Structural-functional properties of direct-pathway striatal neurons at early and chronic stages of dopamine denervation

Abstract

The dendritic arbour of striatal projection neurons (SPNs) is the primary anatomical site where dopamine and glutamate inputs to the basal ganglia functionally interact to control movement. These dendritic arbourisations undergo atrophic changes in Parkinson's disease. A reduction in the dendritic complexity of SPNs is found also in animal models with severe striatal dopamine denervation. Using 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle as a model, we set out to compare morphological and electrophysiological properties of SPNs at an early versus a chronic stage of dopaminergic degeneration. Ex vivo recordings were performed in transgenic mice where SPNs forming the direct pathway (dSPNs) express a fluorescent reporter protein. At both the time points studied (5 and 28 days following 6-OHDA lesion), there was a complete loss of dopaminergic fibres through the dorsolateral striatum. A reduction in dSPN dendritic complexity and spine density was manifest at 28, but not 5 days post-lesion. At the late time point, dSPN also exhibited a marked increase in intrinsic excitability (reduced rheobase current, increased input resistance, more evoked action potentials in response to depolarising currents), which was not present at 5 days. The increase in neuronal excitability was accompanied by a marked reduction in inward-rectifying potassium (Kir) currents (which dampen the SPN response to depolarising stimuli). Our results show that dSPNs undergo delayed coordinate changes in dendritic morphology, intrinsic excitability and Kir conductance following dopamine denervation. These changes are predicted to interfere with the dSPN capacity to produce a normal movement-related output.

Keywords: animal models; basal ganglia; medium spiny neurons; movement disorders; parkinsonism; plasticity.