How neuronal circuitry arises in the brain during development is a central question in neuroscience. My research seeks to define the molecular mechanisms that govern development of connectivity in the mammalian brain. We have extensively probed the mechanisms of axon guidance and synaptogenesis in normal brain, and are keenly interested in identifying how defective functioning of neural genes perturb connectivity in neuropsychiatric disorders such as autism spectrum disorders (ASD) and schizophrenia. Our approach has been to create novel mouse genetic models designed to reveal how mutation of specific neural adhesion molecules (L1, Close Homolog of L1, NrCAM, and NCAM) perturb cortical connectivity leading to abnormal cortical circuits and behaviors. Notably, our studies of thalamocortical and retino-collicular development also demonstrated that neural cell adhesion molecule signaling plays a vital role in guiding axon populations to appropriate synaptic targets in the brain, essential for neurotransmission, sensory function, learning and memory.
Recently, polymorphisms in the NrCAM gene and its binding partner Ankyrin, an actin adaptor protein, have been linked to ASD. Using novel mouse models for NrCAM loss of function, we showed that NrCAM is vital for normal social behavior and controls connectivity in neural pathways of the prefrontal cortex, which controls executive functions. An exciting new finding is that NrCAM is a pivotal component of a receptor signaling complex for the repellent guidance cue Semaphorin3F. This complex regulates spine pruning of cortical pyramidal neurons, the principle excitatory neuron of the brain, during adolescence. We uncovered a mechanism of selective spine pruning in which distinct spines and synapses are pruned by either Sema3F and NrCAM, or Sema3B and Close Homolog of L1. We generated conditional mutant mouse lines to delete NrCAM or Ankyrin-2 from cortical pyramidal neurons. These genetic tools will be used to define cortical circuits that lead to behaviors such as working memory and sociability, which are impaired in neurodevelopmental diseases..
As a member of the Carolina Institute for Developmental Disabilities and UNC Neuroscience Center, I have productive collaborations with other scientific colleagues addressing neurodevelopmental mechanisms of connectivity with divergent technologies. Our studies probe the connectivity and function of neural circuits in mouse models with electrophysiologist Dr. Paul B. Manis, and use molecular modeling with Dr. Brenda Temple to define the structure of the Semaphorin receptor complexes and Ankyrin interactions. We also collaborate with Dr. Sheryl Moy, Director of the UNC Mouse Behavioral Core Facility, on studies of sociability, working memory, and other behaviors relevant to ASD and Schizophrenia.
I am a member of the UNC Neuroscience Center and Neurobiology Curriculum for Graduate Research. Association with the Neuroscience Center enables our lab to participate in the Neuroscience Mini-Series, weekly neuroscience seminars, and annual symposium. Students from the Neurobiology Curriculum and BBSP are invited to rotate in the lab.