Group I and group II metabotropic glutamate receptors are upregulated in the synapses of infant rats prenatally exposed to valproic acid

D’Antoni, Simona; Schiavi, Sara; Buzzelli, Valeria; Giuffrida, Samuele; Feo, Alessandro; Ascone, Fabrizio; Busceti, Carla Letizia; Nicoletti, Ferdinando; Trezza, Viviana; Catania, Maria Vincenza

doi:10.1007/s00213-023-06457-w

Cited by 3 publications

(1 citation statement)

References 102 publications

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“…Accordingly, several animal models of ASD, including both pharmacological models and genetic models generated by mutations in genes found in patients with ASD, show glutamatergic alterations. Excitotoxicity, altered glutamate homeostasis, and receptor subunit expression and regulation were reported in the brain of a valproic acid model, one of the most widely used animal models of ASD [ 30 , 31 , 32 , 33 ]. Similarly, Shank mutant mice clearly exhibit glutamatergic impairments [ 34 , 35 , 36 , 37 ].…”

Section: Involvement Of Glutamate Excitotoxicity In Autism Spectrum D...mentioning

confidence: 99%

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

Nicosia,

Giovenzana,

Misztak

et al. 2024

IJMS

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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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Section: Involvement Of Glutamate Excitotoxicity In Autism Spectrum D...mentioning

confidence: 99%

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

Nicosia,

Giovenzana,

Misztak

et al. 2024

IJMS

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Influence of the glutamate-glutamine cycle on valproic acid-associated hepatotoxicity in pediatric patients with epilepsy

Ma,

Zhu,

Kong

et al. 2024

Clinical Toxicology

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Impaired metabotropic glutamate type 5 receptor signaling in the dorsal striatum of the R451C-neuroligin 3 mouse model of Autism Spectrum Disorder

Meringolo,

Montanari,

D'Antoni

et al. 2024

Preprint

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Background Human genetics indicates enrichment of synaptic pathway-related mutations in Autism Spectrum Disorder (ASD). Accordingly, several preclinical studies have reported synaptic alterations in different brain areas of relevant ASD mouse models. In particular, we previously showed that corticostriatal long-term synaptic depression is impaired in the dorsal striatum of mice carrying the ASD-associated R451C mutation in the neuroligin3 gene.Methods We used behavioral, proteomic, biochemical, and electrophysiological approaches to explore the dorsal striatum-dependent functions in the R451C-neuroligin3 mouse model of ASD.Results A detailed behavioral analysis confirmed striatum-dependent alterations in these mice. We further explored the corticostriatal synaptic function, disclosing modifications of the glutamatergic postsynaptic density protein composition, which functionally result in the impairment of different forms of corticostriatal synaptic plasticity, namely activity-dependent long-term depression and potentiation, and group I metabotropic glutamate receptor-dependent synaptic depression. We also found reduced protein expression levels of type 5 metabotropic glutamate receptor at striatal synapses, which likely preclude the expression of long-term potentiation and depression by preventing the potentiation of NMDA receptor-mediated currents and a sufficient generation of endocannabinoids, respectively.Conclusions Overall, our findings point to a significant impairment of type 5 metabotropic glutamate receptor signaling, affecting the dorsal striatum function, which underlies specific autism-relevant behaviors in R451C-neuroligin3 mice.

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Group I and group II metabotropic glutamate receptors are upregulated in the synapses of infant rats prenatally exposed to valproic acid

Cited by 3 publications

References 102 publications

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

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

Influence of the glutamate-glutamine cycle on valproic acid-associated hepatotoxicity in pediatric patients with epilepsy

Impaired metabotropic glutamate type 5 receptor signaling in the dorsal striatum of the R451C-neuroligin 3 mouse model of Autism Spectrum Disorder

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