# NKCC1-KCC2 system modulation in rodent models relevant for psychiatric disorders

> **NIH NIH R56** · NORTHWESTERN UNIVERSITY · 2024 · $647,833

## Abstract

Summary
Excitation/inhibition imbalance is considered a major factor leading to cognitive impairment and social
interaction deficits in neurodevelopmental disorders (e.g. schizophrenia), yet the cellular mechanisms
underlying this imbalance are not fully established. Using subchronic phencyclidine (scPCP)-treated mice, a
pharmacological model of cognitive impairment associated with schizophrenia, we discovered that GABAA
function shifts from inhibitory to excitatory in pyramidal neurons of the medial prefrontal cortex of scPCP mice.
We further found that this shift is caused by the selective enhancement of the expression of the chloride
transporter NKCC1, and that NKCC1 antagonism using the NKKC1 inhibitor bumetanide completely restores
the GABAA current reversal potential to the control values. Importantly, we also showed that in-vivo treatment
with bumetanide (IP or local cortical infusion) rescues cognitive performance in scPCP mice. Our preliminary
data further validate these results, showing that bumetanide rescues cognitive performance in male 16p11.2
duplication mice, a genetic model relevant for schizophrenia. We hypothesize that depolarizing GABAA
signaling in the mPFC represents a convergent pathogenic mechanism causing impaired cognition across
multiple genetic models relevant to schizophrenia and that bumetanide treatment may be effective across all
these models. To test this hypothesis, we will take advantage of three etiologically different genetic mouse
models reflecting variable genetic risk for schizophrenia: a copy number variant model (16p11.2 duplication), a
rare variants model (TRIO+/-), and a common variant model (Cacna1C+/-). These models were developed to
mimic genetic conditions known to significantly increase the incidence of psychiatric disorders including
schizophrenia in humans and show numerous deficits in PFC-specific cognitive tasks such as working memory
and reversal learning. In Aim 1 we will use perforated patch recordings in acute cortical slices to determine the
reversal potential of the GABAA current in pyramidal cells of the mPFC, and quantitative in situ hybridization to
quantify expression of NKCC1 and KCC2 transcripts in mPFC from male and female mice. In Aim 2 we will use
behavioral assessment of wild-type mice in which mPFC NKCC1/KCC2 is increased using pharmacologic or
genetic tools to test the hypothesis that increased mPFC NKCC1/KCC2 is a condition sufficient to cause
cognitive impairment, even in the absence of other cellular dysfunctions. We will also the effects of this
manipulation on mPFC gene expression and morphology. Finally, in Aim 3, we will determine the behavioral
effects of NKCC1 inhibition in our three disease models. We will test the effects of acute and chronic treatment
with bumetanide, as well as of selective genetic alteration of the NKCC1/KCC2 ratio in the mPFC of these
mice, on several cognitive tests. We will also test the alternative hypothesis that bumetanide acts on glia rath...

## Key facts

- **NIH application ID:** 11114186
- **Project number:** 1R56MH135860-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** MARCO MARTINA
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $647,833
- **Award type:** 1
- **Project period:** 2024-07-20 → 2026-07-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11114186

## Citation

> US National Institutes of Health, RePORTER application 11114186, NKCC1-KCC2 system modulation in rodent models relevant for psychiatric disorders (1R56MH135860-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11114186. Licensed CC0.

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