# Elucidation of the Role of the Arginase Isoforms in Normal Neuronal Development and Function

> **NIH NIH R03** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $156,000

## Abstract

Project Summary/Abstract
The urea cycle is the major pathway for detoxification of ammonia in mammals. Arginase 1 deficiency is
thought to be the least common of the urea cycle disorders and results in hyperargininemia. In humans,
deficiency of this enzyme is characterized clinically by progressive mental impairment, spasticity, and growth
retardation, with only periodic episodes of hyperammonemia unlike the other urea cycle disorders where this is
much more common. In recent experiments, the Lipshutz Lab has found substantial anatomical, ultrastructural
and electrophysiological differences between knockout animals and wild type controls. Constitutive and global
arginase deficiency led to decreased intrinsic excitability, altered functional synaptic transmission, decreased
dendritic arborization and decreased synapse density. Some of these measures (but not all) were rescued by
hepatic gene therapy that controlled plasma arginine. In addition, and unexpectedly, heterozygotes showed
intermediate neuronal findings where plasma biochemistry is not different than arginase wildtype mice,
suggesting an intrinsic neuronal or cell autonomous role for neuronal arginase activity. These measurable
differences at the neuron, synapse, and circuit level have begun to elucidate the functional abnormalities in
arginase deficiency. This proposal will examine the hypothesis that arginase expression in the central nervous
system (CNS) plays an important role in the developing CNS. In addition to mapping arginase expressing
neurons in the brain, selective arginase 1 loss in neurons will be induced to assess whether this leads to
unique functional deficits. Preliminary data: The Lipshutz lab and collaborators have (amongst other findings):
1) constructed and characterized the arginase 1 knockout mouse; 2) demonstrated long-term survival and
rescue with recombinant adeno-associated viral vectors; 3) demonstrated that only low-level ureagenesis is
necessary for long-term survival; 4) shown that peripheral metabolism can result in control of circulating
plasma arginine; and 5) shown that loss of arginase gene expression results in abnormalities of intrinsic
excitability and the development of the dendritic arbor of neurons. In Aim 1, mapping of arginase-expressing
neurons in the brain will be performed using the tissue-clearing technology of CLARITY. In Aim 2, the
hypothesis that neuron-specific loss of arginase recapitulates the anatomical, electrophysiological, and
behavioral abnormalities seen in the constitutive knockout mouse will be tested. Successful completion of the
proposed studies will provide a greater molecular understanding of and the mechanism behind the alterations
in the brain, neurons, and synapses in arginase 1 deficiency and hyperargininemia.

## Key facts

- **NIH application ID:** 9871997
- **Project number:** 1R03NS114623-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Gerald S Lipshutz
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,000
- **Award type:** 1
- **Project period:** 2020-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9871997

## Citation

> US National Institutes of Health, RePORTER application 9871997, Elucidation of the Role of the Arginase Isoforms in Normal Neuronal Development and Function (1R03NS114623-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9871997. Licensed CC0.

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