Expression of excitatory amino acid transporter interacting protein transcripts in the thalamus in schizophrenia.
The excitatory amino acid transporters (EAATs) are a family of plasma membrane proteins that maintain synaptic glutamate concentration by removing glutamate from the synaptic cleft. EAATs are expressed by glia (EAAT1 and EAAT2) and neurons (EAAT3 and EAAT4) throughout the brain. Glutamate reuptake is regulated, in part, by EAAT-interacting proteins that modulate subcellular localization and glutamate transport activity of the EAATs. Several lines of investigation support the hypothesis of glutamatergic abnormalities in schizophrenia. Previous work in our laboratory demonstrated increased expression of EAAT1 and EAAT2 transcripts in the thalamus, suggesting that alterations in synaptic glutamate levels may contribute to the pathophysiology of schizophrenia. Since EAAT-interacting proteins regulate EAAT function, directly impacting glutamatergic neurotransmission, we hypothesized that expression of EAAT-interacting proteins may also be altered in schizophrenia. Using in situ hybridization in subjects with schizophrenia and a comparison group, we detected increased expression of JWA and KIAA0302, molecules that regulate EAAT3 and EAAT4, respectively, in the thalamus in schizophrenia. In contrast, we did not find changes in the expression of transcripts for the EAAT2 and EAAT4 regulatory proteins GPS-1 and ARHGEF11. To address prior antipsychotic treatment in our schizophrenic subjects, we treated rats with haloperidol and clozapine for 4 weeks, and found changes in transcript expression of the EAAT-interacting proteins in clozapine-, but not haloperidol-, treated rats. These findings suggest that proteins associated with the regulation of glutamate reuptake may be abnormal in this illness, supporting the hypothesis of altered thalamic glutamatergic neurotransmission in schizophrenia.
Molecular and Behavioral Neuroscience Institute and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Ibone
I
Huerta
Robert E
RE
McCullumsmith
Vahram
V
Haroutunian
José Manuel
JM
Giménez-Amaya
James H
JH
Meador-Woodruff
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D000075686:COP9 Signalosome Complex; D003024:Clozapine / Q000494:pharmacology; D005260:Female; D050491:Glutamate Plasma Membrane Transport Proteins / Q000096:biosynthesis* / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis; D006220:Haloperidol / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D007091:Image Processing, Computer-Assisted; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D064067:Rho Guanine Nucleotide Exchange Factors; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology*; D013788:Thalamus / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
C577234:ARHGEF11 protein, human; C484566:ARL6IP5 protein, human; D014150:Antipsychotic Agents; C103315:GPS1 protein, human; D050491:Glutamate Plasma Membrane Transport Proteins; D020662:Guanine Nucleotide Exchange Factors; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D064067:Rho Guanine Nucleotide Exchange Factors; D018698:Glutamic Acid; D000075686:COP9 Signalosome Complex; D003024:Clozapine; D006220:Haloperidol