Fish Kenneth N, Sweet Robert A, MacDonald Matthew L, Lewis David A
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania.
JAMA Psychiatry. 2025 Sep 17. doi: 10.1001/jamapsychiatry.2025.2221.
Schizophrenia (SZ) is characterized by deficits in visual-spatial working memory, a function dependent on a distributed cortical network that includes nodes in the primary visual (V1), posterior parietal (PPC), and dorsolateral prefrontal (DLPFC) cortices. The connections across these regions involve excitatory synapses on the dendritic spines of pyramidal neurons in layer 3 (L3).
To assess whether SZ is associated with regional differences in the magnitude or nature of L3 spine alterations.
DESIGN, SETTING, AND PARTICIPANTS: This case-control study examined brain tissue from 20 individuals with SZ and 20 matched unaffected comparison (UC) individuals, obtained by the Allegheny County Office of the Medical Examiner (Pittsburgh, Pennsylvania). Dendritic spines were labeled using fluorescent phalloidin (for F-actin) and immunolabeling for spinophilin and imaged by confocal microscopy.
Schizophrenia.
Primary outcomes were between-group differences in L3 dendritic spine density and size across V1, PPC, and DLPFC. Secondary outcomes included spine fluorescence intensities of phalloidin and spinophilin.
Forty individuals were studied (20 UC: 14 [70%] male and 6 [30%] female; mean [SD] age, 47.7 [9.6] years; 20 SZ: 14 [70%] male and 6 [30%] female; mean [SD] age, 45.6 [9.5] years). Dendritic spine density reductions in individuals with SZ varied by spine size across regions, with lower densities of small spines in V1 (-18%; 95% CI, -31% to -5%; P = .009), medium spines in PPC (-16%; 95% CI, -28% to -4%; P = .01) and DLPFC (-13%; 95% CI, -21% to -4%; P = .009), and large spines in PPC (-38%; 95% CI, -58% to -17%; P < .001) and DLPFC (-30%; 95% CI, -50% to -11%; P = .004). Phalloidin fluorescence was lower in small (-9.5%; 95% CI, -17% to -1%; P = .04) and medium (-9.8%; 95% CI, -18% to -1%; P = .04) V1 spines and higher in large DLPFC spines (9.5%; 95% CI, 0.4% to 19%; P = .049). Spinophilin fluorescence was lower across all spine sizes and regions (a range from -13%; 95% CI, -24% to -2%, to -34%; 95% CI, -46% to -21%; P values ranging .02 to <.001).
L3 dendritic spine density differs by diagnosis and cortical region in SZ. Because dendritic spine size is associated with synaptic stability (large/medium spines) and plasticity (small spines), regional differences in the sizes of affected spines in SZ may reflect differing functional impairments in the primary sensory and association regions of the cortical visual-spatial working memory network.
精神分裂症（SZ）的特征是视觉空间工作记忆缺陷，该功能依赖于一个分布式皮质网络，该网络包括初级视觉（V1）、后顶叶（PPC）和背外侧前额叶（DLPFC）皮质中的节点。这些区域之间的连接涉及第3层（L3）锥体神经元树突棘上的兴奋性突触。
评估SZ是否与L3棘突改变的程度或性质的区域差异有关。
设计、设置和参与者：这项病例对照研究检查了20名SZ患者和20名匹配的未受影响对照（UC）个体的脑组织，这些脑组织由阿勒格尼县法医办公室（宾夕法尼亚州匹兹堡）提供。使用荧光鬼笔环肽（用于F-肌动蛋白）标记树突棘，并对亲嗜素进行免疫标记，然后通过共聚焦显微镜成像。
精神分裂症。
主要结局是V1、PPC和DLPFC中L3树突棘密度和大小的组间差异。次要结局包括鬼笔环肽和亲嗜素的棘突荧光强度。
共研究了40名个体（20名UC：14名[70%]男性和6名[30%]女性；平均[标准差]年龄，47.7[9.6]岁；20名SZ：14名[70%]男性和6名[30%]女性；平均[标准差]年龄，45.6[9.5]岁）。SZ患者的树突棘密度降低因区域和棘突大小而异，V1中小棘突密度较低（-18%；95%置信区间，-31%至-5%；P = 0.009），PPC中棘突密度降低（-16%；95%置信区间，-28%至-4%；P = 0.01），DLPFC中棘突密度降低（-13%；95%置信区间，-21%至-4%；P = 0.009），PPC中大棘突密度降低（-38%；95%置信区间，-58%至-17%；P < 0.001），DLPFC中大棘突密度降低（-30%；95%置信区间，-50%至-11%；P = 0.004）。V1中小（-9.5%；95%置信区间，-17%至-1%；P = 0.04）和中（-9.8%；95%置信区间，-18%至-1%；P = 0.04）棘突的鬼笔环肽荧光较低，DLPFC中大棘突的鬼笔环肽荧光较高（9.5%；95%置信区间，0.4%至19%；P = 0.049）。在所有棘突大小和区域中，亲嗜素荧光均较低（范围从-13%；95%置信区间，-24%至-2%，至-34%；95%置信区间，-46%至-21%；P值范围为0.02至<0.001）。
在SZ中，L3树突棘密度因诊断和皮质区域而异。由于树突棘大小与突触稳定性（大/中棘突）和可塑性（小棘突）相关，因此SZ中受影响棘突大小的区域差异可能反映了皮质视觉空间工作记忆网络的初级感觉和联合区域中不同的功能损害。
