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Glutamate receptor-interacting protein 1 (GRIP-1)


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.

MeSH Terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Carrier Proteins
  • Discs Large Homolog 1 Protein
  • Female
  • Gene Expression Regulation
  • Geriatrics
  • Humans
  • Male
  • Membrane Proteins
  • Microscopy, Electron, Transmission
  • N-Ethylmaleimide-Sensitive Proteins
  • Nerve Tissue Proteins
  • Prefrontal Cortex
  • Protein Transport
  • Receptors, AMPA
  • Schizophrenia

Expression profiles of schizophrenia susceptibility genes during human prefrontal cortical development.

Disruption in normal development of the human prefrontal cortex (PFC) may lead to cognitive dysfunction that manifests in individuals with schizophrenia. We sought to identify genes associated with age that are implicated in schizophrenia. We generated genome-wide expression profiles for the PFCs of humans ranging in age from 1 month to 49 years using the Affymetrix HG-U133 plus 2.0 microarrays (54 675 transcripts). Based on the criteria of significance (false discovery rate [FDR]-adjusted q < 0.001 and r(2) > 0.6), we identified the genes associated with age in the PFC. We then performed functional annotation analyses of age-associated genes using the Gene Ontology and the Genetic Association Database (GAD). We found robust age-dependent changes in gene expression in the PFCs of humans (2281 transcripts). The GAD analysis revealed that schizophrenia was an over-represented disease class, with 42 susceptibility genes included (p < 0.001, fold enrichment = 1.66, FDR = 1.5%). Among the 42 genes, glutamate receptor genes (GRIA1, GRIK1, GRIK2, GRIN2D, GRIP1, GRM5, GRM7 and SLC1A6) were consistently downregulated across age. We confirmed microarray gene expression changes by the quantitative polymerase chain reaction experiment. Although numerous genes undergo robust changes in expression during the PFC development, some of the changes may be confounded by known and unknown factors that are intrinsic to the postmortem brain studies. Multiple schizophrenia susceptibility genes undergo age-dependent expression changes in the human PFC, and any disruption in those genes during the critical period of development may predispose the individuals to schizophrenia.

MeSH Terms

  • Adolescent
  • Adult
  • Aging
  • Brain Chemistry
  • Child
  • Child, Preschool
  • Female
  • Gene Expression
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Prefrontal Cortex
  • Quality Control
  • Regression Analysis
  • Reproducibility of Results
  • Reverse Transcriptase Polymerase Chain Reaction
  • Schizophrenia
  • Young Adult