Psychopharmacology · 2025
Alteration in hippocampal mitochondria ultrastructure and cholesterol accumulation linked to mitochondrial dysfunction in the valproic acid rat model of autism spectrum disorders.
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Prince Paula D, Codagnone Martín G, Opezzo Javier A W, Adán Areán Juan S, Höcht Christian, Arnal Nathalie, Alvarez Silvia, Zárate Sandra, Reinés Analía
Аннотация
RATIONALE: Autism spectrum disorders (ASD) are a group of neurodevelopmental and multifactorial conditions with cognitive manifestations. The valproic acid (VPA) rat model is a well-validated model that successfully reproduces the behavioral and neuroanatomical alterations of ASD. Previous studies found atypical brain connectivity and metabolic patterns in VPA animals: local glucose hypermetabolism in the prefrontal cortex, with no metabolic changes in the hippocampus.
AIM: This study aimed to explore mitochondrial structural features, lipid content, and functionality in the hippocampus and cerebral cortex in the VPA model.
METHODS: On embryonic day 10.5, pregnant Wistar rats were injected with VPA (450 mg/kg) or saline solution. In the hippocampus and cerebral cortex of male offspring (postnatal day 35), the mitochondrial structure was evaluated by transmission electron microscopy, oxidized/reduced glutathione was determined by high-performance liquid chromatography, mitochondrial membrane cholesterol, and phospholipids were determined by thin-layer chromatography, and oxygen consumption and ATP synthesis were measured in isolated mitochondria.
RESULTS: Mitochondrial increased oxygen consumption and decreased ATP production, increased oxidized/reduced glutathione, cholesterol accumulation in mitochondrial membrane and altered mitochondrial structure were found in the hippocampus of VPA animals. All parameters were preserved in the cerebral cortex of VPA rats.
CONCLUSIONS: These findings reveal brain region-specific mitochondrial structural and functional alterations in VPA-treated animals, with preserved mitochondria in regions with high glucose demand and impaired mitochondria in metabolically normal areas. Moreover, cholesterol accumulation in hippocampal mitochondrial membranes is a potential cause of mitochondrial dysfunction, contributing to a prooxidant state.
AIM: This study aimed to explore mitochondrial structural features, lipid content, and functionality in the hippocampus and cerebral cortex in the VPA model.
METHODS: On embryonic day 10.5, pregnant Wistar rats were injected with VPA (450 mg/kg) or saline solution. In the hippocampus and cerebral cortex of male offspring (postnatal day 35), the mitochondrial structure was evaluated by transmission electron microscopy, oxidized/reduced glutathione was determined by high-performance liquid chromatography, mitochondrial membrane cholesterol, and phospholipids were determined by thin-layer chromatography, and oxygen consumption and ATP synthesis were measured in isolated mitochondria.
RESULTS: Mitochondrial increased oxygen consumption and decreased ATP production, increased oxidized/reduced glutathione, cholesterol accumulation in mitochondrial membrane and altered mitochondrial structure were found in the hippocampus of VPA animals. All parameters were preserved in the cerebral cortex of VPA rats.
CONCLUSIONS: These findings reveal brain region-specific mitochondrial structural and functional alterations in VPA-treated animals, with preserved mitochondria in regions with high glucose demand and impaired mitochondria in metabolically normal areas. Moreover, cholesterol accumulation in hippocampal mitochondrial membranes is a potential cause of mitochondrial dysfunction, contributing to a prooxidant state.