Synaptic Dysfunction in Cognitive Disorders
Normal cognitive function requires excitatory synaptic transmission. Malfunction of these synapses is associated with mental retardation, autism, Alzheimer's disease, and hearing loss. My research goal is to define molecular mechanisms, in vivo, that direct the assembly and function of excitatory synapses. Work in my lab has identified the only protein known to target nicotinic receptors to neuronal synapses. We have identified the adenomatous polyposis coli protein (APC) as a key synapse organizer that is essential for coordinating presynaptic and postsynaptic maturation in vertebrate peripheral neurons. We are currently testing our model that APC is a key organizer of nicotinic and glutamatergic synapses in the brain. Our newly generated transgenic mouse model with targeted depletion of APC in excitatory neurons shows changes in synaptic protein levels, function and plasticity that are indicative of cognitive impairment.
Figure 1. Abnormal architecture of the hippocampus of the APC conditional knock out mouse (right panel) as compared to that of control littermate (left panel).
Synapse Re-formation on Regenerated Auditory Sensory Hair Cells
In another new project, we are identifying molecular mechanisms that direct nicotinic synapse assembly in developing and regenerating sensory hair cells of the inner ear. Our goal is to define new therapeutic approaches to enhance hearing restoration in deafened mammals.
Figure 2. Regeneration of sensory hair cells of the inner ear following noise overexposure.
Overall, our data are providing novel insights into molecular interactions that direct synaptic maturation and function in the vertebrate nervous system.