The cellular and synaptic mechanisms of parkinsonism and levodopa-induced dyskinesia
Parkinson’s disease (PD) is a neurodegenerative disease, in which the progressive loss of dopamine neurons is associated with prominent motor deficits, including a loss of voluntary movement. Although the mechanisms underlying PD are poorly understood, these motor deficits can be effectively treated pharmacologically through dopamine replacement therapy with the dopamine precursor, levodopa. However, while levodopa is highly effective, the majority of patients develop motor complications, including levodopa-induced dyskinesia (LID) after 5-10 years of treatment. The excessive, involuntary movements observed in LID, which are triggered by levodopa administration, limit its therapeutic use. In Chapter 1, I will discuss prominent theories and experimental evidence suggesting aberrant activity of neurons in the striatum, the primary input nucleus of the basal ganglia, plays a crucial role in the abnormal movements seen in both PD and LID. This will be focused on the two main cell-types in the striatum, whose activity is thought to underlie the generation and coordination of movement in health and disease: the direct and indirect pathway medium spiny neurons (dMSNs and iMSNs, respectively). However, the precise cellular and circuit mechanisms of striatal dysfunction in PD and LID, or how aberrant striatal activity relates to behavioral dysfunction, are poorly understood. To gain a better understanding of these circuit mechanisms, in Chapter 2, I use a mouse model of PD and LID combined with in vivo electrophysiological recordings of dMSNs and iMSNs. Using this approach, I identified the changes in striatal physiology that correlate with the abnormal movements seen in parkinsonism and LID. In particular, this work converges on a distinct subpopulation of dMSNs with aberrant levodopa-evoked activity. In Chapter 3, I investigate how the differential regulation of the intrinsic and synaptic properties of these LID-associated dMSNs shape their response to levodopa, using synaptic tracing, combined with in vivo and ex vivo electrophysiology experiments. Together, these studies elucidate the cellular and circuit dysfunction that arises following chronic changes in dopamine and shed light on how the heterogeneous properties of direct pathway neurons in LID contribute to the differential therapeutic and dyskinetic effects of levodopa.