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Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3?-dependent modulation of Kv4.2 channels.

ABSTRACT: Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3? (GSK3?) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3? activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3? in spike timing-dependent long-term potentiation (tLTP) in the chronic unpredictable mild stress (CUMS) mouse model of depression. To assess the specific role of GSK3? in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3?. In addition, we examined the role of the voltage-gated potassium Kv4.2 subunit, a molecular determinant of A-type K+ currents, as a potential downstream target of GSK3?. We found increased levels of active GSK3? and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3? knockdown. Furthermore, knockdown of GSK3? in the NAc ameliorated depressive-like behavior in CUMS mice. Electrophysiological, immunohistochemical, biochemical, and pharmacological experiments revealed that inhibition of the Kv4.2 channel through direct phosphorylation at Ser-616 mediated the GSK3?-dependent tLTP changes in CUMS mice. Our results identify GSK3? regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3?-Kv4.2 axis may be an attractive therapeutic target for MDD.

SUBMITTER: Aceto G

PROVIDER: S-EPMC7149226 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels.

Aceto Giuseppe G Colussi Claudia C Leone Lucia L Fusco Salvatore S Rinaudo Marco M Scala Federico F Green Thomas A TA Laezza Fernanda F D'Ascenzo Marcello M Grassi Claudio C

Proceedings of the National Academy of Sciences of the United States of America 20200324 14

Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc an ...[more]

PMID: 32209671

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Project description:BACKGROUND:Cannabis is the most widely used illicit drug, but knowledge of the neurological consequences of cannabis use is deficient. Two primary components of cannabis are ?9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We established a THC+CBD model of self-administration and reinstated drug seeking to determine if, similar to other addictive drugs, cannabis produces enduring synaptic changes in nucleus accumbens core (NAcore) thought to contribute vulnerability to drug reinstatement. METHODS:Sprague Dawley rats were trained to self-administer THC+CBD (n = 165) or were used as vehicle self-administering control animals (n = 24). Reinstatement was initiated by context, cues, drug priming, and stress (yohimbine injection). Enduring neuroadaptations produced by THC+CBD self-administration were assayed using four measures: dendritic spine morphology, long-term depression, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate ratios, and behavioral pharmacology. RESULTS:We described a novel rodent model of cannabis relapse involving intravenous THC+CBD self-administration and drug seeking induced by conditioned context, cues, and stress. Cued reinstatement of THC+CBD seeking depended on a sequence of events implicated in relapse to other addictive drugs, as reinstatement was prevented by daily treatment with N-acetylcysteine or acute intra-NAcore pretreatment with a neuronal nitric oxide synthase or matrix metalloprotease-9 inhibitor, all of which normalize impaired glutamate homeostasis. The capacity to induce N-methyl-D-aspartate long-term depression in NAcore medium spiny neurons was abolished and dendritic spine density was reduced, but alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate ratio was unaltered in THC+CBD-trained animals, akin to opioids, but not to psychostimulants. CONCLUSIONS:We report enduring consequences of THC+CBD use on critical relapse circuitry and synaptic physiology in NAcore following rat self-administration and provide the first report of cue- and stress-induced reinstatement with this model.

Dataset Information

Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3?-dependent modulation of Kv4.2 channels.

Publications

Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels.

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