Fragile X syndrome is a common disorder with clear relevance to autism spectrum disorders (ASD). Recently, it was discovered that the protein underlying this syndrome, FMRP, plays important regulatory roles in neuronal translation of RNA into protein. This discovery has opened up tremendous opportunity to study related mechanisms that are likely to be associated with autism. One common, but poorly understood, mechanism of translational control involves endogenous small RNAs. Small RNAs, including microRNAs (miRNAs) are expressed during development and through adulthood and it is clear that they play important regulatory roles in neuronal function. The greatest variety of miRNAs are expressed in the nervous system, including the cortex and cerebellum, making it paramount to understand what role miRNAs play in normal neuronal function and disease. To date only two miRNA has been investigated in hippocampal neurons in vitro and these miRNA were found to regulate process outgrowth and synapse formation. Importantly, computational analyses of likely targets of their action indicate that numerous signaling pathways impacting neuronal function are regulated by miRNAs. Because cortical pyramidal and cerebellar Purkinje neurons are consistently affected in ASD, this project will use the power of mouse genetics to initially remove all miRNAs from cortical circuits and cerebellar Purkinje neurons after they have developed and ask what role miRNAs play in neuron survival, synaptic connectivity, and function. What this means for people with autism: This project investigates the potential involvement in autism of a newly discovered pathway that regulates brain function. By focusing on the molecular mechanisms of the disorder, targeted therapeutic strategies for intervention can be developed.