Slc25a12 Disruption Alters Myelination and Neurofilaments: A Model for a Hypomyelination Syndrome and Childhood Neurodevelopmental Disorders

Background SLC25A12 , a susceptibility gene for autism spectrum disorders that is mutated in a neurodevelopmental syndrome, encodes a mitochondrial aspartate-glutamate carrier (aspartate-glutamate carrier isoform 1 [AGC1]). AGC1 is an important component of the malate/aspartate shuttle, a crucial sy...

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Published in:Biological psychiatry (1969) 2010-05, Vol.67 (9), p.887-894
Main Authors: Sakurai, Takeshi, Ramoz, Nicolas, Barreto, Marta, Gazdoiu, Mihaela, Takahashi, Nagahide, Gertner, Michael, Dorr, Nathan, Gama Sosa, Miguel A, De Gasperi, Rita, Perez, Gissel, Schmeidler, James, Mitropoulou, Vivian, Le, H. Carl, Lupu, Mihaela, Hof, Patrick R, Elder, Gregory A, Buxbaum, Joseph D
Format: Article
Language:English
Subjects:
Aggrecans - metabolism
Animals
Animals, Newborn
Brain - cytology
Calbindins
Cells, Cultured
Cerebellum - cytology
Developmental Disabilities - genetics
Developmental Disabilities - metabolism
Disease Models, Animal
Embryo, Mammalian
Encephalitis - genetics
Encephalitis - metabolism
Encephalitis - pathology
Gene Expression Regulation, Developmental - drug effects
Gene Expression Regulation, Developmental - genetics
Green Fluorescent Proteins - genetics
Malate/aspartate shuttle
Male
Membrane Transport Proteins - deficiency
Membrane Transport Proteins - metabolism
Mice
Mice, Knockout
mitochondria
Mitochondrial Membrane Transport Proteins
Mitochondrial Proteins - deficiency
Mitochondrial Proteins - metabolism
Myelin Basic Protein - metabolism
Myelin-Associated Glycoprotein
N-acetylaspartate (NAA)
neuron-oligodendrocyte interactions
Neurons - metabolism
Neurons - pathology
Oligodendroglia - drug effects
Oligodendroglia - physiology
Organ Culture Techniques
Psychiatry
pyruvate
Pyruvic Acid - therapeutic use
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
S100 Calcium Binding Protein G - metabolism
Stem Cells - physiology
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Summary:Background SLC25A12 , a susceptibility gene for autism spectrum disorders that is mutated in a neurodevelopmental syndrome, encodes a mitochondrial aspartate-glutamate carrier (aspartate-glutamate carrier isoform 1 [AGC1]). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate production. Methods We characterized mice with a disruption of the Slc25a12 gene, followed by confirmatory in vitro studies. Results Slc25a12 -knockout mice, which showed no AGC1 by immunoblotting, were born normally but displayed delayed development and died around 3 weeks after birth. In postnatal day 13 to 14 knockout brains, the brains were smaller with no obvious alteration in gross structure. However, we found a reduction in myelin basic protein (MBP)-positive fibers, consistent with a previous report. Furthermore, the neocortex of knockout mice contained abnormal neurofilamentous accumulations in neurons, suggesting defective axonal transport and/or neurodegeneration. Slice cultures prepared from knockout mice also showed a myelination defect, and reduction of Slc25a12 in rat primary oligodendrocytes led to a cell-autonomous reduction in MBP expression. Myelin deficits in slice cultures from knockout mice could be reversed by administration of pyruvate, indicating that reduction in AGC1 activity leads to reduced production of aspartate/ N -acetylaspartate and/or alterations in the dihydronicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide+ ratio, resulting in myelin defects. Conclusions Our data implicate AGC1 activity in myelination and in neuronal structure and indicate that while loss of AGC1 leads to hypomyelination and neuronal changes, subtle alterations in AGC1 expression could affect brain development, contributing to increased autism susceptibility.
ISSN:0006-3223
1873-2402
DOI:10.1016/j.biopsych.2009.08.042