Dienel Samuel J, Wade Kirsten L, Fish Kenneth N, Lewis David A
Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Neuroscience, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania.
Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Biol Psychiatry. 2025 Jul 15;98(2):156-166. doi: 10.1016/j.biopsych.2025.01.010. Epub 2025 Jan 21.
Certain cognitive processes require inhibition provided by the somatostatin (SST) class of GABA (gamma-aminobutyric acid) neurons in the dorsolateral prefrontal cortex (DLPFC). This inhibition onto pyramidal neuron dendrites depends on both SST and GABA signaling. Although SST messenger RNA (mRNA) levels are lower in the DLPFC in schizophrenia, it is not known whether SST neurons exhibit alterations in the capacity to synthesize GABA, principally via the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67).
GAD67 and SST mRNA levels were quantified in individual SST neurons using fluorescence in situ hybridization in DLPFC layers 2/superficial 3, where SST neurons are enriched, in individuals with schizophrenia (n = 46) and unaffected comparison (n = 46) individuals. Findings were compared with GAD67 and SST mRNA levels quantified by polymerase chain reaction and to final educational attainment, a proxy measure for cognitive functioning.
GAD67 (F = 13.1, p = .0005, Cohen's d = -0.78) and SST (F = 10.1, p = .002, Cohen's d = -0.64) mRNA levels in SST neurons were lower in schizophrenia, with no group differences in the relative density of SST neurons (F = 0.21, p = .65). A presynaptic index of dendritic inhibition, derived by summing the alterations in GAD67 and SST mRNAs, was lower in 80.4% of individuals with schizophrenia and was associated with final educational attainment (adjusted odds ratio = 1.44, p = .022).
Deficits in both GAD67 and SST mRNAs within SST neurons indicate that these neurons have a markedly reduced ability to inhibit postsynaptic pyramidal neuron dendrites in schizophrenia. These alterations likely contribute to cognitive dysfunction in schizophrenia.
某些认知过程需要背外侧前额叶皮质（DLPFC）中生长抑素（SST）类γ-氨基丁酸（GABA）神经元提供抑制作用。这种对锥体神经元树突的抑制作用依赖于SST和GABA信号传导。尽管精神分裂症患者DLPFC中的SST信使核糖核酸（mRNA）水平较低，但尚不清楚SST神经元在合成GABA的能力方面是否存在改变，主要是通过谷氨酸脱羧酶67千道尔顿异构体（GAD67）。
在富含SST神经元的DLPFC第2层/浅表层3中，使用荧光原位杂交技术对精神分裂症患者（n = 46）和未受影响的对照个体（n = 46）的单个SST神经元中的GAD67和SST mRNA水平进行定量。将研究结果与通过聚合酶链反应定量的GAD67和SST mRNA水平以及最终教育程度（认知功能的替代指标）进行比较。
精神分裂症患者SST神经元中的GAD67（F = 13.1，p = .0005，Cohen's d = -0.78）和SST（F = 10.1，p = .002，Cohen's d = -0.64）mRNA水平较低，SST神经元的相对密度在两组之间无差异（F = 0.21，p = .65）。通过汇总GAD67和SST mRNA的变化得出的树突抑制突触前指数在80.4%的精神分裂症患者中较低，并且与最终教育程度相关（调整后的优势比 = 1.44，p = .022）。
SST神经元中GAD67和SST mRNA均缺乏表明，在精神分裂症中这些神经元抑制突触后锥体神经元树突的能力明显降低。这些改变可能导致精神分裂症患者的认知功能障碍。
