Neuronal circuits underlie all human behaviors, thoughts, emotions and memories. Precise control of the migration of neural progenitors and the development of trillions of synapses is critical for accurate neuronal network formation and normal brain function. Defects in these developmental programs are associated with neurodevelopment and psychiatric disorders. Because CNS function depends on proper neuronal migration and complex synaptic connections, it is a highly tractable model system to analyze Rho-family GTPase signaling to the cytoskeleton that is directly relevant to human health. Our laboratory studies how actin signaling pathways are organized and how their disruption in mice can model multiple neurologic disorders, including intellectual disability, schizophrenia, and autism spectrum disorders. Our current projects involve mouse models of disorders based on mutations in actin signaling proteins, studies of synapse development downstream of Rho-family GTPases, and the development of cutting-edge proteomic approaches to unravel the spatial organization of neuronal signaling.
1) Organization and dynamics of protein interactions during synapse development and plasticity. We are using new proteomic approaches and single spine imaging to ask how molecular mechanisms of synapse formation and plasticity occur through modulation of the actin cytoskeleton.
2) The role of forebrain excitatory synaptic Arp2/3-dependent actin remodeling in Schizophrenia-related disorders. We are currently working to better understand how loss of Arp2/3 leads to progressive synaptic abnormalities that is associated with the development of cognitive, negative, and positive Schizophrenia-like behavioral abnormalities. We want to know the circuitries involved in these behaviors and why certain behavioral abnormalities cluster together in their temporal emergence.
3) Synaptic alterations downstream of the loss of FMRP relevant to Fragile-X syndrome. We have identified targets of the translational regulator FMRP that appear to be upregulated in mouse models of Fragile-X syndrome. We are now working to better understand their role in the pathogenesis of the syndrome.
4) Pathways upstream of Arp2/3 involved in neuronal migration and morphogenesis. Arp2/3 is activated by multiple upstream regulators, leading to the hypothesis that individual signaling pathways are optimized to integrate Arp2/3 activity for specific neural processes.