Evidence for abnormal forward trafficking of AMPA receptors in frontal cortex of elderly patients with schizophrenia.
Several lines of evidence point to alterations of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor trafficking in schizophrenia. Multiple proteins, including synapse-associated protein 97 (SAP97), glutamate receptor-interacting protein 1 (GRIP1), and N-ethylmaleimide sensitive factor (NSF), facilitate the forward trafficking of AMPA receptors toward the synapse. Once localized to the synapse, AMPA receptors are trafficked in a complex endosomal system. We hypothesized that alterations in the expression of these proteins and alterations in the subcellular localization of AMPA receptors in endosomes may contribute to the pathophysiology of schizophrenia. Accordingly, we measured protein expression of SAP97, GRIP1, and NSF in the dorsolateral prefrontal cortex and found an increase in the expression of SAP97 and GRIP1 in schizophrenia. To determine the subcellular localization of AMPA receptor subunits, we developed a technique to isolate early endosomes from post-mortem tissue. We found increased GluR1 receptor subunit protein in early endosomes in subjects with schizophrenia. Together, these data suggest that there is an alteration of forward trafficking of AMPA receptors as well as changes in the subcellular localization of an AMPA receptor subunit in schizophrenia.
Hammond
John C
JC
Department of Neurobiology, University of Alabama Birmingham, 35294-0021, USA. hammondj@uab.edu
McCullumsmith
Robert E
RE
Funk
Adam J
AJ
Haroutunian
Vahram
V
Meador-Woodruff
James H
JH
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D002352:Carrier Proteins / Q000378:metabolism; D000074288:Discs Large Homolog 1 Protein; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005853:Geriatrics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission / Q000379:methods; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000648:ultrastructure; D021381:Protein Transport / Q000502:physiology; D018091:Receptors, AMPA / Q000378:metabolism* / Q000648:ultrastructure; D012559:Schizophrenia / Q000473:pathology* / Q000503:physiopathology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; C491310:GRIP1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D052066:N-Ethylmaleimide-Sensitive Proteins