The Nature of Prefrontal Cortical GABA Neuron Alterations in Schizophrenia: Markedly Lower Somatostatin and Parvalbumin Gene Expression Without Missing Neurons

被引:22
作者
Dienel, Samuel J. [1 ,2 ,3 ,4 ]
Fish, Kenneth N. [2 ]
Lewis, David A. [2 ,3 ,4 ]
机构
[1] Univ Pittsburgh, Sch Med, Med Scientist Training Program, Pittsburgh, PA USA
[2] Univ Pittsburgh, Sch Med, Dept Psychiat, Translat Neurosci Program, Pittsburgh, PA 15260 USA
[3] Univ Pittsburgh, Dietrich Sch Arts & Sci, Dept Neurosci, Pittsburgh, PA 15260 USA
[4] Carnegie Mellon Univ, Ctr Neural Basis Cognit, Pittsburgh, PA 15213 USA
关键词
GAMMA-AMINOBUTYRIC-ACID; MESSENGER-RNA EXPRESSION; CALCIUM-BINDING PROTEINS; HUMAN FRONTAL-CORTEX; HIPPOCAMPAL INTERNEURONS; COGNITIVE DEFICITS; INHIBITORY NEURONS; GABAERGIC NEURONS; PYRAMIDAL NEURONS; VISUAL-CORTEX;
D O I
10.1176/appi.ajp.20220676
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
Objective: In schizophrenia, somatostatin (SST) and parvalbumin (PV) mRNA levels are lower in the dorsolateral prefrontal cortex (DLPFC), but it remains unclear whether these findings reflect lower transcript levels per neuron, fewer neurons, or both. Distinguishing among these alternatives has implications for understanding the pathogenesis of, and developing new treatments for, DLPFC dysfunction in schizophrenia.Methods: To identify SST and PV neurons in postmortem human DLPFC, the authors used fluorescent in situ hybridization to label cells expressing two transcripts not altered in schizophrenia: vesicular GABA transporter (VGAT; a marker of all GABA neurons) and SOX6 (a marker of only SST and PV neurons). In cortical layers 2 and 4, where SST and PV neurons, respectively, are differentially enriched, levels of SST and PV mRNA per neuron and the relative densities of SST-, PV-, and VGAT/SOX6-positive neurons were quantified.Results: In individuals with schizophrenia, mRNA levels per positive neuron were markedly and significantly lower for SST in both layers (effect sizes .1.48) and for PV only in layer 4 (effect size51.14) relative to matched unaffected individuals. In contrast, the relative densities of all SST-, PV-, or VGAT/ SOX6-positive neurons were unaltered in schizophrenia.Conclusions: Novel multiplex fluorescent in situ hybridization techniques permit definitive distinction between cellular levels of transcripts and the presence of neurons expressing those transcripts. In schizophrenia, pronounced SST and PV mRNA deficits are attributable to lower levels of each transcript per neuron, not fewer neurons, arguing against death or abnormal migration of these neurons. Instead, these neurons appear to be functionally altered and thus amenable to therapeutic interventions.
引用
收藏
页码:495 / 507
页数:13
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