Arline J. & Curtis F. Garvin Professor of Medicine Emerita
Professor Emerita of Neurosciences
Distinguished University Professor
Department of Neurosciences
Case Western Reserve University
School of Medicine, Room E643
We are interested in understanding how genetically encoded molecular signals and the environment interact to form complex neural circuits during embryonic and postnatal development. We focus on the spinal motor circuits in birds and mammals that enable normal movement and locomotion and on elucidating mechanisms of motor axon pathfinding, synapse formation, the assembly of locomotor circuits, and the role of electrical activity (environmentally or self-generated) in these processes. We believe that mechanisms used during development to assemble circuits in the brain and spinal cord will be relevant to strategies for restoring neural circuits damaged by disease or injury. Techniques range from molecular-genetic and cell culture to electrical and optical recording from intact neural circuits and using optogenetics to activate neural circuits in-vivo by light. Current efforts are focused on two projects:
1) Role of spontaneous electrical activity in neural circuit formation. Rhythmic waves of propagating electrical activity are widespread in the developing nervous systems of birds and mammals. By altering such activity in intact chick embryos via the light activated channel, ChR2, we showed that motor axon pathfinding was highly sensitive to the precise frequency of activity, and that motoneuron pathfinding errors caused by slowing activity with drugs, could be rescued by driving activity at the normal frequency with light. Thus modest alterations in activity caused by maternally taken drugs or by various neurological disorders may cause defects in neural circuit formation. We are interested in defining the downstream signaling pathways activated by such activity, including transients of cAMP, using a light activated adenylyl cyclase BPAC.
2) Role of different isoforms of NCAM in formation and maturation of neuromuscular junctions. While NMJs form in NCAM deficient mice, they exhibit multiple structural and functional defects. By dynamically imaging synapse formation in cultures of NCAM deficient motoneurons and myotubes which exogenously express single isoforms of NCAM in motoneurons or myotubes, we found that certain isoforms of NCAM are required either pre- and post-synaptically for stable synapse formation. We are currently studying the cellular and molecular mechanisms by which NCAM enables motor axons to firdt be attracted to myotubes and to then transform their motile growth cones into stable synapses. Alterations in synapse formation, maturation, and stabilization contribute to a number of neurological disorders, including spinal muscular atrophy or SMA.