GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions

Gerhard, Danielle M.; Pothula, Santosh; Liu, Rong-Jian; Wu, Min; Li, Xiaoyuan; Girgenti, Matthew J.; Taylor, Seth R.; Duman, Catharine H.; Delpire, Eric; Picciotto, Marina R.; Wohleb, Eric S.; Duman, Ronald S.

doi:10.1172/jci130808

Cited by 224 publications

(158 citation statements)

References 62 publications

(91 reference statements)

Supporting

Mentioning

147

Contrasting

Order By: Relevance

“…A potential link between the acute calcium elevations and subsequent synaptic strengthening is supported by studies that have shown postsynaptic calcium influx to be required and sufficient to induce activity-dependent synaptic plasticity 56,57 . It agrees with the observation that the antidepressant effect is blunted if ketamine is administered while excitatory transmission is blocked 50,58 , and that manipulations of SST interneurons can tune depressive-like behaviors in rodents 21,26,59 . SST interneurons are also known to connect densely with pyramidal networks 60 and thereby regulate their correlated firing 61 , which may relate to a very recent observation that ketamine restores coordinated activity in prefrontal ensembles 52 .…”

Section: Discussionsupporting

confidence: 89%

See 1 more Smart Citation

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

et al. 2020

Self Cite

View full text Add to dashboard Cite

A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and sustained antidepressant effects. In prefrontal cortex, the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine act preferentially on GABAergic neurons. However, cortical interneurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine's actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine.

show abstract

Section: Discussionsupporting

confidence: 89%

“…This virus was confirmed to reduce GluN2B expression in a Cre-dependent manner in vitro (−42 ± 3% relative to controls; Supplementary Fig. 6) and to decrease NMDAR-mediated currents in brain slices 26 . Injected into Cg1/M2 of SST-IRES-Cre animals ( Fig.…”

Section: Resultsmentioning

confidence: 74%

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Other drugs have shown neurotrophic effects (71), such as ketamine for the treatment of depressive episodes (72). Recent studies have shown that the antidepressant action of ketamine is mediated by its activity on NMDA receptor of GABA neurons (73,74). Further studies will be needed to identify what could be the mechanism of action of GL-II-73 allowing this neurotrophic effect, and if it has shared pathways with ketamine.…”

Section: Discussionmentioning

confidence: 99%

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

Prevot

Sumitomo

Tomoda

et al. 2020

Preprint

View full text Add to dashboard Cite

Over the last 15 years, worldwide life expectancy increased by 5 years jumping from 66 years to 71 years.With progress in science, medicine, and care we tend to live longer. Such extended life expectancy is still associated with age-related changes, including in the brain. The aging brain goes through various changes that can be called morphomolecular senescence. Overall, the brain volume changes, neuronal activity is modified and plasticity of the cells diminishes, sometimes leading to neuronal atrophy and death.Altogether, these changes contribute to the emergence of cognitive decline that still does not have an efficient treatment available. Many studies in the context of cognitive decline focused on pathological aging, targeting β-amyloid in Alzheimer's disease, for example. However, β-amyloid plaques are also present in healthy adults and treatments targeting plaques have failed to improve cognitive functions. In order to improve the quality of life of aging population, it is crucial to focus on the development of novel therapies targeting different systems altered during aging, such as the GABAergic system. In previous studies, it has been shown that positive allosteric modulators (PAM) acting at the α5-containing GABA-A receptors improve cognitive performances, and that these α5-GABA-A receptors are implicated in dendritic growth of pyramidal neurons. Here, we hypothesized that targeting the α5-GABA-A receptors could contribute to the reduction of cognitive decline, directly through activity of the receptors, and indirectly by increasing neuronal morphology. Using primary neuronal culture and chronic treatment in mice, we demonstrated that an α5-PAM increased dendritic length, spine count and spine density in brain regions involved in cognitive processes (prefrontal cortex and hippocampus). We also confirmed the procognitive efficacy of the α5-PAM and showed that the washout period diminishes the precognitive effects without altering the effect on neuronal morphology. Future studies will be needed to investigate what downstream mechanisms responsible for the neurotrophic effect of the α5-PAM.

show abstract

“…There is extensive evidence that stress disrupts the structural integrity of specific GABAergic interneurons and this also affects the functioning of hippocampal GABAergic networks [28][29][30][31]. Preclinical data has shown that hippocampal PV or SST interneurons are vulnerable to psychosocial stressors, thus PV and SST deficits are frequently observed pathological features in depression and other neurological disorders with mood disturbances [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Parvabumin interneuron-mediated hippocampal network activity disruption in a two-hit model with relevance to postintensive care syndrome: prevention by fluoxetine

Ji¹,

Tong²,

Zhou³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Postintensive care syndrome (PICS) is defined as a new or worsening impairment in cognition, mental health, and physical function after critical illness, which is associated with reduced quality of life and increased mortality. We recently have developed a clinically relevant animal model of PICS, which can mimic most features of human PICS. However, the underlying mechanism remains largely to be elucidated. Accumulating evidence has suggested that hippocampal GABAergic interneuron dysfunction is implicated in various mood disorders induced by stress. Methods We explored the role of hippocampal GABAergic interneurons and relevant neural activities in an animal model of PICS based on two-hit hypothesis. In addition, we tested whether fluoxetine treatment early following combined stress can prevent subsequent anatomical and behavioral pathologies. Results Here our study further supported our previous findings that this PICS model displayed reproducible anxiety- and depression like behavior and cognitive impairments, which resembles clinical features of human PICS. This behavioral state is accompanied by hippocampal neuroinflammation, reduced parvalbumin (PV) expression, and decreased theta and gamma power. Importantly, chronic fluoxetine treatment reversed most of these abnormities. Conclusions Our study provides additional evidence that PV interneuron-mediated hippocampal network activity disruption might play a key role in the pathological of PICS, while fluoxetine offers protection via modulation of the hippocampal PV interneuron and relevant network activities.

show abstract

GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions

Cited by 224 publications

References 62 publications

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

Parvabumin interneuron-mediated hippocampal network activity disruption in a two-hit model with relevance to postintensive care syndrome: prevention by fluoxetine

Contact Info

Product

Resources

About