Dopamine regulates spine density in striatal projection neurons in a concentration-dependent manner

Abstract

Dopaminergic afferents innervate spiny projection neurons (SPNs) in the striatum, maintaining basal ganglia activity. The loss of striatal innervation is the hallmark of Parkinson's disease (PD), which is characterized by dopaminergic denervation. A lack of dopamine in the dorsal striatum induces plasticity changes in SPNs. However, PD-associated denervation is progressive, and how plasticity is modified in partially innervated areas is poorly understood. The most studied models of PD are based on the use of neurotoxins that induce an almost complete striatal denervation. To investigate the impact of partial dopamine (DA) innervation in striatal plasticity, we use a genetic model of PD, Aphakia (Ak) mice, whose striatum presents an increasing dorso-ventral gradient of dopamine innervation. We studied SPNs in three different areas (dorsal, middle and ventral, with low, moderate and high innervation by tyrosine hydroxylase TH-positive axons, respectively) using fast scan cyclic voltammetry, microiontophoresis, immunohistochemistry and patch clamp techniques. Our data show an increasing dorso-ventral gradient of extracellular DA levels, overlapping with the gradient of TH innervation. Interestingly, spine loss in both direct (d-SPN) and indirect SPNs (i-SPN) decreases from dorsal to ventral in the parkinsonian striatum of Ak mice, following the decrease in DA levels. However, their dendritic trees and the number of nodes are only reduced in the poorly innervated dorsal areas and remain unaltered in moderate and highly innervated areas. The firing rate of direct SPNs does not change in either moderate or highly innervated areas, but increases in poorly innervated areas. In contrast, action potential frequency of indirect SPNs does not change along the dorso-ventral innervation gradient. Our findings indicate that spine density in d-SPNs and i-SPNs varies in a dopamine concentration-dependent manner, indicating that both d- and i-SPN are similarly innervated by DA.