responsible for these cognitive disorders and possibly identify new therapeutic targets or strategies.