Differential alterations of kainate receptor subunits in inhibitory interneurons in the anterior cingulate cortex in schizophrenia and bipolar disorder

Abstract

The aim of this study was to examine whether glutamatergic inputs onto GABA interneurons via the kainate receptor in the anterior cingulate cortex may be altered in schizophrenia and bipolar disorder. Hence, in a cohort of 60 post-mortem human brains from schizophrenia, bipolar disorder, and normal control subjects, we simultaneously labeled the mRNA for the GluR5 or GluR6 subunit of the kainate receptor with [(35)S] and the mRNA for the 67 kD isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD)(67) with digoxigenin using an immunoperoxidase method. The density of the GAD(67) mRNA-containing neurons that co-expressed GluR5 mRNA was decreased by 43% and 40% in layer 2 of the anterior cingulate cortex in schizophrenia and bipolar disorder, respectively. In contrast, the density of the GAD(67) mRNA-containing cells that expressed GluR6 mRNA was unaltered in either condition. Furthermore, the amount of GluR5 or GluR6 mRNA in the GAD(67) mRNA-expressing cells that contained a detectable level of these transcripts was also unchanged. Finally, the density of cells that did not contain GAD(67) mRNA, which presumably included all pyramidal neurons, but expressed the mRNA for the GluR5 or GluR6 subunit was not altered. Thus, glutamatergic modulation of inhibitory interneurons, but not pyramidal neurons, via kainate receptors containing the GluR5 subunit appears to be selectively altered in the anterior cingulate cortex in schizophrenia and bipolar disorder.

Vitamin D3Supplemental Treatment for Mania in Youth with Bipolar Spectrum Disorders

“…Consistent with our hypothesis, we observed lower ACC GABA in patients with manic or mixed episodes when compared with TD. Overall, our findings are in agreement with studies implicating the GABAergic neurotransmitter system (Schousboe 2003;Bak et al 2006;Wang et al 2006;Bhagwagar et al 2007;Woo et al 2007;Brady et al 2013) in the pathophysiology of BD.…”

“…Abnormalities within the c-aminobutyric acid (GABA)ergic neurotransmitter system have also been implicated in the pathophysiology of BD through GABA receptor gene polymorphisms (Benes and Berretta 2001;Massat et al 2002;Otani et al 2005), postmortem (Benes and Berretta 2001;Knable et al 2004;Torrey et al 2005;Woo et al 2007) and MRS studies (Wang et al 2006;Bhagwagar et al 2007;Brady et al 2013). Specifically, irregularities in ACC GABA have been shown in patients with BD (Bhagwagar et al 2007;Woo et al 2007;Brady et al 2013). The changes in excitatory (i.e., glutamatergic) and inhibitory (i.e., GABAergic) neurotransmission may be synergistic: Glial produced glutamine is the source for both neuronal glutamate and GABA.…”

Neuropathological and neuromorphometric abnormalities in bipolar disorder: View from the medial prefrontal cortical network

“…However, because only ∼10% of all CB mRNA-containing cells express NR2A mRNA, conceivably small changes in the magnitude of mRNA expression would not be detectable by in situ hybridization (Woo et al, 2008b). In an independent sample, the density of GAD 67 -containing GABAergic neurons that express the GluR5 subunit of the kainate receptor was found to be decreased by ∼40% in layer II of the pgACC in BD and schizophrenia (Woo et al, 2007). No change in mRNA expression was observed in GluR6-containing neurons; the GluR6 receptor is expressed predominantly on pyramidal cells.…”

Common Proteomic Changes in the Hippocampus in Schizophrenia and Bipolar Disorder and Particular Evidence for Involvement of Cornu Ammonis Regions 2 and 3

“…It has been suggested that this region shows a particular vulnerability in schizophrenia 17 possibly owing to altered basolateral amygdala projections to CA2/3. 17,[76][77][78][79] The CA2/3 region has close functional connections to many other brain regions including the hypothalamus, septal nucleus, 80 subiculum, 81 and the CA1 region of the hippocampus. 82 Thus, while we confirm and extend the knowledge implicating the hippocampus and the CA2/3 region in schizophrenia 20,83 and bipolar disorder, changes in this region will have widespread consequences within the brain.…”