Differential excitability and modulation of striatal medium spiny neuron dendrites

The loss of striatal dopamine (DA) in Parkinson's disease (PD) models triggers a cell-type-specific reduction in the density of dendritic spines in D₂ receptor-expressing striatopallidal medium spiny neurons (D ₂ MSNs). How the intrinsic properties of MSN dendrites, where the vast majority of DA receptors are found, contribute to this adaptation is not clear. To address this question, two-photon laser scanning microscopy (2PLSM) was performed in patch-clamped mouse MSNs identified in striatal slices by expression of green fluorescent protein (eGFP) controlled by DA receptor promoters. These studies revealed that single backpropagating action potentials (bAPs) produced more reliable elevations in cytosolic Ca²⁺ concentration at distal dendritic locations in D₂ MSNs than at similar locations in D₁ receptor-expressing striatonigral MSNs (D₁ MSNs). In both cell types, the dendritic Ca²⁺ entry elicited by bAPs was enhanced by pharmacological blockade of Kv4, but not Kv1K⁺ channels. Local application of DA depressed dendritic bAP-evoked Ca²⁺ transients, whereas application of ACh increased these Ca²⁺ transients in D₂ MSNs, but not in D₁ MSNs. After DA depletion, bAP-evoked Ca²⁺ transients were enhanced in distal dendrites and spines in D₂ MSNs. Together, these results suggest that normally D₂ MSN dendrites are more excitable than those of D₁ MSNs and that DA depletion exaggerates this asymmetry, potentially contributing to adaptations in PD models.