A computational study of regional variations in the excitability of midbrain dopamine neurons that have differential vulnerability in Parkinson's disease
Anderson, Eric R.
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In Parkinson's disease (PD), dopaminergic (DA) neurons of the substantia nigra (SN) often degenerate years before those of the ventral tegmental area (VTA). The DA neurons in VTA and SN diverge both in their intrinsic biophysical features and in their embeddings within forebrain circuits. Improved PD therapies may depend on a deeper understanding of the implications of these intrinsic features and embeddings. This thesis surveyed intrinsic characteristics of the least and most vulnerable DA subpopulations. To evaluate how differences may effect neural excitability and signal integration, two computational models of the biophysical mechanisms and types of inputs that characterize these classes of DA neurons were developed, simulated, and compared. The two multi-compartment models were constructed using the NEURON simulator. An SN model was built by extending a prior model of DA neurons. The new model includes 20 ionic currents and receives synaptic input from simulated spike trains via glutamatergic and GABAergic receptors. Then a VTA model was built by modifying features of the SN model, in accord with published data. These mathematical models enabled simulations of current injection experiments and arbitrary synaptic input patterns. With realistic inputs, previously reported differences between VTA and SN, in firing rate and bursting, emerged in the simulations. Neurodegeneration research suggests that persistent elevated calcium levels can induce excitotoxic cell death. Beyond excessive calcium influx through NMDA-type glutamatergic receptors, a constellation of factors, including calcium-binding proteins and release of calcium from intracellular stores, may contribute to prolonged increases of calcium. To assess complex emergent interactions, the models included explicit representations of several such factors. The simulations revealed that the higher expression of calcium mechanisms in the SN model, together with higher autoinhibition, via somatodendritic DA release and type-two DA-receptor-induced activation of potassium channels, result in lower SN excitability, relative to the VTA. The SN model generates stronger pacemaking and a higher effective threshold for excitatory inputs to generate bursting. Such differences in electrophysiological properties covary with other factors, such as energy demands and mitochondria levels, and further extensions to these models will enable weighing their roles in the differential vulnerabilities of DA neurons.
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