Elevated GRIA1 mRNA expression in Layer II/III and V pyramidal cells of the DLPFC in schizophrenia

Abstract

The functional integrity of the dorsolateral prefrontal cortex (DLPFC) is altered in schizophrenia leading to profound deficits in working memory and cognition. Growing evidence indicates that dysregulation of glutamate signaling may be a significant contributor to the pathophysiology mediating these effects; however, the contribution of NMDA and AMPA receptors in the mediation of this deficit remains unclear. The equivocality of data regarding ionotropic glutamate receptor alterations of subunit expression in the DLPFC of schizophrenics is likely reflective of subtle alterations in the cellular and molecular composition of specific neuronal populations within the region. Given previous evidence of Layer II/III and V pyramidal cell alterations in schizophrenia and the significant influence of subunit composition on NMDA and AMPA receptor function, laser capture microdissection combined with quantitative PCR was used to examine the expression of AMPA (GRIA1-4) and NMDA (GRIN1, 2A and 2B) subunit mRNA levels in Layer II/III and Layer V pyramidal cells in the DLPFC. Comparisons were made between individuals diagnosed with schizophrenia, bipolar disorder, major depressive disorder and controls (n=15/ group). All subunits were expressed at detectable levels in both cell populations for all diseases as well as for the control group. Interestingly, GRIA1 mRNA was significantly increased in both cell types in the schizophrenia group compare to controls, while similar trends were observed in major depressive disorder (Layers II/III and V) and bipolar disorder (Layer V). These data suggest that increased GRIA1 subunit expression may contribute to schizophrenia pathology.

Sex differences in glutamate receptor gene expression in major depression and suicide

“…Our data are consistent with previously reported data indicating a trend for increased NMDAR and AMPAR subunit expression in the DLPFC of a smaller group of MDD subjects. 54 Indeed, it has been suggested that the antidepressant effects of ketamine are dependent on the enhancement of AMPAR activation. 55 Evidence that AMPAR potentiators possess antidepressant-like properties 56 suggests that a relative increase in AMPAR activation produces antidepressant efficacy.…”

Adolescent THC exposure in female rats leads to cognitive deficits through a mechanism involving chromatin modifications in the prefrontal cortex

“…[39][40][41][42][43] Moreover, 2 other genes whose THCmediated deregulation during adolescence persisted at 75 PND, Gria1 and Reln, have also been found to be modified in postmortem studies per formed in the cortex of patients with schizophrenia. [44][45][46][47] Thus, the 2 main THCinduced epigenetic events, the early (0-24 h) H3K9me3 upregulation followed by a delayed (24-48 h) in crease of H3 acetylation, dramatically change the physiologic expression of the analyzed genes. These genes may play a cru cial role in the correct developmental trajectory of the adolescent brain, thus their aberrant expression could affect the shaping of adult brain organization.…”

Structural basis of PI(4,5)P2-dependent regulation of GluA1 by phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP5K2A)

“…Interestingly, GluA1 has also been implicated in the pathophysiology of schizophrenia [9, 21, 24, 25]. Decreased expression levels of GluA1 have been found in the brain of some schizophrenic patients.…”