| The striatum is a critical way station for cortical information, as primary and associative inputs converge to coordinate motor behavior. The influence of glutamatergic input is dynamically manipulated by dopamine (DA), as the balance of these neurotransmitters shapes the postsynaptic response. Once either presynaptic glutamate release or DAergic tone is permanently altered, postsynaptic neurons must adjust their intrinsic excitabilities to reflect a new homeostatic set point.;Both Parkinson's disease (PD) and schizophrenia represent disrupted dopaminergic states. Whereas the loss of DA-producing cells in PD is causally linked to motor symptoms, excessive DA in schizophrenia has been hypothesized since the realization of dopaminergic antagonists as potent antipsychotic drugs. Similarly, in both conditions, the corticostriatal axis represents a locus of pathophysiology. The goal of this dissertation is to elucidate and compare the means by which neurons in the dorsal striatum adapt to dopamine withdrawal in a chronic model of PD and to longterm antipsychotic (i.e. dopamine antagonist) treatment. These alterations were investigated using: transcriptomic profiling of striatal neurons, in vitro slice electrophysiology to probe activity, and morphological reconstruction to examine remodeling of somatodendritic architecture.;50% of striatal projection neurons, termed medium spiny neurons (MSN), express the dopamine 2 receptor (D2 MSNs), while the remaining 50% show mutually exclusive expression of the dopamine 1 receptor (D 1 MSNs). Using whole-cell current clamp recording, it was found that D2 MSNs were more excitable. A relatively larger dendritic tree in D1 MSNs accompanied this physiological divergence. Simulations of this anatomical dichotomy suggested a significant parallel between anatomical and electrophysiological differences.;Striatal adaptations were remarkably similar in a PD model, a chronic 6-hydroxydopamine (6-OHDA) lesion, and following long-term treatment with haloperidol, a common antipsychotic therapy. In D1 and D2 MSNs, there were opposing changes in somatic excitability. In D 1 MSNs, an increase in excitability was largely explained by a reduction in dendritic surface area and thus decreased capacitative load. In D 2 MSNs, upregulation of an inwardly rectifying potassium conductance carried by Kir2 channels decreased somatic excitability. This decrease may counteract an apparent increase in presynaptic glutamate release, opposed by activity-dependent functional upregulation of retrograde endocannabinoid signaling. |
