Evoked responses to single pulse electrical stimulation demonstrate impaired striatal excitability in a rodent model of Parkinson’s disease

Abstract

Background: Sensorimotor beta oscillations are increased in Parkinson’s disease (PD) due to the alteration of dopaminergic transmission. This electrophysiological read-out is reported both in patients and in animal models such as the 6-OHDA rat model obtained with unilateral nigral injection of 6-hydroxydopamine (6-OHDA). Current treatments, based on dopaminergic replacement, transiently normalize this pathological beta activity and improve patients’ quality of life. Objectives: We wanted to assess in vivo whether the abnormal beta oscillations can be directly linked to the striato-cortical excitability of the sensorimotor system and whether it is modulated by the pharmacological manipulation of the dopaminergic system. Methods: In the unilateral 6-OHDA rat model and control animals, we used intra-striatal and intra-cortical single-pulse electrical stimulation (SPES) and concurrent local field potentials (LFP) recordings. In the two groups, we quantified basal cortico-striatal excitability from time-resolved spectral analyses of LFP evoked responses induced remotely by intracerebral stimulations. The temporal dependance of cortico-striatal excitability to dopaminergic transmission was further tested using electrophysiological recordings combined with levodopa injection. Results: LFP evoked responses after striatal stimulation showed a transient reduction of power in a large time-frequency domain in the 6-OHDA group compared to the sham group. This observation is specific to the striatum, as no significant difference was observed in cortical LFP evoked responses between the two groups, and corresponds to an impaired striatal excitability in the 6-OHDA group compared to the controls. This PD-specific effect was observed in the striatum at least during the first 3 months after the lesion. In addition, the striatum responses to SPES during a levodopa challenge showed a transient potentiation of the decrease of responsiveness in frequencies below 40 Hz. Conclusion: The spectral properties of striatal responses to SPES show high sensitivity to dopaminergic transmission in the unilateral 6-OHDA rat model. We thus propose that this approach could be used in preclinical models as a time-resolved biomarker of impaired dopaminergic transmission capable of monitoring progressive neurodegeneration and/or challenges to drug intake.