INVESTIGATION OF PROGRESSIVE BEHAVIORAL DEFICITS AND CIRCUIT DYSFUNCTION IN THE STRIATUM DURING GRADUAL DOPAMINE DEPLETION

Carnegie-Mellon University, Pittsburgh PA

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Abstract

? DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating movement disorder that results from the gradual loss of dopaminergic innervation of the striatum. Our goal is to study the synaptic function of circuits in the striatum under conditions of progressively decreasing levels of dopamine by utilizing a modified 6-hydroxydopamine animal model of PD. This modified model involves gradually depleting dopamine over 1-2 months, instead of the traditional 2-3 days. The focus of our investigation of synaptic function will be within the striatum, which acts as the main input nucleus of the basal ganglia. Activity within the striatum i modulated by dopamine, and thus, when dopamine is depleted; the striatum falls into a state of dysfunction. This causes an imbalance between the two output pathways of the striatum that have opposing effects on movement: output from the motor depressing `indirect' pathway is too strong, while output from the motor facilitating `direct' pathway is too weak. We know from previous studies of acutely dopamine depleted animals that optogenetically increasing direct pathway activity restores movement in a mouse model of PD, suggesting that circuit dysfunction in the striatum plays a causal role in the expression of motor deficits. However, we know very little about the progression of circuit dysfunction, or compensatory plasticity leading up to the appearance of motor impairments, an understanding that may be critical to halting disease progression before it becomes irreversible. Thus, the short-term objective of this proposal is to utilize a gradual depletion paradigm to study how neural circuits in the striatum, a primary state of brain dysfunction in PD, adapt to progressive dopamine loss. In Aim 1, we will determine how long-term depression at excitatory synapses changes as a function of progressive dopamine loss. These experiments will determine whether this loss of long-term depression correlates with the onset of motor symptoms. In Aim 2, we will evaluate the innervation of fast-spiking interneurons onto direct and indirect pathway medium spiny neurons as a function of progressive dopamine loss. Together we hope that these results will provide insights into the progression of synaptic dysfunction in the striatum during progressive dopamine and in turn, aid in correlating synaptic dysfunction to motor deficits in disease. The long-term goal is to be able to selectively target and intervene at a certain level of dopamine depletion to prevent further circuit dysfunction that would otherwise lead to more severe motor impairment in the progression of PD.