Jan 16 2026

A research group led by Dr. Yusuke Nasu and Professor Miho Terunuma in the Division of Oral Biochemistry at Niigata University Graduate School of Medical and Dental Sciences identified that the expression level of glutamine synthetase (GS)¹, an enzyme that metabolizes the excitatory neurotransmitter glutamate², that are found substantially in astrocytes³ is controlled by ammonia, a metabolic product of amino acids. GS, which terminates excessive neural excitation in the brain, is found to be reduced in patients with epilepsy⁴ and Alzheimer's disease. Increased blood ammonia levels have also been reported in these patients, but the pathophysiological significance of GS reduction remained unclear. The research group found that GS expression in the brain is controlled by the Hippo signaling pathway⁵. When ammonia concentrations in the brain were elevated, the activation of the Hippo signaling pathway reduced GS expression, impaired glutamate and ammonia metabolic function, thus enabling these substances to exert neurotoxic effects. Because inhibiting the Hippo pathway restored GS expression and suppressed neuronal cell death, this mechanism may be led to the development of new treatment for neurological and psychiatric disorders involving elevated ammonia concentrations in the brain, such as epilepsy and Alzheimer's disease. Part of this research was conducted by two dentists Mamiko Imai and Nozomi Yokoyama while they were undergraduate students at Niigata University Faculty of Dentistry. This research was published online in the international academic journal Communications Biology on December 13, 2025.

Key points

• We demonstrated that elevated extracellular ammonia concentrations reduce GS expression in astrocytes and impaired metabolism of neurotoxin glutamate.
• We demonstrated that astrocytic GS expression is controlled by the transcriptional cofactor YAP⁶
• We demonstrated that elevated ammonia and glutamate concentrations in the brain activate the Hippo signaling pathway, suppress YAP nuclear translocation and inhibit GS synthesis.
• In an animal model of epilepsy, we found that the Hippo pathway inhibitor XMU-MP-1 restored GS expression in astrocytes and suppressed neuronal cell death after seizures.
• These research findings are expected to contribute to the development of novel treatment strategies for neurological and psychiatric disorders associated with elevated ammonia concentrations in the brain.

[Term explanations]

1. Glutamine synthetase (GS)
An enzyme specifically expressed in astrocytes that converts neurotoxic compounds ammonia and glutamate into harmless amino acids glutamine.

2. Glutamate
A major neurotransmitter that transmits neuronal excitation. Necessary for learning and memory formation, but excess glutamate can cause neuronal cell death.

3. Astrocytes
Star-shaped cells in the brain that support the functions and metabolism of neurons. They are the most abundant glial cells in the brain.

4. Epilepsy
A chronic brain disease caused by various factors. The prevalence is estimated to be around 0.5-1 percent of the population, with onset occurring at a wide range of ages from infancy to old age. Characterized by repeated seizures caused by excessive excitation of neurons.

5. Hippo signaling pathway
A signaling pathway that regulates cell growth and organ size. Acts as a brake to suppress excessive cell proliferation.

6. YAP (Yes-associated protein)
A transcriptional cofactor downstream of the Hippo signaling pathway that plays a role in regulating cell proliferation and survival.

Publication Details

Journal: Communications Biology
Title:Ammonia reduces glutamine synthetase expression in astrocytes via activation of Hippo-YAP signaling pathways
Authors:Yusuke Nasu, Sari Kishikawa, Mamiko Imai, Nozomi Yokoyama, Izumi Iida, Koichi Tabeta & Miho Terunuma
Doi: 10.1038/s42003-025-09191-5