Postmortem brain abnormalities of the glutamate neurotransmitter system in autism.
BACKGROUND
Studies examining the brains of individuals with autism have identified anatomic and pathologic changes in regions such as the cerebellum and hippocampus. Little, if anything, is known, however, about the molecules that are involved in the pathogenesis of this disorder.


OBJECTIVE
To identify genes with abnormal expression levels in the cerebella of subjects with autism.


METHODS
Brain samples from a total of 10 individuals with autism and 23 matched controls were collected, mainly from the cerebellum. Two cDNA microarray technologies were used to identify genes that were significantly up- or downregulated in autism. The abnormal mRNA or protein levels of several genes identified by microarray analysis were investigated using PCR with reverse transcription and Western blotting. alpha-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)- and NMDA-type glutamate receptor densities were examined with receptor autoradiography in the cerebellum, caudate-putamen, and prefrontal cortex.


RESULTS
The mRNA levels of several genes were significantly increased in autism, including excitatory amino acid transporter 1 and glutamate receptor AMPA 1, two members of the glutamate system. Abnormalities in the protein or mRNA levels of several additional molecules in the glutamate system were identified on further analysis, including glutamate receptor binding proteins. AMPA-type glutamate receptor density was decreased in the cerebellum of individuals with autism (p < 0.05).


CONCLUSIONS
Subjects with autism may have specific abnormalities in the AMPA-type glutamate receptors and glutamate transporters in the cerebellum. These abnormalities may be directly involved in the pathogenesis of the disorder.
Purcell
A E
AE
Department of Neurology, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
Jeon
O H
OH
Zimmerman
A W
AW
Blue
M E
ME
Pevsner
J
J
D000328:Adult; D001321:Autistic Disorder / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001345:Autoradiography; D001923:Brain Chemistry / Q000235:genetics*; D002531:Cerebellum / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D027341:Excitatory Amino Acid Transporter 1 / Q000032:analysis / Q000235:genetics; D027342:Excitatory Amino Acid Transporter 2 / Q000032:analysis / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D018091:Receptors, AMPA / Q000032:analysis / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid; D012333:RNA, Messenger; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate