Scaling of smaller pyramidal neuron size and lower energy production in schizophrenia

• Published in: Neurobiology of disease Vol. 191; p. 106394
• Main Authors: Schoonover, Kirsten E., Miller, Nora E., Fish, Kenneth N., Lewis, David A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2024; Elsevier
• Subjects: COX4I1; Female; Humans; In Situ Hybridization, Fluorescence; Layer 3; Male; Postmortem; Prefrontal Cortex; Pyramidal Cells; RNA, Messenger; Schizophrenia; VGLUT1; Working memory; VGLUT1; Prefrontal cortex; Working memory; Layer 3; COX4I1; Postmortem
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2023.106394

Dorsolateral prefrontal cortex (DLPFC) dysfunction in schizophrenia appears to reflect alterations in layer 3 pyramidal neurons (L3PNs), including smaller cell bodies and lower expression of mitochondrial energy production genes. However, prior somal size studies used biased strategies for identifying L3PNs, and somal size and levels of energy production markers have not been assessed in individual L3PNs.
We combined fluorescent in situ hybridization (FISH) of vesicular glutamate transporter 1 (VGLUT1) mRNA and immunohistochemical-labeling of NeuN to determine if the cytoplasmic distribution of VGLUT1 mRNA permits the unbiased identification and somal size quantification of L3PNs. Dual-label FISH for VGLUT1 mRNA and cytochrome C oxidase subunit 4I1 (COX4I1) mRNA, a marker of energy production, was used to assess somal size and COX4I1 transcript levels in individual DLPFC L3PNs from schizophrenia (12 males; 2 females) and unaffected comparison (13 males; 1 female) subjects.
Measures of L3PN somal size with NeuN immunohistochemistry or VGLUT1 mRNA provided nearly identical results (ICC = 0.96, p < 0.0001). Mean somal size of VGLUT1-identified L3PNs was 8.7% smaller (p = 0.004) and mean COX4I1 mRNA levels per L3PN were 16.7% lower (p = 0.01) in schizophrenia. These measures were correlated across individual L3PNs in both subject groups (rrm = 0.81–0.86).
This preliminary study presents a novel method for combining unbiased neuronal identification with quantitative assessments of somal size and mRNA levels. We replicated findings of smaller somal size and lower COX4I1 mRNA levels in DLPFC L3PNs in schizophrenia. The normal scaling of COX4I1 mRNA levels with somal size in schizophrenia suggests that lower markers of energy production are secondary to L3PN morphological alterations in the illness.
•Unbiased quantification of layer 3 pyramidal neuron (L3PN) size and mRNA levels.•L3PN somal size was 8.7% smaller in schizophrenia relative to comparison subjects.•L3PN COX4I1 mRNA, a marker of energy production, was 16.7% lower in schizophrenia.•Somal size and COX4I1 mRNA levels were highly positively correlated in both groups.•In schizophrenia, lower energy production might be due to altered L3PN morphology.