Current Research and Scholarly Interests
What are the cellular and molecular mechanisms underlying synapse formation, stability, and elimination? This question is central to understanding both how the nervous system becomes wired during development, and how stable circuits, such as those thought to underlie the processes of learning and memory, are formed and maintained in the adult. To address these issues, our laboratory is studying synapse formation, stability and elimination at a variety of levels, e.g. from molecules to behavior. A major component of the lab is focused on the molecules that structurally define glutamatergic synapses, the major excitatory synapses of the nervous system. Here, we have used molecular strategies to identify and characterize many components of both the presynaptic active zone and the postsynaptic density. Our presynaptic studies are oriented towards a collection of active zone proteins, including Piccolo, Bassoon, RIM and Munc13, and their roles in active zone formation and function, with an emerging focus on molecular mechanisms of presynaptic forms of plasticity. Similarly, our work on postsynaptic proteins is focused on several classes of multidomain proteins, including PSD95/SAP90, SAP97, SAP102, ProSAP and SAPAPs, and their roles in assembling the postsynaptic density and establishing postsynaptic forms of plasticity via the directed trafficking of glutamate receptors. In addition to studying how these molecules are trafficked and recruited to nascent synapses, and their functional roles in synaptic plasticity, we are also examining mechanisms that determine their turnover and exchange rates within the synapse. We believe that these studies will be instrumental for understanding the development and function of neuronal circuits.
A new direction of the laboratory is to link changes in synaptic dynamics and plasticity to the cognitive deficits found in humans with genetic forms of mental retardation. Current efforts are directed towards understanding the root causes of cognitive impairment in individuals with Down syndrome. Here, we are employing mouse models of Down syndrome to address three questions. First, do neurons differentiate and form synaptic contacts at normal rates and numbers? Second, are there changes in the circuit properties of neuronal networks? Third, are there changes in neuronal excitability and if so, do these lead to changes in behavior and cognitive performance? Our studies reveal that neurons from these mice make synapses in normal numbers, but that their circuit properties are subtly altered. Of particular note, we find that the balance of excitation and inhibition in the brains of these mice is shifted such that there is too much inhibition. We are currently employing behavioral studies of these mice to examine if this is indeed the case and whether drugs that reduce inhibition lead to an increase in cognitive performance.