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

45 Citations (Scopus)

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

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Corpus Striatum
Signal Transduction
Dopamine
Motor Activity
Glutamic Acid
Neuronal Plasticity
Dopamine and cAMP-Regulated Phosphoprotein 32
Neurons
Neurophysiology
Dopamine Receptors
Knockout Mice
Leucine
Synaptic Transmission
Neurodegenerative Diseases
Synapses
Parkinson Disease
Phosphotransferases
Mutation
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Beccano-Kelly, D. A., Volta, M., Lise, L. N., Paschall, S. A., Tatarnikov, I., Co, K., ... 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

LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory. / Beccano-Kelly, Dayne A.; Volta, Mattia; Lise, Lise N.; Paschall, Sarah A.; Tatarnikov, Igor; Co, Kimberley; Chou, Patrick; Cao, Li Ping; Bergeron, Sabrina; Mitchell, Emma; Han, Heather; Melrose, Heather L; Tapia, Lucia; Raymond, Lynn A.; Matthew, Matthew J.; Milnerwood, Austen J.

In: Human Molecular Genetics, Vol. 24, No. 5, 01.03.2015, p. 1336-1349.

Research output: Contribution to journalArticle

Beccano-Kelly, DA, Volta, M, Lise, LN, Paschall, SA, Tatarnikov, I, Co, K, Chou, P, Cao, LP, Bergeron, S, Mitchell, E, Han, H, Melrose, HL, Tapia, L, Raymond, LA, Matthew, MJ & Milnerwood, AJ 2015, 'LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory', Human Molecular Genetics, vol. 24, no. 5, pp. 1336-1349. https://doi.org/10.1093/hmg/ddu543
Beccano-Kelly, Dayne A. ; Volta, Mattia ; Lise, Lise N. ; Paschall, Sarah A. ; Tatarnikov, Igor ; Co, Kimberley ; Chou, Patrick ; Cao, Li Ping ; Bergeron, Sabrina ; Mitchell, Emma ; Han, Heather ; Melrose, Heather L ; Tapia, Lucia ; Raymond, Lynn A. ; Matthew, Matthew J. ; Milnerwood, Austen J. / LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 5. pp. 1336-1349.
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