# Modulation of KCC2 activity and the postnatal development of synaptic inhibition

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2021 · $457,238

## Abstract

GABAA receptors are Cl– permeable ion channels that mediate hyperpolarizing fast synaptic inhibition in the adult
brain, while in immature developing neurons GABAA receptors depolarize and excite neurons. This shift in the
signaling of GABAA receptors is due to the postnatal increase in the activity of KCC2, the neuron-specific K+/Cl-
co-transporter. KCC2 is the major protein mechanism that allows neurons to pump Cl– out of the cell. In rodents
KCC2 expression is evident at birth and increases substantially during the critical periods of early brain
development between postnatal days 7 and 14. Deficits in KCC2 activity in humans lead to epilepsy, and are
strongly implicated in chronic pain and developmental disorders such as Fragile X and Rett syndromes.
Therefore, understanding the mechanisms by which neurons determine the proper postnatal increase of KCC2
activity and its maintenance in adults is clinically significant.
KCC2 function is dynamically controlled by signals within neurons that can rapidly and reversibly modify
its structure. Modification of KCC2's structure in one region increases its activity, while modification of KCC2's
structure in another region decreases its activity. Our overarching hypothesis is that the correct balance between
these opposing modifications contributes to the proper early postnatal development and adult maintenance of
synaptic inhibition in the brain. To address this issue we have created two new genetic tools that can prevent
the modification of KCC2's structure. Importantly, one of the genetic tools is the first of its kind to allow scientists
to increase the function of KCC2, and so our proposal constitutes the first test of the theory which states that
increasing KCC2 function can be utilized as a therapy. To date, no medications exist that can directly and rapidly
increase the function of KCC2. The aims of our proposal are threefold: 1) demonstrate that preventing the
modification of KCC2's structure is critical during early brain development; 2) examine the mechanisms by which
disease causing factors influence the structure of KCC2 both in immature and more mature neurons; and 3)
demonstrate that increasing the function of KCC2 can reduce the likelihood and severity of epileptic seizures.
 Our study will provide new insights on how KCC2 structure and function is controlled under normal
conditions and during disease states. This information may aid in the development of new and improved
treatments to alleviate the burdens of a range of neurological disorders.

## Key facts

- **NIH application ID:** 10224348
- **Project number:** 5R01NS101888-05
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Tarek Ziad Deeb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $457,238
- **Award type:** 5
- **Project period:** 2017-09-30 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224348

## Citation

> US National Institutes of Health, RePORTER application 10224348, Modulation of KCC2 activity and the postnatal development of synaptic inhibition (5R01NS101888-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10224348. Licensed CC0.

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