Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice.

Mattia Volta,Emma Mitchell,Matthew J Farrer,Sarah A Paschall,Chelsie A Kadgien,Igor Tatarnikov,Jaskaran Khinda,Naila Kuhlmann,Stefano Cataldi,Heather Melrose,Dayne A Beccano-Kelly,Jesse Fox,Austen J Milnerwood,Sarah E Macisaac,Sabrina Bergeron

doi:10.7554/elife.28377

Abstract

LRRK2 mutations produce end-stage Parkinson's disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2019S mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across a range of ages. Young GKI mice exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses. These phenomena decline with age, but are stable in littermates. In young GKI mice, dopamine transients are slower, independent of dopamine transporter (DAT), increasing the lifetime of extracellular dopamine. Slowing of dopamine transients is observed with age in littermates, suggesting premature ageing of dopamine synapses in GKI mice. Thus, GKI mice exhibit early, but declining, synaptic and behavioral phenotypes, making them amenable to investigation of early pathophysiological, and later parkinsonian-like, alterations. This model will prove valuable in efforts to develop neuroprotection for PD.

Highlights

Parkinson’s disease (PD) is clinically diagnosed when patients are presented with characteristic progressive motor symptoms, post-mortem detection of Lewy pathology and nigral cell loss are currently required for confirmation
We have previously demonstrated that sEPSCs in our coronal slice preparation are TTX-insensitive, and predominantly miniature EPSCs (Milnerwood et al, 2010); the possibility remains that an increase in basal G2019S mutant knock-in (GKI) event frequency is due to anomalous preservation of action potential-dependent release
We find that similar increases are observed in glutamate release onto striatal neurons in brain slices from young GKI animals, without changes in synapse number

Summary

Introduction

Parkinson’s disease (PD) is clinically diagnosed when patients are presented with characteristic progressive motor symptoms, post-mortem detection of Lewy pathology and nigral cell loss are currently required for confirmation. A recent study suggests nigral cell death may be as low as 0–10% 1–3 years from diagnosis, whereas dopamine functional markers such as tyrosine hydroxylase (TH) and dopamine transporter (DAT) are profoundly reduced at the earliest points assessed (Kordower et al, 2013). The rapid and near complete loss of dopamine functional markers at, or within a few years of, diagnosis argues that ongoing clinical deterioration over several years is due to loss of compensatory mechanisms and/or dysfunction of non-dopaminergic neurons. Motor symptoms respond well to current therapy (e.g., dopamine replacement by L-DOPA or deep brain stimulation; DBS), PD is a multisystem disorder with a host of L-DOPA

Methods

Results

Conclusion