In humans with Parkinson's disease, and in monkeys treated with the neurotoxin MPTP, neurons in the subthalamic nucleus (STN) and globus pallidus external segment (GPe) exhibit correlated periodic firing not normally seen in these structures. This correlated rhythmic firing is strongly implicated in the pathogenesis of Parkinson's disease. A variety of experimental evidence and theoretical considerations suggest that the STN and GPe may generate rhythmic but not correlated firing patterns intrinsically when not subject to suppressing inputs from the cerebral cortex and striatum. The rhythmic activity arises largely from the intrinsic pacemaking of the neurons of the STN, and the correlation of inputs arise from synaptic connections between the STN and GPe, which interact with the pacemaker mechanism in the STN neurons. Although the cellular properties of STN and GPE neurons are entirely due to the interactions among ion channels which have been and continue to be studied in isolation, they do not allow an immediate prediction of the physiological properties of the cells under natural conditions, or their peculiar responses to synaptic input. We propose to make the connection between biophysical/molecular properties and cellular activity using mathematical modeling and computer simulation. Similarly the rhythmic activity seen in the intact network do not resemble those of isolated neurons, and this again offers an opportunity for a theoretical approach. This project proposes to use mathematical modeling and computer simulations to bridge the gap between biophysical information on ion channels (including their modulation after dopaminergic denervation) and cellular properties playing a key role in STN-GPe rhythmogenesis in Parkinsonism. Biophysical and cellular data from other projects in the program will be the principal source of new information on ion channel properties and modulation. Some aspects of the models will be tested directly within the project using whole cell recording and calcium imaging to reveal voltage and calcium dynamics in single neurons of the STN or GPe in slices. The results will reveal the dynamic properties of single neurons in the two structures that are critical in generating network rhythmic correlated firing in vivo.
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