Dataset Information

Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum.

ABSTRACT: Endocannabinoids are important mediators of short- and long-term synaptic plasticity, but the mechanisms of endocannabinoid release have not been studied extensively outside the hippocampus and cerebellum. Here, we examined the mechanisms of endocannabinoid-mediated long-term depression (eCB-LTD) in the dorsal striatum, a brain region critical for motor control and reinforcement learning. Unlike other cell types, strong depolarization of medium spiny neurons was not sufficient to yield detectable endocannabinoid release. However, when paired with postsynaptic depolarization sufficient to activate L-type calcium channels, activation of postsynaptic metabotropic glutamate receptors (mGluRs), either by high-frequency tetanic stimulation or an agonist, induced eCB-LTD. Pairing bursts of afferent stimulation with brief subthreshold membrane depolarizations that mimicked down-state to up-state transitions also induced eCB-LTD, which not only required activation of mGluRs and L-type calcium channels but also was bidirectionally modulated by dopamine D2 receptors. Consistent with network models, these results demonstrate that dopamine regulates the induction of a Hebbian form of long-term synaptic plasticity in the striatum. However, this gating of plasticity by dopamine is accomplished via an unexpected mechanism involving the regulation of mGluR-dependent endocannabinoid release.

SUBMITTER: Kreitzer AC

PROVIDER: S-EPMC6725809 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum.

Kreitzer Anatol C AC Malenka Robert C RC

The Journal of neuroscience : the official journal of the Society for Neuroscience 20051101 45

Endocannabinoids are important mediators of short- and long-term synaptic plasticity, but the mechanisms of endocannabinoid release have not been studied extensively outside the hippocampus and cerebellum. Here, we examined the mechanisms of endocannabinoid-mediated long-term depression (eCB-LTD) in the dorsal striatum, a brain region critical for motor control and reinforcement learning. Unlike other cell types, strong depolarization of medium spiny neurons was not sufficient to yield detectabl ...[more]

PMID: 16280591

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Project description:Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the dorsolateral striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias toward use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu2) is a Gi/o-coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu2 function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu2 function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a 2-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the striatum to assess CIE effects on mGlu2-mediated synaptic plasticity. We report that CIE differentially disrupts mGlu2-mediated long-term depression in the DLS vs. dorsomedial striatum (DMS). Interestingly, CIE-induced impairment of mGlu2-LTD in the dorsolateral striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu2 fully rescues mGlu2-LTD. In contrast to the 2-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE exposure fails to disrupt mGlu2-LTD. We did not observe a reduction of mGlu2 mRNA or protein levels following CIE exposure, suggesting that alcohol effects on mGlu2 occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu2 activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.

Dataset Information

Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum.

Publications

Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum.

Similar Datasets

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