Objective: To determine if chemogenetic and pharmacological modulation of pedunculopontine nucleus (PPN) cholinergic neurons can alter L-DOPA-induced dyskinesia and gait deficits in hemi-parkinsonian rats.

Background: PPN cholinergic neurons are implicated in PD gait dysfunction and akinesia (1). Recent evidence shows that cholinergic signaling may mediate L-DOPA-induced dyskinesia (LID) and that this could be regulated by targeting mAChR M4R (2).

Method: All rats were rendered hemi-parkinsonian by unilateral 6-OHDA infusion. In experiment 1, ChAT-cre+ Long-Evans rats were transfected with PPN-infused pAAV8 containing excitatory (hM3dq), inhibitory (hM4di), or control (mCherry) DREADDs viral vectors for selective modulation of Ach PPN neurons. Rats in experiment 1 received the DREADD ligand Compound 21 (C21; 0, 5 mg/kg) to determine chemogenetic effects onmotor parameters. Thereafter, L-DOPA was then administered daily for 2 weeks to elicit stable LID. Thereafter, in experiment 1, rats received C21 30 min before L-DOPA to examine effects on treatment-induced improvements and LID. In experiment 2, wild-type Long-Evans rats received unilateral PPN cannulae. After establishment of baseline deficits and LID, PPN microinfusions of the M4R positive allosteric modulator VU0467154 (0, 1, 10 µg/µL) were given before L-DOPA. In both experiments, after L-DOPA, dyskinesia was tested for 3h, and gait testing and motor efficacy were assayed at the 30- and 60-min time points, respectively. At study end, lesion efficacy (TH-ir or HPLC), successful transfection (measured by PPN ChAT and mCherry co-expression), and cannula placement were verified.

Results: Uniformly, 6-OHDA lesion and L-DOPA treatment led to motor deficits and LID development. Chemogenetic stimulation of PPN cholinergic neurons off L-DOPA can improve movement while increasing LID severity. Inhibition can worsen motor performance but reduce LID severity.Coupled with findings that in VU0467154 can dose-dependently reduce LID without affecting L-DOPA efficacy suggests a unique role for PPN in PD treatment.

Conclusion: PPN cholinergic neurons are a promising target for improving motor symptoms and LID. Moreover, positive allosteric modulators of M4R may reduce LID partially through PPN actions.

References: 1. Bohnen et al. 2009 PMID: 19917989 2. Shen et al. 2015 PMID: 26590347

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MDS Abstracts - https://www.mdsabstracts.org/abstract/contribution-of-pedunculopontine-nucleus-cholinergic-neurons-to-l-dopa-induced-dyskinesia-and-pd-motor-deficits-in-hemi-parkinsonian-rats/