LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory

Dayne A. Beccano-Kelly, Mattia Volta, Lise N. Lise, Sarah A. Paschall, Igor Tatarnikov, Kimberley Co, Patrick Chou, Li Ping Cao, Sabrina Bergeron, Emma Mitchell, Heather Han, Heather L. Melrose, Lucia Tapia, Lynn A. Raymond, Matthew J. Matthew, Austen J. Milnerwood

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Mutations in leucine-rich repeat kinase 2 (Lrrk2) are the most common genetic cause of Parkinson's disease (PD), a neurodegenerative disorder affecting 1-2% of those >65 years old. The neurophysiology of LRRK2 remains largely elusive, although protein loss suggests a role in glutamatergic synapse transmission and overexpression studies showaltered dopamine release in aged mice. We show that glutamate transmission is unaltered onto striatal projection neurons (SPNs) of adult LRRK2 knockout mice and that adult animals exhibit no detectable cognitive or motor deficits. Basal synaptic transmission is also unaltered in SPNs of LRRK2 overexpressing mice, but they do exhibit clear alterations to D2-receptor-mediated short-term synaptic plasticity, behavioral hypoactivity and impaired recognition memory. These phenomena are associated with decreased striatal dopamine tone and abnormal dopamine-and cAMP-regulated phosphoprotein 32 kDa signal integration. The data suggest that LRRK2 acts at the nexus of dopamine and glutamate signaling in the adult striatum, where it regulates dopamine levels, presynaptic glutamate release via D2-dependent synaptic plasticity and dopamine-receptor signal transduction.

Original languageEnglish (US)
Pages (from-to)1336-1349
Number of pages14
JournalHuman molecular genetics
Volume24
Issue number5
DOIs
StatePublished - Mar 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory'. Together they form a unique fingerprint.

  • Cite this

    Beccano-Kelly, D. A., Volta, M., Lise, L. N., Paschall, S. A., Tatarnikov, I., Co, K., Chou, P., Cao, L. P., Bergeron, S., Mitchell, E., Han, H., Melrose, H. L., Tapia, L., Raymond, L. A., Matthew, M. J., & Milnerwood, A. J. (2015). LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory. Human molecular genetics, 24(5), 1336-1349. https://doi.org/10.1093/hmg/ddu543