Regulation of Intrinsic Plasticity by CaMKII

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DESCRIPTION (provided by applicant): CaMKII plays an important role in learning and memory formation in Drosophila as well as in other animals. We have recently found that CaMKII alters the excitability of identified neurons in the third instar larval nervous system of Drosophila. We will study the mechanisms of this modulation and explore its possible role in neuronal plasticity. Genetic access to these identified neurons will allow mechanistic studies of intrinsic property modulation that have not been possible in other systems. Our specific aims are: 1) Determine the effects of genetic and pharmacological manipulation of CaMKII on the excitability and behavior of central neurons. We will look at the effects of CaMKII on firing properties such as threshold, spike amplitude, spike waveform and firing frequency. We will define the voltage-dependent currents that are modulated by short-term and long-term alteration of kinase activity. 2) Determine the cellular mechanisms of activity-dependent modulation of intrinsic properties. We have shown that activity can induce a long-lasting increase in neuronal excitability in Drosophila motor neurons. We will investigate this phenomenon to determine the roles of firing pattern, calcium influx and activity of the postsynaptic cell in induction. We will determine if activity can change the response of the neuron to its normal presynaptic partners. 3) Determine the signal transduction mechanisms of activity-dependent modulation of intrinsic properties. We will define the conductances that are modulated by this process and investigate the role of CaMKII using transgenes and drugs. These studies will provide insight into a fundamental mechanism of plasticity and define novel roles for CaMKII in the regulation of short-term and long-term changes in excitability. Understanding these pathways will advance our knowledge of the basic processes that shape behavior.