# Leucine as a Probe of Kynurenine-Induced Glutamate and Neural Circuit Dysfunction in Midlife Depression

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $687,736

## Abstract

Project Summary: Chronic inflammation and glutamate dysregulation are pathological processes that precede
and hasten brain aging and degeneration in major depression (MD). Herein, we propose the kynurenine (KYN)
pathway as a mediator of the association between inflammation and glutamate pathologies. Kynurenines are
neuroactive molecules that readily access the brain from the periphery via dedicated transporters known as
large neutral amino acid transporters (LAT-1) located in the blood-brain barrier. Once inside the brain, KYN is
converted by activated microglial cells into metabolites such as quinolinic acid (QA) and 3-hydroxykynurenine
(3HK). These downstream metabolites of KYN exert robust excitotoxicity (QA) and oxidative stress (3HK) and
ultimately can lead to neuronal dysfunction and death. Extensive preclinical data and our preliminary data
indicate that the production and transfer of kynurenines into the brain from peripheral tissues is substantially
increased by biological factors such as immune activation and aging. Preclinical data also indicate that
blockade of KYN influx into the brain via competitive blockade of LAT-1 by leucine (a higher affinity ligand)
abrogates depressive-like behavior induced by immune activation in rodents. Our preliminary data in humans
indicate that peripheral KYN drives KYN metabolites in the brain, leading to increased basal ganglia glutamate,
reduced coherence of local neuronal activity, decreased functional connectivity among brain regions, and
depressive behaviors, including anhedonia and psychomotor slowing. Based on these data, we propose a 6-
week challenge paradigm in which middle-aged MD patients with increased inflammation will be randomized to
either leucine or lysine (n= 75 total). In contrast to leucine, lysine does not inhibit the influx of KYN as it uses a
different set of transporters (cationic transporters) to access the brain. We will estimate glutamate and inositol
(astroglial marker) using magnetic resonance spectroscopy (MRS); and study the coherence of local brain
activity and functional connectivity in basal ganglia and dorsomedial prefrontal cortical (dmPFC) regions using
resting-state functional magnetic resonance imaging (fMRI) at baseline, 1 and 6-weeks of treatment. Using
standardized instruments, we will measure anhedonia and psychomotor slowing while sampling blood and
cerebrospinal fluid (6 weeks only) for inflammatory mediators and KYN metabolites. This study design will test
the hypotheses that a 6-week leucine challenge will decrease glutamate and inositol (Aim 1), improve local
activity coherence and functional connectivity in the basal ganglia and dmPFC (Aim 2), and reduce anhedonia
and psychomotor slowing (Aim 3). If supported, these aims will implicate KYN dysregulation as a key mediator
of the brain and behavioral changes induced by inflammation and aging in MD. Moreover, this proof-of-
mechanism proposal will identify KYN and its transporters in the BBB as key targets...

## Key facts

- **NIH application ID:** 10753154
- **Project number:** 1R01MH132059-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ebrahim Haroon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $687,736
- **Award type:** 1
- **Project period:** 2023-07-17 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10753154

## Citation

> US National Institutes of Health, RePORTER application 10753154, Leucine as a Probe of Kynurenine-Induced Glutamate and Neural Circuit Dysfunction in Midlife Depression (1R01MH132059-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10753154. Licensed CC0.

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