# Targeted Manipulation of KYNA in Mice by Genetic and Pharmacological Means:  Biochemical and Functional Effects

> **NIH NIH P50** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $467,615

## Abstract

Project Summary
Pathological events during early brain development are believed to hold the key to the emergence of
schizophrenia (SZ) in adulthood. Deficits in memory, attention and executive function, i.e. core domains of the
psychopathology of SZ, might be causally related to dysfunctional glutamatergic and nicotinergic transmission.
Kynurenine acid (KYNA), an astrocytic metabolite of the kynurenine pathway of tryptophan degradation, is an
endogenous inhibitor of ±7nACh and NMDA receptors in the brain and has been implicated in the pathology of
SZ. Studies using cerebrospinal fluid (CSF) or post-mortem brain tissue of patients with SZ suggest that an
excess of KYNA might play a causative role in the disease. As an endogenous antagonist at ±7nAChRs and
NMDARs, which are both critically involved in cognitive functions, increased KYNA levels in the brain might be
especially involved in the cognitive deficits that are seen in individuals with SZ. Importantly, a polymorphism in
the gene for kynurenine 3-monooxygenase (KMO), an enzyme involved in the regulation of KYNA
neosynthesis, has been associated with elevated KYNA levels and increased risk of developing SZ.
The connection between KYNA and SZ may have a developmental dimension as several of the risk factors
associated with SZ result in increased formation of kynurenine, the direct bioprecursor of KYNA. The
proposed project is based on recent studies showing that elevating brain KYNA in the last week of gestation
impaires cognitive functions in the adult offspring. In this context, we propose to build on the model by using
genetically modified mice, heterozygous for the Kmo gene, and increasing brain KYNA during the last week of
embryonic development. Making comparisons to wild-type controls, we will examine the impact of prolonged
exposure to kynurenine in a vulnerable animal that has reduced KMO enzymatic activity. The central
hypothesis of this proposal is that elevated KYNA during the prenatal development, produced from its
bioprecursor kynurenine, influences the development of the brain and, as a result, alters KP dynamics,
extracellular glutamate, modulates hippocampal-mediated cognitive behaviors, and interhemispheric
transmission in adulthood. It follows, and will be tested here, that inhibition of KYNA synthesis is a valuable
therapeutic strategy to combat cognitive deficits in SZ.

## Key facts

- **NIH application ID:** 10016394
- **Project number:** 5P50MH103222-07
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** ROBERT SCHWARCZ
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,615
- **Award type:** 5
- **Project period:** 2014-05-09 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10016394

## Citation

> US National Institutes of Health, RePORTER application 10016394, Targeted Manipulation of KYNA in Mice by Genetic and Pharmacological Means:  Biochemical and Functional Effects (5P50MH103222-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10016394. Licensed CC0.

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