Kainate Receptors Inhibit Glutamate Release Via Mobilization of Endocannabinoids in Striatal Direct Pathway Spiny Projection Neurons
Open accessAbstract
Kainate receptors are members of the glutamate receptor family that function by both generating ionotropic currents through an integral ion channel pore and coupling to downstream metabotropic signaling pathways. They are highly expressed in the striatum, yet their roles in regulating striatal synapses are not known. Using mice of both sexes, we demonstrate that GluK2-containing kainate receptors expressed in direct pathway spiny projection neurons (dSPNs) inhibit glutamate release at corticostriatal synapses in the dorsolateral striatum. This inhibition requires postsynaptic kainate-receptor-mediated mobilization of a retrograde endocannabinoid (eCB) signal and activation of presynaptic CB1 receptors. This pathway can be activated during repetitive 25 Hz trains of synaptic stimulation, causing short-term depression of corticostriatal synapses. This is the first study to demonstrate a role for kainate receptors in regulating eCB-mediated plasticity at the corticostriatal synapse and demonstrates an important role for these receptors in regulating basal ganglia circuits. SIGNIFICANCE STATEMENTTheGRIK2gene, encoding the GluK2 subunit of the kainate receptor, has been linked to several neuropsychiatric and neurodevelopmental disorders including obsessive compulsive disorder (OCD). Perseverative behaviors associated with OCD are known to result from pathophysiological changes in the striatum and kainate receptor knock-out mice have striatal-dependent phenotypes. However, the role of kainate receptors in striatal synapses is not known. We demonstrate that GluK2-containing kainate receptors regulate corticostriatal synapses by mobilizing endocannabinoids from direct pathway spiny projection neurons. Synaptic activation of GluK2 receptors during trains of synaptic input causes short-term synaptic depression, demonstrating a novel role for these receptors in regulating striatal circuits.
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At either presynaptic or postsynaptic location, kainate receptors can have metabotropic (G-protein coupled) actions to suppress or facilitate both glutamate or GABA release.
“At either location, they can have metabotropic (G-protein coupled) actions to suppress or facilitate both glutamate or GABA release (Contractor et al., 2011;Marshall et al., 2018).”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Marshall et al., 2018
Kainate receptors have been implicated in the mobilization of endocannabinoid signaling in distinct brain regions, as well as in the promotion of GABAergic signaling in the PVN.
“Kainate receptors have been implicated in the mobilization of endocannabinoid signaling in distinct brain regions, as well as in the promotion of GABAergic signaling in the PVN (Evanson and Herman, 2015;Lourenço et al., 2011;Marshall et al., 2018).”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Marshall et al., 2018
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- Authors
- Marshall, J. J., Xu, J., & Contractor, A.
- Affiliations
- Northwestern University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2018-03-14
- Volume
- 38
- Issue
- 16
- Pages
- 3901-3910
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5907053
- OpenAlex
- W2790677490
- Cited by
- 30
- References
- 71
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 9 · 2023: 2 · 2022: 1 · 2021: 8 · 2020: 2 · 2019: 1 · 2018: 1
- FWCI
- 1.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (F31MH099807, R01MH099114, K01MH094464)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- kainate receptors, GluK2, endocannabinoids, corticostriatal synapses, CB1 receptor, short-term synaptic depression, striatum, basal ganglia, synaptic plasticity, obsessive-compulsive disorder, perseveration
- MeSH terms
- GluK2 Kainate Receptor, Animals, Corpus Striatum, Female, Male, Mice, Inbred C57BL, Synaptic Transmission, Neuronal Plasticity, Neurons, Synapses, Kainic Acid Receptors, Glutamic Acid, Mice, Endocannabinoids
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