Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

Ali, Farhan; Gerhard, Danielle M.; Sweasy, Katherine; Pothula, Santosh; Pittenger, Christopher; Duman, Ronald S.; Kwan, Alex C.

doi:10.1038/s41467-019-13809-8

Cited by 137 publications

(89 citation statements)

References 71 publications

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“…However, the measurable NM-DAR conductances within PV interneurons are relatively small in comparison to other MGE subtypes [12]. Additionally, NMDA signaling in non-PV interneuron subtypes drives robust dendritic inhibition in pyramidal neurons [114, 115]. Moreover, while NMDAR-ablation in Pvalb -Cre lines produces other behavioral deficits unrelated to the Sz-like phenotypes [30, 33], a developmental, but not adult-onset Grin1 -ablation in Ppp1r2 -Cre line [29] that targets a subset of PV interneurons among other subtypes [116], recapitulates core Sz-like phenotypes.…”

Section: Discussionmentioning

confidence: 99%

NMDAR-mediated transcriptional control of gene expression during the development of medial ganglionic eminence-derived interneurons

Mahadevan

Mitra²,

Zhang

et al. 2020

Preprint

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Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+ and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical and physiological properties. However, the molecular mechanisms regulating their diversity remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates subtype-specific transcriptional regulation of gene expression in MGE-derived interneurons, leading to altered subtype identities. Notably, MGE-specific conditional Grin1 loss results in a systemic downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders, particularly schizophrenia.Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders. 14

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Section: Discussionmentioning

confidence: 99%

NMDAR-mediated transcriptional control of gene expression during the development of medial ganglionic eminence-derived interneurons

Mahadevan

Mitra²,

Zhang

et al. 2020

Preprint

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“…Notably, ketamine rapidly decreases GABAergic synaptic transmission onto hippocampal CA1 pyramidal neurons (Widman and McMahon, 2018). Ketamine more effectively inhibits the NMDARs on GABAergic interneurons than those on pyramidal neurons, resulting in decreased firing of interneurons and subsequent bursting of pyramidal neurons (Homayoun and Moghaddam, 2007;Duman et al, 2016;Ali et al, 2020). These findings suggest that the rapid antidepressant effect of ketamine is attributable (either in full or in part) to the enhanced E/I ratio caused by disinhibition.…”

Section: Discussionmentioning

confidence: 97%

Altered GABAergic inhibition in CA1 pyramidal neurons modifies despair-like behavior in mice

Yoon

Chung

Song

et al. 2020

Preprint

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Despair is a core symptom of depressive disorders. However, little is known about the neural circuits mediating despair and how they are modified by antidepressants. Here we show that the balance between excitatory and inhibitory neurotransmission (E/I balance) in the hippocampus affects behavioral despair in mice. Reduced interneuron density, knockdown of Gabrg2 or DREADD-mediated suppression of interneuron activity resulted in disinhibition of CA1 neurons and anti-despair-like behaviors in mice. Conversely, pharmacological and chemogenetic potentiation of GABAergic transmission in CA1 neurons rapidly induced despair-like behaviors. Disinhibition induced by the GABAAR antagonist pentylenetetrazol produced transient antidepressant effects without BDNF elevation in the hippocampus, while ketamine exhibited rapid and sustained antidepressant effects, but the latter was sensitive to the TrkB receptor blocker ANA-12. These results suggest that rapid disinhibition and BDNFinduced long-lasting synaptic modification leads to enhanced E/I balance, which may contribute to acute and sustained behavioral effects of rapid-acting antidepressants.

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“…While ketamine impacts glutamatergic transmission directly in the HPC, these effects are indirect in the mPFC given that, here, ketamine acts directly on GABAergic transmission. Reports have implicated PFC GABAergic interneurons, specifically somatostatin-expressing (SST) interneurons, in controlling ketamine’s antidepressant effects (Fuchs et al, 2017 ; Ali et al, 2020 ; Gerhard et al, 2020 ). Within the PFC, SST interneurons act as a microcircuit to provide inhibitory control over glutamatergic excitatory pyramidal neurons (Kepecs and Fischell, 2014 ).…”

Section: Ketamine As a Potential Aud Treatment Optionmentioning

confidence: 99%

“…Furthermore, it has been shown that the disinhibition of PFC pyramidal neurons through knockdown of GABA A receptors on SST interneurons produced antidepressant and anxiolytic effects in mice, indicating that SST interneurons may be a prime target for antidepressant effects (Fuchs et al, 2017 ). A recent study used calcium (Ca 2+ ) imaging to show that ketamine inhibited SST interneurons in the mPFC, which led to the disinhibition of mPFC pyramidal neurons and enhanced glutamatergic transmission (Ali et al, 2020 ). Importantly, two reports have shown that ketamine’s effect on SST inhibition was through NMDAR antagonism since it was dependent upon the GluN2B subunit of the NMDAR (Ali et al, 2020 ; Gerhard et al, 2020 ).…”

Section: Ketamine As a Potential Aud Treatment Optionmentioning

confidence: 99%

Neural Mechanisms Underlying the Rewarding and Therapeutic Effects of Ketamine as a Treatment for Alcohol Use Disorder

Strong

Kabbaj

2020

Front. Behav. Neurosci.

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Alcohol use disorder (AUD) is the most prevalent substance use disorder and causes a significant global burden. Relapse rates remain incredibly high after decades of attempting to develop novel treatment options that have failed to produce increased rates of sobriety. Ketamine has emerged as a potential treatment for AUD following its success as a therapeutic agent for depression, demonstrated by several preclinical studies showing that acute administration reduced alcohol intake in rodents. As such, ketamine’s therapeutic effects for AUD are now being investigated in clinical trials with the hope of it being efficacious in prolonging sobriety from alcohol in humans (ClinicalTrials.gov, Identifier: NCT01558063). Importantly, ketamine’s antidepressant effects only last for about 1-week and because AUD is a lifelong disorder, repeated treatment regimens would be necessary to maintain sobriety. This raises questions regarding its safety for AUD treatment since ketamine itself has the potential for addiction. Therefore, this review aims to summarize the neuroadaptations related to alcohol’s addictive properties as well as ketamine’s therapeutic and addictive properties. To do this, the focus will be on reward-related brain regions such as the nucleus accumbens (NAc), dorsal striatum, prefrontal cortex (PFC), hippocampus, and ventral tegmental area (VTA) to understand how acute vs. chronic exposure will alter reward signaling over time. Additionally, evidence from these studies will be summarized in both male and female subjects. Accordingly, this review aims to address the safety of repeated ketamine infusions for the treatment of AUD. Although more work about the safety of ketamine to treat AUD is warranted, we hope this review sheds light on some answers about the safety of repeated ketamine infusions.

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Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

Cited by 137 publications

References 71 publications

NMDAR-mediated transcriptional control of gene expression during the development of medial ganglionic eminence-derived interneurons

NMDAR-mediated transcriptional control of gene expression during the development of medial ganglionic eminence-derived interneurons

Altered GABAergic inhibition in CA1 pyramidal neurons modifies despair-like behavior in mice

Neural Mechanisms Underlying the Rewarding and Therapeutic Effects of Ketamine as a Treatment for Alcohol Use Disorder

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