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

Beccano-Kelly, Dayne A., Volta, Mattia, Munsie, 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., Farrer, Matthew J., Milnerwood, Austen J.·2015·Human Molecular Genetics
DOI 10.1093/hmg/ddu543
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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 show altered 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.

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  • Multiple studies point to a role for LRRK2 at the presynaptic terminal where it plays a role in release of dopamine from striato-nigral neurons, and glutamate from corticostriatal neurons.

    “Multiple studies point to a role for LRRK2 at the presynaptic terminal where it plays a role in release of dopamine from striato-nigral neurons, and glutamate from corticostriatal neurons [5, 6, 11, 50, 86, 92, 95].”

    From Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain (2023) · cites this paper as [6]

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Metadata

Authors
Beccano-Kelly, D. A., Volta, M., Munsie, 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., Farrer, M. J., & Milnerwood, A. J.
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2014-10-24
Volume
24
Issue
5
Pages
1336-1349
ISSN
  • 0964-6906
  • 1460-2083
DOI
10.1093/hmg/ddu543
Cited by
91
References
2
Language
en

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