Cargando…

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

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 G2...

Descripción completa

Detalles Bibliográficos
Autores principales: Volta, Mattia, Beccano-Kelly, Dayne A, Paschall, Sarah A, Cataldi, Stefano, MacIsaac, Sarah E, Kuhlmann, Naila, Kadgien, Chelsie A, Tatarnikov, Igor, Fox, Jesse, Khinda, Jaskaran, Mitchell, Emma, Bergeron, Sabrina, Melrose, Heather, Farrer, Matthew J, Milnerwood, Austen J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633343/
https://www.ncbi.nlm.nih.gov/pubmed/28930069
http://dx.doi.org/10.7554/eLife.28377
Descripción
Sumario: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.