Lentivector‐mediated delivery of GDNF protects complex motor functions relevant to human Parkinsonism in a rat lesion model

TLDR

Viral vector–mediated delivery of GDNF shows promise as a neuroprotective strategy for Parkinson’s disease, but its effect on complex motor functions has not yet been demonstrated. The study aimed to determine whether lentiviral GDNF delivery protects complex motor behaviours in a rat Parkinsonism model. This was evaluated using an operant nose‑poke task in Lister Hooded rats, with lentiviral GDNF injected into the striatum and substantia nigra before 6‑OHDA lesioning. Unilateral 6‑OHDA lesions impaired trial attempts, increased errors, induced ipsilateral bias, reduced contralateral accuracy, slowed contralateral reactions and bilateral movements, yet EIAV‑GDNF pre‑treatment significantly improved all these metrics and rescued deficits in corridor, staircase, stepping, cylinder tasks and prevented rotational asymmetry, confirming GDNF’s protective effect on both complex and simple behaviours and supporting EIAV vectors for PD therapy.

Abstract

Abstract Although viral vector‐mediated delivery of glial cell‐line derived neurotrophic factor (GDNF) to the brain has considerable potential as a neuroprotective strategy in Parkinson's disease (PD), its ability to protect complex motor functions relevant to the human condition has yet to be established. In this study, we used an operant task that assesses the selection, initiation and execution of lateralized nose‐pokes in Lister Hooded rats to assess the efficacy with which complex behaviours are protected against neurotoxic lesions by prior injection of a lentiviral vector expressing GDNF. Unilateral injection of 6‐hydroxydopamine (6‐OHDA) into the medial forebrain bundle (MFB) caused rats to attempt fewer trials and to make more procedural errors. Lesioned rats also developed a pronounced ipsilateral bias, with a corresponding drop in contralateral accuracy. They were also slower to react to contralateral stimuli and to execute movements bilaterally. Rats that were pre‐treated 4 weeks prior to lesion surgery with an equine infectious anaemia virus (EIAV) vector carrying GDNF [EIAV‐GDNF, injected into the striatum and above the substantia nigra (SN)] performed significantly better on all of these parameters than control rats. In addition to the operant task, EIAV‐GDNF successfully rescued contralateral impairments in the corridor, staircase, stepping and cylinder tasks, and prevented drug‐induced rotational asymmetry. This study confirms that GDNF can protect against 6‐OHDA‐induced impairments in complex as well as simple behaviours, and reinforces the use of EIAV‐based vectors for the treatment of PD.