# Role of GABA Interneurons in the Rapid Antidepressant Actions of NMDA Receptor Blockade

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $477,728

## Abstract

Major depressive disorder (MDD) is one of the most prevalent and debilitating illnesses world wide, affecting
~17 percent of the population and causing enormous personal and economic burden. The impact of MDD is
underscored by the limitations of currently available medications, including low response rates, treatment
resistant patients, and time-lag (weeks-months). These data highlight a major unmet need for more efficacious
and faster-acting antidepressant agents. Recent studies demonstrate that a single low dose of ketamine, a
glutamate-NMDA receptor antagonist, produces rapid antidepressant actions (2 hr) that last for up to 7 days in
treatment resistant patients. This rapid action, by a mechanism completely different from typical monoamine
reuptake inhibitors, represents one of the most significant advances in the field of depression over the past 6
decades. We have reported that ketamine causes a rapid increase of synaptic connections in the medial
prefrontal cortex (mPFC), which targets and corrects the synaptic deficits caused by chronic stress and
depression. Despite this progress, the cellular mechanisms underlying the synaptic actions of ketamine, and
increased glutamate transmission have not been determined. We hypothesize that the initial trigger for the
rapid actions of ketamine is blockade of NMDA receptors that stimulate tonic firing of GABA interneurons,
resulting in disinhibition of glutamate transmission and increased synapse formation in mPFC. Alternatively,
ketamine could act directly on pyramidal neurons. This application describes an integrated multidisciplinary
approach, including molecular, biochemical, electrophysiological, morphological, and behavioral studies to test
this disinhibition hypothesis. Aim 1 will use cell type specific knockdown of NMDA receptors on GABA
interneuron subtypes as well as pyramidal neurons in the mPFC. Based on pharmacological evidence, the
GluN2B subunit will be targeted using viral expression of floxed-GluN2B shRNA and cell specific Cre
recombinase transgenic lines. Preliminary results indicate that the rapid behavioral actions of ketamine are
blocked by GluN2B knockdown on GABA interneurons, consistent with the disinhibition hypothesis. Aim 2 will
extend these studies by characterizing NMDA/GluN2B receptor regulation of somatostatin (SST) and
parvalbumin (PV) interneuron subtypes by patch recordings in reporter mice to identify the cellular basis for
differences in NMDA and ketamine sensitivity of these interneurons. The influence of ketamine on inhibitory
plasticity will also be determined, and the role of GABA interneuron subtypes in the actions of ketamine will be
tested using cell specific optogenetic approaches. Stress and depression are reported to alter GABA
neurotransmission with greater effects in women than men. Aim 3 will use reporter mice to determine the role
of GABA interneuron subtypes in the effects of chronic stress and ovarian steroids, including molecular,
cellular, and tr...

## Key facts

- **NIH application ID:** 10246314
- **Project number:** 5R01MH093897-10
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** RALPH J DILEONE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $477,728
- **Award type:** 5
- **Project period:** 2011-03-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246314

## Citation

> US National Institutes of Health, RePORTER application 10246314, Role of GABA Interneurons in the Rapid Antidepressant Actions of NMDA Receptor Blockade (5R01MH093897-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246314. Licensed CC0.

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