1. ¹INSERM U675, IFR2, Faculté de Médecine Xavier Bichat, Paris, France
2. ²Department of Basic Neuroscience, Centre Medical Universitaire, Geneva, Switzerland
3. ³Histotechnology and Pathology Unit, Institut Pasteur, Paris, France
4. ⁴Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan
5. ⁵Biologie du développement, Hôpital Robert Debré, AP-HP, Paris, France
6. ⁶The Rebecca L Cooper Research Laboratories, Mental Health Research Institute of Victoria, Parkville, VIC, Australia
7. ⁷CREST, Japan Science and Technology Agency, Saitama, Japan
8. ⁸Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA
9. ⁹Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

Correspondence: Professor M Simonneau, INSERM U675, IFR2, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, Paris 75018, France. E-mail: simonneaumi@wanadoo.fr

Received 24 October 2006; Revised 20 May 2007; Accepted 18 June 2007; Published online 8 January 2008.

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.