Diana Pettit

     I am investigating neuron-neuron communication in the mammalian brain. Neuronal communication involves a complicated sequence of events from the release of transmitter by the presynaptic cell to the integration of synaptic signals by the postsynaptic cell. We are focusing on the response of the postsynaptic cell including the subcellular distribution, functional properties, and physiological role of postsynaptic dendritic neurotransmitter receptors on inhibitory and excitatory neurons. We use a number of methods to examine these properties including whole-cell voltage clamp recordings, local photolysis and imaging techniques.

     One of our current projects involves the study of inhibitory transmission. Hippocampal interneuron activity has been linked to the oscillatory synaptic output observed during cognitive tasks, sensory processing, and exploratory behavior. While interneuron firing at specific time points in the rhythmic cycles occurs during these oscillations, the mechanisms controlling interneuron firing remain unclear. We have found that synaptic kainate receptor-mediated (KAR) currents as small as 4 pA increase instantaneous firing frequency and reset the phase of spontaneously firing stratumoriens interneurons. While KAR currents are particularly effective at producing this phase reset, while AMPA receptor currents are relatively ineffective. The efficacy of KAR-mediated currents is probably due to their 4-fold longer decay. Given the small amplitude of the currents needed for this phase reset, coincident activation of only a few synapses would synchronize firing in groups of interneurons.
These data suggest that KARs are potent modulators of circuit behavior and their activation alters hippocampal interneuron output.

     We are also investigating NMDA receptor physiology. Activation of these receptors can result in both long and short-term plasticity, promote cell survival, initiate cell death, and is also critical for normal synaptogenesis during development. A number of studies suggest that the consequences of NMDAR activation can vary widely depending on receptor localization, temporal characteristics, and size of the signal. The focus of this study is the physiological role of extrasynaptic vs. synaptic NMDARs. Cultured neuron studies have suggested that NMDARs can exist as synaptic and extrasynaptic receptors which may be coupled to very different cellular processes, with calcium entry through extrasynaptic NMDARs activating cell death mechanisms and LTD rather than LTP. We have determined the ratio, developmental expression, and subunit composition of synaptic vs. extrasynaptic NMDARs. We have also examined the physiological parameter necessary to activate the extrasynaptic receptors and future experiments will examine their role in plasticity. These experiments will provide vital information about the basic processes underlying brain function and are a critical step in understanding how to treat the errors of transmission that occur in neurological disorders such as Alzheimer's and Parkinson's Disease.

Skeberdis, V.A., Chevaleyre, V., Lau, C.-Y.G., Goldberg, J.H., Pettit, D.L., Suadicani, S.O., Lin, Y., Bennett, M.V.L., Yuste, R., Castillo, P.E. and Zukin, R.S. (2006) Protein kinase A promotes LTP induction by increasing calcium permeability of NMDA receptors in dendritic spines. In press, Nature Neuroscience.

Yang, E.J., Harris, A.Z. and Pettit, D.L. (2006) Interneuron subtype-dependent kainate receptor distributions. In press Journal of Neurophysiology.

Yang, E.J., Harris, A.Z. and Pettit, D.L. (Submitted) Synaptic kainate currents reset interneuron firing phase.

Harris, A.Z. and Pettit, D.L. (In preparation) Extrasynaptic NMDA receptors, a moving target.

Pettit, D.L., Wang, S.S.-H., Gee, K.R. and Augustine, G.J. (1997) Chemical two-photon uncaging: A novel approach to mapping glutamate receptors. Neuron 19:465-471.

Pettit, D.L., Perlman, S., and Malinow, R. (1994) Potentiated transmission and prevention of further LTP by increased CaMKII activity in postsynaptic hippocampal slice neurons. Science 266:1881-1885.