Low levels of muscarinic M1 receptor-positive neurons in cortical layers III and V in Brodmann areas 9 and 17 from individuals with schizophrenia

Abstract

Background: Results of neuroimaging and postmortem studies suggest that people with schizophrenia may have lower levels of muscarinic M1 receptors (CHRM1) in the cortex, but not in the hippocampus or thalamus. Here, we use a novel immunohistochemical approach to better understand the likely cause of these low receptor levels.

Methods: We determined the distribution and number of CHRM1-positive (CHRM1+) neurons in the cortex, medial dorsal nucleus of the thalamus and regions of the hippocampus from controls (n = 12, 12 and 5, respectively) and people with schizophrenia (n = 24, 24 and 13, respectively).

Results: Compared with controls, levels of CHRM1+ neurons in people with schizophrenia were lower on pyramidal cells in layer III of Brodmann areas 9 (-44%) and 17 (-45%), and in layer V in Brodmann areas 9 (-45%) and 17 (-62%). We found no significant differences in the number of CHRM1+ neurons in the medial dorsal nucleus of the thalamus or in the hippocampus.

Limitations: Although diagnostic cohort sizes were typical for this type of study, they were relatively small. As well, people with schizophrenia were treated with antipsychotic drugs before death.

Conclusion: The loss of CHRM1+ pyramidal cells in the cortex of people with schizophrenia may underpin derangements in the cholinergic regulation of GABAergic activity in cortical layer III and in cortical/subcortical communication via pyramidal cells in layer V.

Fig. 1

(A) A photomicrograph showing anti-muscarinic M1 receptor antibody immunolabelled cells in Brodmann area 9 (arrows highlighting CHRM+ neurons). (B) An adjacent tissue section that was treated identically but not exposed to the anti-muscarinic M1 receptor antibody. (C) Levels (mean ± SEM) of [³H]pirenzepine binding to Brodmann area 9 for the cases included in this study that were part of a larger published cohort. (D–G) Levels (mean ± SEM) of CHRM1+ neurons, total neurons and total glia in (D) layer III and (E) layer V in Brodmann area 9 and (F) layer III and (G) layer V in Brodmann area 17 from people with schizophrenia, a subgroup of people with MRDS and people with schizophrenia who did not have that deficit (non-MRDS). a = p < 0.05, b = p < 0.01, c = p < 0.001, d = p < 0.0001. CHRM+ = muscarinic M1 receptor–positive; MRDS = muscarinic receptor deficit form of schizophrenia; SEM = standard error of the mean.

Fig. 2

(A) A photomicrograph showing antimuscarinic M1 receptor antibody immunolabelled cells in the medial dorsal nucleus (arrows highlighting examples of CHRM+ neurons). (B–F) Levels (mean ± SEM) of CHRM1+ neurons, total neurons and total glia in (B) the medial dorsal nucleus, (C) the polymorphic layer of the dentate gyrus, (D) CA1, (E) CA2 and (F) CA3 from people with schizophrenia, a subgroup of people with MRDS and people with schizophrenia who did not have that deficit (non-MRDS). a = p < 0.05. CA = cornu ammonis; CHRM1+ = muscarinic M1 receptor–positive; MRDS = muscarinic receptor deficit form of schizophrenia; SEM = standard error of the mean.