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 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.
Sakurai
Takeshi
T
Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York 10029, USA.
Ramoz
Nicolas
N
Barreto
Marta
M
Gazdoiu
Mihaela
M
Takahashi
Nagahide
N
Gertner
Michael
M
Dorr
Nathan
N
Gama Sosa
Miguel A
MA
De Gasperi
Rita
R
Perez
Gissel
G
Schmeidler
James
J
Mitropoulou
Vivian
V
Le
H Carl
HC
Lupu
Mihaela
M
Hof
Patrick R
PR
Elder
Gregory A
GA
Buxbaum
Joseph D
JD
D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D064026:Calbindins; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002658:Developmental Disabilities / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000378:metabolism*; D004676:Myelin Basic Protein / Q000378:metabolism*; D018992:Myelin-Associated Glycoprotein; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D019289:Pyruvic Acid / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology
C508320:Acan protein, mouse; D053674:Aggrecans; D064026:Calbindins; C104739:Mag protein, mouse; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D004676:Myelin Basic Protein; D018992:Myelin-Associated Glycoprotein; D011956:Receptors, Cell Surface; D064030:S100 Calcium Binding Protein G; C491956:Slc25a12 protein, mouse; D049452:Green Fluorescent Proteins; D019289:Pyruvic Acid