Changes in cortical N-methyl-D-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide

Abstract

Objectives: In humans, depending on dose, blocking the N-methyl-D-aspartate receptor (NMDAR) with ketamine can cause psychomimetic or antidepressant effects. The overall outcome for drugs such as ketamine depends on dose and the number of its available binding sites in the central nervous system, and to understand something of the latter variable we measure NMDAR in the frontal pole, dorsolateral prefrontal, anterior cingulate and parietal cortices from people with schizophrenia, bipolar disorder, major depressive disorders and age/sex matched controls.

Method: We measured levels of NMDARs (using [(3)H]MK-801 binding) and NMDAR sub-unit mRNAs (GRINs: using in situ hybridisation) as well as post-synaptic density protein 95 (anterior cingulate cortex only; not major depressive disorders: an NMDAR post-synaptic associated protein) in bipolar disorder, schizophrenia and controls.

Results: Compared to controls, levels of NMDAR were lower in the outer laminae of the dorsolateral prefrontal cortex (-17%, p = 0.01) in people with schizophrenia. In bipolar disorder, levels of NMDAR binding (laminae IV-VI; -19%, p < 0.01) and GRIN2C mRNA (laminae I-VI; -27%, p < 0.05) were lower in the anterior cingulate cortex and NMDAR binding was lower in the outer lamina IV of the dorsolateral prefrontal cortex (-19%, p < 0.01). In major depressive disorders, levels of GRIN2D mRNA were higher in frontal pole (+22%, p < 0.05). In suicide completers, levels of GRIN2B mRNA were higher in parietal cortex (+20%, p < 0.01) but lower (-35%, p = 0.02) in dorsolateral prefrontal cortex while post-synaptic density protein 95 was higher (+26%, p < 0.05) in anterior cingulate cortex.

Conclusion: These data suggest that differences in cortical NMDAR expression and post-synaptic density protein 95 are present in psychiatric disorders and suicide completion and may contribute to different responses to ketamine.

Keywords: NMDA; Schizophrenia; bipolar disorders; cortex; major depressive disorders.

Figure 1.

A typical autoradiograph showing the binding of [³H]MK-801 to the NMDAR in human cortex in the absence (a) (total binding [TB]) or presence (b) (non-specific binding [NSB]) of 100-μM MK-801 and (c) the levels of specific binding of [³H]MK-801 (mean ± standard error of the mean [SEM]) in the inner radioligand binding layer of the anterior cingulate (ACx) and the outer radioligand binding layer of the dorsolateral prefrontal cortex (DLPFC) from the controls and people with schizophrenia (Sz) and bipolar disorder (BPD). Specific binding was calculated as TB – NSB. **p = 0.01; ***p < 0.01.

Figure 2.

Levels of [³⁵S]riboprobe hybridisation (mean ± standard error of the mean [SEM]) to the GRIN2D sub-unit in the frontal pole from people with major depressive disorders (MDD) and GRIN2D sub-unit in the ACx from people with bipolar disorder BPD) compared to that in the same regions from age/sex matched controls. *p < 0.05.

Figure 3.

Levels of [³⁵S]riboprobe hybridisation (mean ± standard error of the mean [SEM]) to the GRIN2B sub-unit in the frontal pole and dorsolateral prefrontal cortex (DLPFC) from suicide completers and people who had died from other causes. **p < 0.01; ***p = 0.02.

Figure 4.

(a) A typical Western blot showing post-synaptic density protein 95 (PSD 95) immunogenic bands in two cases and the internal control (IC). The IC is run on every gel to control for gel to gel variation and (b) levels of PSD 95 (mean ± standard error of the mean [SEM]) in the ACx from suicide completers and people who had died from other causes.