Upregulation of D2-class signaling in dopamine-denervated striatum is in part mediated by D3 receptors acting on CaV2.1 channels via PIP2 depletion

The loss of dopaminergic neurons in the substantia nigra compacta followed by striatal dopamine depletion is a hallmark of Parkinson's disease. After dopamine depletion, dopaminergic D2 receptor (D2R)-class supersensitivity develops in striatal neurons. The supersensitivity results in an enhanced modulation of Ca2+ currents by D2R-class receptors. However, the relative contribution of D2R, D3R, and D4R types to the supersensitivity, as well as the mechanisms involved, have not been elucidated. In this study, whole cell voltage-clamp recordings were performed to study Ca2+ current modulation in acutely dissociated striatal neurons obtained from rodents with unilateral 6-hydroxydopamine lesions in the substantia nigra compacta. Selective antagonists for D2R, D3R, and D4R types were used to identify whether the modulation by one of these receptors experiences a selective change after dopaminergic denervation. It was found that D3R-mediated modulation was particularly enhanced. Increased modulation targeted CaV2.1 (P/Q) Ca2+ channels via the depletion of phosphatidylinositol 4,5-bisphosphate, an intracellular signaling cascade hard to detect in control neurons and hypothesized as being amplified by dopamine depletion. An imbalance in the striatal expression of D3R and its splice variant, D3nf, accompanied enhanced D3R activity. Because CaV2.1 Ca2+ channels mediate synaptic GABA release from the terminals of striatal neurons, reinforcement of their inhibition by D3R may explain in part the profound decrease in synaptic strength in the connections among striatal projection neurons observed in the dopamine-depleted striatum.