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Synaptic Plasticity and Neuromodulation in the Basal Ganglia

  • Author(s): Javier, Robyn M.
  • Advisor(s): Nicoll, Roger
  • et al.
Abstract

The basal ganglia are a set of interconnected subcortical nuclei with critical roles in adaptive behavior and motor learning. Many mechanisms are in place to fine-tune neuronal activity and connectivity within this network - essential processes whose dysfunction is implicated in many disorders, including Parkinson's disease, Huntington's disease, and Tourette's syndrome. Despite tremendous effort to understand such mechanisms, important questions remain unanswered. In this dissertation, I seek to increase our understanding of how the basal ganglia can change in normal and pathophysiological states. Using whole-cell patch-clamp electrophysiology in acute brain slices, I explore mechanisms of synaptic plasticity and neuromodulation in two nuclei of the basal ganglia: the striatum (the input nucleus) and the substantia nigra pars reticulata (SNr, the output nucleus). I show that excitatory and inhibitory afferents to the SNr can be differentially modulated by dopamine and GABAB receptors. This neuromodulatory signaling alters the gain of synaptic inputs on both slow and rapid timescales. Moving upstream, I investigate striatal changes in the BACHD mouse model of Huntington's disease. Intrinsic neuronal properties in these mice are altered selectively in striatal projection neurons of the indirect pathway. Using a well-characterized protocol for inducing long-term depression (LTD) at corticostriatal synapses, I examine neuromodulatory control of synaptic plasticity under non-pathological conditions. I find that LTD is not altered in "patches," which lack markers of cholinergic transmission. In contrast, the 5-HT4 serotonin receptor is a critical regulator of LTD in the direct pathway. This is a novel form of dopamine-independent plasticity within the striatum and raises the possibility of pathway-specific manipulations involving serotonin signaling. Together the results presented in this dissertation demonstrate important principles of modulation at multiple levels within the basal ganglia.

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