Cited by 735Cannabis and Cannabinoid ResearchParkinson's Disease Mechanisms and TreatmentsNeuroscience and Neuropharmacology Research

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Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models

Kreitzer, Anatol C., Malenka, Robert C.·2007·Nature

DOI 10.1038/nature05506

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Abstract

The striatum is a major forebrain nucleus that integrates cortical and thalamic afferents and forms the input nucleus of the basal ganglia. Striatal projection neurons target the substantia nigra pars reticulata (direct pathway) or the lateral globus pallidus (indirect pathway). Imbalances between neural activity in these two pathways have been proposed to underlie the profound motor deficits observed in Parkinson's disease and Huntington's disease. However, little is known about differences in cellular and synaptic properties in these circuits. Indeed, current hypotheses suggest that these cells express similar forms of synaptic plasticity. Here we show that excitatory synapses onto indirect-pathway medium spiny neurons (MSNs) exhibit higher release probability and larger N-methyl-d-aspartate receptor currents than direct-pathway synapses. Moreover, indirect-pathway MSNs selectively express endocannabinoid-mediated long-term depression (eCB-LTD), which requires dopamine D2 receptor activation. In models of Parkinson's disease, indirect-pathway eCB-LTD is absent but is rescued by a D2 receptor agonist or inhibitors of endocannabinoid degradation. Administration of these drugs together in vivo reduces parkinsonian motor deficits, suggesting that endocannabinoid-mediated depression of indirect-pathway synapses has a critical role in the control of movement. These findings have implications for understanding the normal functions of the basal ganglia, and also suggest approaches for the development of therapeutic drugs for the treatment of striatal-based brain disorders.

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Authors: Kreitzer, A. C., & Malenka, R. C.
Affiliations: Stanford Medicine (US)
Corresponding author: Malenka, Robert C.
ORCID: Kreitzer, Anatol C.
Malenka, Robert C.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2007-02
Volume: 445
Issue: 7128
Pages: 643-647
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature05506
OpenAlex: W2003314029
Cited by: 735
References: 35
Citations by year: 2026: 12 · 2025: 21 · 2024: 21 · 2023: 17 · 2022: 17 · 2021: 34 · 2020: 28 · 2019: 41 · 2018: 41 · 2017: 45 · 2016: 37 · 2015: 34 · 2014: 37 · 2013: 31 · 2012: 47
FWCI: 44.31
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: striatum, indirect pathway, direct pathway, medium spiny neurons, dopamine D2 receptor, basal ganglia, motor impairment, synaptic plasticity, NMDA receptor currents, release probability, transgenic mouse model, therapeutic target, Huntington's disease, substantia nigra pars reticulata
MeSH terms: Animals, Benzamides, Carbamates, Disease Models, Animal, Dopamine, Mice, Transgenic, Morpholines, Naphthalenes, Neuronal Plasticity, Parkinson Disease, Piperidines, Psychomotor Performance, Pyrazoles, Reserpine, Synapses, Receptors, N-Methyl-D-Aspartate, Oxidopamine, Neostriatum, Receptors, Dopamine D2, Excitatory Postsynaptic Potentials, Long-Term Synaptic Depression, Receptor, Cannabinoid, CB1, Benzoxazines, Mice, Cannabinoid Receptor Modulators, Endocannabinoids, Dopamine D2 Receptor Antagonists, In Vitro Techniques

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Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models

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