Computational and Experimental Investigation into the Role of Calcium in Striatal Plasticity




Evans, Rebekah

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This dissertation presents a detailed computational model of a striatal medium spiny neuron and uses it to investigate post-synaptic calcium dynamics during carefully timed plasticity protocols. We measure the calcium through the NMDA receptor and use it as a predictor of long term potentiation (LTP) during spike timing dependent plasticity (STDP) protocols. We show that same timing intervals that result in high calcium elevations also result in LTP. The kinetics of the calcium influx through the NMDA receptor is altered by the GluN2 subunit it contains. Therefore, we modeled all for GluN2 subunits (GluN2A,B,C, and D) and ran simulations comparing the calcium peaks during a range of timing intervals. Simulations show that the available subunit controls the timing intervals that result in high calcium elevations in the model, and that induce LTP in slice experiments. We extend this work by including a sophisticated model of calcium diffusion, buffering, and pump extrusion. This more physiological model was used to simulate the cortico-striatal upstates that are seen in medium spiny neurons during sleep. There is a relationship between the amplitude of the calcium elevation in the dendrite and the timing of a single action potential during the upstate. We use this updated model to predict that calcium dependent inactivation (CDI) governs this relationship between calcium and action potential timing. Using voltage clamp experiments, we confirm that CDI does occur in striatal neurons. We further find that CDI changes with age and striatal region. Specifically, these experiments show that there is an increase in CDI at eye opening in the medial striatum. We also determine that L type calcium channels contribute to this increase in CDI. This dissertation presents the most sophisticated model of a medium spiny neuron to date, and presents the first experiments characterizing CDI in striatal neurons.



Striatal Plasticity