Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics

Abstract

Background: Metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5) are novel therapeutic targets for major depression (MD), bipolar disorder (BD) and schizophrenia. We aimed to determine whether mGluR2/3 and mGluR5 binding in the anterior cingulate cortex (ACC), a brain region essential for the regulation of mood, cognition and emotion, were differentially altered in these pathologies.

Methods: Using postmortem human brains derived from 2 cohorts, [(3)H]LY341495 binding to mGluR2/3 and [(3)H]MPEP binding to mGluR5 were measured by receptor autoradiography in the ACC. The first cohort comprised samples from individuals who had MD with psychosis (MDP), MD without psychosis (MDNP) and matched controls (n = 11-12 per group). The second cohort comprised samples from individuals who had MDNP, BD, schizophrenia and matched controls (n = 15 per group).

Results: No differences in mGluR2/3 or mGluR5 binding were observed in the MDP, MDNP, BD or schizophrenia groups compared with the control group (all p > 0.05). Importantly, there were also no differences in binding densities between the psychiatric disorders (p > 0.05). We did, however, observe age-related effects, with consistent negative associations between mGluR2/3 and age in the control group (r < -0.575, p < 0.025) and the psychotic disorder groups (MDP and schizophrenia: r = -0.765 to -0.515, p < 0.05), but not in the mood disorder groups (MDNP, BD).

Limitations: Replication in larger independent cohorts and medication-naive individuals would strengthen these findings.

Conclusion: Our findings suggest that mGluRs are unaltered in the ACC; however, the presence of altered receptor function cannot be discounted and requires further investigation. Taken together with previous studies, which report differential changes in mGluR2, 3 and 5 across these disorders, we suggest mGluRs may be affected in a brain region-specific manner.

Fig. 1

Representative receptor autoradiographs of mGluR2/3 [³H]LY341495 and mGluR5 [³H]MPEP binding from the anterior cingulate cortex of samples from the (A) Stanley Depression Collection (control, major depression with psychosis, major depression without psychosis) and the (B) Stanley Neuropathology Consortium (control, major depression, bipolar disorder and schizophrenia). A representative nonspecific binding has been included for each cohort. mGluR2/3 [³H]LY341495 and mGluR5 [³H]MPEP binding densities were not different between pathological and control groups.

Fig. 2

Normalized (A) mGluR2/3 [³H]LY341495 and (B) mGluR5 [³H]MPEP binding density (as measured in fmol/mg tissue) in the anterior cingulate cortex of control (CT; diamonds = Depression Collection; solid circles = Neuropathology Consortium), major depression with psychosis (MDP; hollow circles), major depression without psychosis (MDNP; Depression Collection = hollow squares; Neuropathology Consortium = upward arrowheads), bipolar disorder (BD; downward arrowheads), and schizophrenia (SZ; solid squares) groups. mGluR2/3 and mGluR5 binding densities were not altered or differentially expressed in the anterior cingulate cortex in these neuropathologies.