# Deciphering the Roles of Kainate Receptors in Developing CNS Circuits

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $517,155

## Abstract

SUMMARY
Kainate receptor signaling is required for the appropriate development of the central nervous system. Children
with de novo loss-of-function or missense mutations exhibit intellectual disability and other severe
developmental phenotypes. Why this occurs is unknown, in part because we do not have a clear
understanding of how aberrant kainate receptor function disrupts neural development. The objectives of this
project are to (i) gain insight into normal neurodevelopmental roles played by kainate receptors and (ii) to
determine the nature of circuit and behavioral disruptions when kainate receptor signaling is aberrant or
completely lost in mouse models. We will pursue these objectives using comparative studies in mice that
model known genetic variants causative for human disorders. These include a new mouse line generated in
the Swanson laboratory, GluK2(A657T), that models a human de novo missense mutation in the Grik2 gene
that causes intellectual disability (ID) and ataxia, as well as mice which model Grik2 haploinsufficiency which is
associated with developmental delay and ID in human populations. The Contractor, Swanson and Savas
laboratories will use these mice to test the hypotheses that kainate receptors establish an appropriate balance
between excitation and inhibition in developing hippocampal circuits, are required for correct development of
synapses, and regulate intrinsic excitability in the CNS. In the first Specific Aim, we will determine how
missense or loss-of-function mutations in Grik2 alter synaptic connectivity, function, morphology and
expression of the synaptic and non-synaptic proteome in brain regions associated with altered behaviors. In
the second Specific Aim, we determine how intrinsic excitability is altered in kainate receptor mutant mice. In
the third Specific Aim, we will carry out behavioral studies on kainate receptor mutant mice to determine the
expanse of cognitive, social, habitual, and motor dysfunction, which will also inform the physiological studies in
Aims 1 and 2. We anticipate these studies will reveal some of the underlying circuit disruptions that give rise to
human cognitive and motor phenotypes. We therefore aim to develop a comprehensive and integrated
understanding of the importance of kainate receptor signaling to establishment of appropriate neuronal function
in the CNS and establish how aberrant signaling leads to maladaptive development and behaviors in mice that
are correlates of the core symptoms of human developmental disorders.

## Key facts

- **NIH application ID:** 10146497
- **Project number:** 5R01NS105502-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Anis Contractor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $517,155
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146497

## Citation

> US National Institutes of Health, RePORTER application 10146497, Deciphering the Roles of Kainate Receptors in Developing CNS Circuits (5R01NS105502-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10146497. Licensed CC0.

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