title: SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects.
abstract: Autism is a neurodevelopmental disorder with a strong genetic component, probably involving several genes. Genome screens have provided evidence of linkage to chromosome 2q31-q33, which includes the SLC25A12 gene. Association between autism and single-nucleotide polymorphisms in SLC25A12 has been reported in various studies. SLC25A12 encodes the mitochondrial aspartate/glutamate carrier functionally important in neurons with high-metabolic activity. Neuropathological findings and functional abnormalities in autism have been reported for Brodmann's area (BA) 46 and the cerebellum. We found that SLC25A12 was expressed more strongly in the post-mortem brain tissues of autistic subjects than in those of controls, in the BA46 prefrontal cortex but not in cerebellar granule cells. SLC25A12 expression was not modified in brain subregions of bipolar and schizophrenic patients. SLC25A12 was expressed in developing human neuronal tissues, including neocortical regions containing excitatory neurons and neocortical progenitors and the ganglionic eminences that generate neocortical inhibitory interneurons. At mid-gestation, when gyri and sulci start to develop, SLC25A12 molecular gradients were identified in the lateral prefrontal and ventral temporal cortex. These fetal structures generate regions with abnormal activity in autism, including the dorsolateral prefrontal cortex (BA46), the pars opercularis of the inferior frontal cortex and the fusiform gyrus. SLC25A12 overexpression or silencing in mouse embryonic cortical neurons also modified dendrite length and the mobility of dendritic mitochondria. Our findings suggest that SLC25A12 overexpression may be involved in the pathophysiology of autism, modifying neuronal networks in specific subregions, such as the dorsolateral prefrontal cortex and fusiform gyrus, at both pre- and postnatal stages.
authors.affiliation: INSERM U675, IFR2, Faculté de Médecine Xavier Bichat, Paris, France.
authors.forename: A-M
authors.initials: AM
authors.lastname: Lepagnol-Bestel
authors.forename: G
authors.initials: G
authors.lastname: Maussion
authors.forename: B
authors.initials: B
authors.lastname: Boda
authors.forename: A
authors.initials: A
authors.lastname: Cardona
authors.forename: Y
authors.initials: Y
authors.lastname: Iwayama
authors.forename: A-L
authors.initials: AL
authors.lastname: Delezoide
authors.forename: J-M
authors.initials: JM
authors.lastname: Moalic
authors.forename: D
authors.initials: D
authors.lastname: Muller
authors.forename: B
authors.initials: B
authors.lastname: Dean
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: P
authors.initials: P
authors.lastname: Gorwood
authors.forename: J D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: N
authors.initials: N
authors.lastname: Ramoz
authors.forename: M
authors.initials: M
authors.lastname: Simonneau
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002889:Chromosomes, Human, Pair 2; D005333:Fetus; D020022:Genetic Predisposition to Disease; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D015810:Linkage Disequilibrium; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011180:Postmortem Changes; D017397:Prefrontal Cortex / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D064546:Protein Kinase C beta; D012333:RNA, Messenger / Q000378:metabolism; D013687:Telencephalon / Q000166:cytology; D014162:Transfection; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C114606:SLC25A12 protein, human; D049452:Green Fluorescent Proteins; D011493:Protein Kinase C; D064546:Protein Kinase C beta