Optostimulation of striatonigral terminals in substantia nigra induces dyskinesia that increases after L‐DOPA in a mouse model of Parkinson's disease

Abstract

Background and Purpose L‐DOPA‐induced dyskinesia (LID) remains a major complication of L‐DOPA therapy in Parkinson's disease. LID is believed to result from inhibition of substantia nigra reticulata (SNr) neurons by GABAergic striatal projection neurons that become supersensitive to dopamine receptor stimulation after severe nigrostriatal degeneration. Here, we asked if stimulation of direct medium spiny neuron (dMSN) GABAergic terminals at the SNr can produce a full dyskinetic state similar to that induced by L‐DOPA. Experimental Approach Adult C57BL6 mice were lesioned with 6‐hydroxydopamine in the medial forebrain bundle. Channel rhodopsin was expressed in striatonigral terminals by ipsilateral striatal injection of adeno‐associated viral particles under the CaMKII promoter. Optic fibres were implanted on the ipsilateral SNr. Optical stimulation was performed before and 24 hr after three daily doses of L‐DOPA at subthreshold and suprathreshold dyskinetic doses. We also examined the combined effect of light stimulation and an acute L‐DOPA challenge. Key Results Optostimulation of striatonigral terminals inhibited SNr neurons and induced all dyskinesia subtypes (optostimulation‐induced dyskinesia [OID]) in 6‐hydroxydopamine animals, but not in sham‐lesioned animals. Additionally, chronic L‐DOPA administration sensitised dyskinetic responses to striatonigral terminal optostimulation, as OIDs were more severe 24 hr after L‐DOPA administration. Furthermore, L‐DOPA combined with light stimulation did not result in higher dyskinesia scores than OID alone, suggesting that optostimulation has a masking effect on LID. Conclusion and Implications This work suggests that striatonigral inhibition of basal ganglia output (SNr) is a decisive mechanism mediating LID and identifies the SNr as a target for managing LID.

The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease

“…Previous work showed that this distinct pattern of sensorimotor-dominant gene regulation after L-DOPA treatment is not specific for dynorphin, but extends to other genes as well, for example, the transcription factors dFosB and JunB [ 32 , 73 ], the serotonin receptor 5-HT1B ([ 33 ]; present study), and other genes [ 74 , 75 ]. These findings thus highlight the close association between abnormal signaling in dMSNs of the sensorimotor striatum and dyskinesia, in general [ 76 , 77 , 78 , 79 ].…”

Interneuron NMDA Receptor Ablation Induces Hippocampus-Prefrontal Cortex Functional Hypoconnectivity after Adolescence in a Mouse Model of Schizophrenia

“…These mice were injected with adeno-associated virus (AAV) particles 13-14 weeks before experiments. An AAV vector tagged with enhanced yellow fluorescent protein (eYFP) and expressing channel rhodopsin (ChR2) under the CaMKII promoter (AAV-CaMKIIa-hChR2(H134R)-EYFP, Therapy Center Vector Core, University of North Carolina) was injected into either the left or right vHP under deep surgical anesthesia (1% isoflurane) as described previously (Keifman et al, 2019). Briefly, animals were mounted on a stereotaxic frame (Kopf Instruments), and two 0.5 ml injections of AAV (2.46 Â 10 13 viral particles per ml) at 0.1 ml/min were performed at the following coordinates: 3.3 mm posterior to bregma, 3.3 and 3.2 mm lateral from midline, and 3.2 and 2.7 mm below cortex surface.…”

Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

“…Mechanisms underlying l-DOPA induced dyskinesia. Alterations in D1R signalling play a central role in the development of LID, which is causally dependent on D1R activation and signalling [45][46][47][48] . In animal models of PD based on dopamine depletion, D1R signalling becomes more responsive to agonist stimulation, resulting in increased activation of PKA and ERK1/2.…”

“…Longterm treatment with l-DOPA in PD patients frequently leads to the emergence of acute l-DOPA-induced dyskinesia (LID), a debilitating adverse drug effect characterized by abnormal involuntary movements 41,42 . In animal models of PD, dyskinesia can also be induced by D1R agonists 43,44 or optogenetic activation of dMSNs [45][46][47] and the development of LID is dependent on D1R activation 48 and signalling through PKA and ERK1/2 49,50 .…”