Retrograde endocannabinoid signaling in the cerebellar cortex

Safo, Patrick; Cravatt, Benjamin F.; Regehr, Wade G.

doi:10.1080/14734220600791477

Cited by 70 publications

(63 citation statements)

References 84 publications

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“…On the contrary, the amplitude of EPSCs evoked by stimulation of the CF-PC synapse was reduced and the paired-pulse depression was enhanced in PTEN-KO mice, suggesting a presynaptic mechanism (Hashimoto and Kano, 1998). At this synapse, presynaptic changes induced by postsynaptic signals have been described both during development (Bosman and Konnerth, 2009) and in the adult (Safo et al, 2006). Since CFs exert a powerful tonic inhibition on PCs (Montarolo et al, 1982), a weaker CF input and a stronger PF synapse have additive effects, resulting in a greatly enhanced excitatory drive.…”

Section: Pc Functional Alterationsmentioning

confidence: 99%

Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice

Cupolillo

Hoxha

Faralli

et al. 2015

Neuropsychopharmacol

137

107

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Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impaired social interaction, isolated areas of interest, and insistence on sameness. Mutations in Phosphatase and tensin homolog missing on chromosome 10 (PTEN) have been reported in individuals with ASDs. Recent evidence highlights a crucial role of the cerebellum in the etiopathogenesis of ASDs. In the present study we analyzed the specific contribution of cerebellar Purkinje cell (PC) PTEN loss to these disorders. Using the Cre-loxP recombination system, we generated conditional knockout mice in which PTEN inactivation was induced specifically in PCs. We investigated PC morphology and physiology as well as sociability, repetitive behavior, motor learning, and cognitive inflexibility of adult PC PTEN-mutant mice. Loss of PTEN in PCs results in autistic-like traits, including impaired sociability, repetitive behavior and deficits in motor learning. Mutant PCs appear hypertrophic and show structural abnormalities in dendrites and axons, decreased excitability, disrupted parallel fiber and climbing fiber synapses and late-onset cell death. Our results unveil new roles of PTEN in PC function and provide the first evidence of a link between the loss of PTEN in PCs and the genesis of ASD-like traits.

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Section: Pc Functional Alterationsmentioning

confidence: 99%

Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice

Cupolillo

Hoxha

Faralli

et al. 2015

Neuropsychopharmacol

137

107

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“…CB 1 R knock-out mice have deficits in delay eye-blink conditioning, which is a form of learning known to rely on cerebellar circuits (Kishimoto and Kano, 2006). One possible explanation is that endocannabinoids are required for long-term depression in the cerebellar cortex (Safo et al, 2006). However, climbing fibers convey the activity from the IO to the cerebellar cortex and play a crucial role in cerebellar learning (Raymond et al, 1996;Thompson, 2005).…”

Section: Synaptic Modulation In the Iomentioning

confidence: 99%

Serotonin Evokes Endocannabinoid Release and Retrogradely Suppresses Excitatory Synapses

Best

Regehr²

2008

Journal of Neuroscience

101

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5-HT 2 -type serotonin receptors (5-HT 2 Rs) are widely expressed throughout the brain and mediate many of the modulatory effects of serotonin. It has been thought that postsynaptic 5-HT 2 Rs act primarily by depolarizing neurons and thereby increasing their excitability. However, it is also known that 5-HT 2 Rs are coupled to G q/11 -type G-proteins and that some other types of G q/11 -coupled receptors can regulate synapses by evoking endocannabinoid release and activating presynaptic cannabinoid-type 1 receptors (CB 1 Rs). Here, we examine whether activation of 5-HT 2 Rs can regulate synapses through such a mechanism by studying excitatory synapses onto cells in the inferior olive (IO). These cells express 5-HT 2 Rs on their soma and dendrites, and the IO receives extensive serotonergic input. We find that the excitatory synaptic inputs onto IO cells are strongly suppressed by serotonin receptor agonists as well as release of endogenous serotonin. Both 5-HT 2 Rs and 5-HT 1B Rs contribute to this modulation by decreasing the probability of glutamate release from presynaptic boutons. The suppression by 5-HT 2 Rs is of particular interest because it is prevented by CB 1 R antagonists, and 5-HT 2 Rs are thought to be located only postsynaptically on IO cells. Our results indicate that serotonin activates 5-HT 2 Rs on IO neurons, thereby releasing endocannabinoids that act retrogradely to suppress glutamate release by activating presynaptic CB 1 Rs. These findings establish a link between serotonin signaling and endocannabinoid signaling. Based on the extensive distribution of 5-HT 2 Rs and CB 1 Rs, it seems likely that this mechanism could mediate many of the actions of 5-HT 2 Rs throughout the brain.

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“…Thus, this form of LTD first requires the retrograde transmission of endocannabinoids from the Purkinje neuron back to presynaptic terminals and then the anterograde travel of a messenger from the presynaptic terminal to the Purkinje neuron from the expression of LTD. It has been speculated the nitric oxide might be the anterograde messenger (Safo et al, 2006). This form of LTD has been suggested to be involved in certain forms of cerebellar learning (Kishimoto andKano, 2006, Skosnik et al, 2007).…”

Section: Endocannabinoid-mediated Cerebellar Ltdmentioning

confidence: 99%

Signaling via CNS cannabinoid receptors

Mackie

2008

Molecular and Cellular Endocrinology

106

102

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Because of the prominent psychoactive effects of cannabis and its preparations, much research has focused on the actions of cannabinoids, the primary psychoactive components of cannabis, on neuronal function. A convergence of research has identified (1) cannabinoid receptors, (2) endogenous compounds that activate these receptors (endocannabinoids), and (3) drugs that interact with these receptors and the proteins that synthesize and degrade the endocannabinoids. This review will first consider how endogenous cannabinoids signal through cannabinoid receptors and the various forms of synaptic plasticity mediated by endocannabinoids. Next the interactions between exogenous cannabinoids such as Δ 9 -tetrahydrocannabinol and endocannabinoids and endocannabinoid-mediated plasticity will be examined. Finally, a model will be presented that can explain the prominent psychoactivity of these plant-derived cannabinoids.

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Retrograde endocannabinoid signaling in the cerebellar cortex

Cited by 70 publications

References 84 publications

Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice

Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice

Serotonin Evokes Endocannabinoid Release and Retrogradely Suppresses Excitatory Synapses

Signaling via CNS cannabinoid receptors

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