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Cited by 135Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersAmino Acid Enzymes and Metabolism

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders

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Nicosia, Noemi, Giovenzana, Mattia, Misztak, Paulina, Mingardi, Jessica, Musazzi, Laura·2024·International Journal of Molecular Sciences
DOI 10.3390/ijms25126521PMC PMC11203689
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Abstract

Glutamate is the main excitatory neurotransmitter in the brain wherein it controls cognitive functional domains and mood. Indeed, brain areas involved in memory formation and consolidation as well as in fear and emotional processing, such as the hippocampus, prefrontal cortex, and amygdala, are predominantly glutamatergic. To ensure the physiological activity of the brain, glutamatergic transmission is finely tuned at synaptic sites. Disruption of the mechanisms responsible for glutamate homeostasis may result in the accumulation of excessive glutamate levels, which in turn leads to increased calcium levels, mitochondrial abnormalities, oxidative stress, and eventually cell atrophy and death. This condition is known as glutamate-induced excitotoxicity and is considered as a pathogenic mechanism in several diseases of the central nervous system, including neurodevelopmental, substance abuse, and psychiatric disorders. On the other hand, these disorders share neuroplasticity impairments in glutamatergic brain areas, which are accompanied by structural remodeling of glutamatergic neurons. In the current narrative review, we will summarize the role of glutamate-induced excitotoxicity in both the pathophysiology and therapeutic interventions of neurodevelopmental and adult mental diseases with a focus on autism spectrum disorders, substance abuse, and psychiatric disorders. Indeed, glutamatergic drugs are under preclinical and clinical development for the treatment of different mental diseases that share glutamatergic neuroplasticity dysfunctions. Although clinical evidence is still limited and more studies are required, the regulation of glutamate homeostasis is attracting attention as a potential crucial target for the control of brain diseases.

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Cited by

Sorted by citations

Authors
Nicosia, N., Giovenzana, M., Misztak, P., Mingardi, J., & Musazzi, L.
Affiliations
University of Milano-Bicocca (IT)
Corresponding author
  • Mingardi, Jessica
  • Musazzi, Laura
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2024-06-13
Volume
25
Issue
12
Pages
6521
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms25126521
PMC
PMC11203689
OpenAlex
W4399676124
Cited by
135
References
23
Citations by year
2026: 76 · 2025: 52 · 2024: 7
FWCI
8.10
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion, cc-by)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Funders
Cariplo Foundation (2019–3357)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
glutamate excitotoxicity, glutamate homeostasis, glutamatergic neurotransmission, neurodevelopmental disorders, autism spectrum disorder, substance abuse, mental illness, neuroplasticity, glutamatergic drugs, oxidative stress, calcium overload, mitochondrial dysfunction, hippocampus, prefrontal cortex, amygdala
MeSH terms
Autism Spectrum Disorder, Adult, Animals, Mental Disorders, Brain, Humans, Neuronal Plasticity, Glutamic Acid, Substance-Related Disorders, Neurodevelopmental Disorders

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