Dopamine D2 receptor dependent and independent structural, intrinsic and synaptic adaptations in experimental...

The main motor symptoms of Parkinson's disease (PD) emerge following dopamine depletion in the dorsal striatum and are associated with structural and functional adaptations of striatal medium spiny neurons (MSN). Although the indirect pathway MSN (iMSN) selectively expresses dopamine D2 receptors (D2R), the contribution of D2R signaling to these adaptations remains incompletely understood. Here, we examined neuronal morphology, dendritic spine density, corticostriatal transmission, and intrinsic excitability in direct pathway MSN (dMSN) and iMSN from constitutive D2R knockout mice, with or without chronic nigrostriatal lesions induced by 6-hydroxydopamine. D2R ablation reduced dendritic length and complexity in both MSN subtypes, although the effects were markedly greater in iMSN. In iMSN, D2R ablation also reduced spine density and increased intrinsic excitability, reproducing well known effects of nigrostriatal lesions and largely occluding additional effects of dopamine denervation. In contrast, D2R ablation produced only modest changes in dMSN spine density and excitability and did not prevent the additional spine loss and hyperexcitability induced by 6-OHDA lesions. Basal corticostriatal transmission remained largely preserved after D2R ablation in either MSN subtype, except for a slower excitatory postsynaptic current decay in iMSN, which was not enhanced further by the dopamine depleting lesion. Remarkably, nigrostriatal lesions continued to depress corticostriatal excitatory postsynaptic currents in D2R-deficient mice, indicating that this synaptic adaptation does not require D2R signaling. Together, these findings identify D2R signaling as a major determinant of iMSN structural and intrinsic physiological integrity and demonstrate that global loss of D2R function reproduces many of the adaptations induced by dopamine depletion. More broadly, they indicate that dopamine depletion drives distinct forms of plasticity through separable D2R dependent and independent mechanisms, with depression of corticostriatal synaptic currents in iMSN arising independently of D2R signaling.