Sapienza Jacopo, Spangaro Marco, Comai Stefano, Sabé Michel, La Torre Joseph, Buonarroti Matteo, Cavallaro Roberto, Bosia Marta
IRCCS San Raffaele Scientific Institute, 20127 Milan, Italy.
Department of Humanities and Life Sciences, University School for Advanced Studies IUSS, 27100 Pavia, Italy.
Int J Mol Sci. 2025 Sep 14;26(18):8949. doi: 10.3390/ijms26188949.
Schizophrenia is a highly polygenic disease, and several genetic variants associated with the disease converge on altered synaptic homeostasis. In particular, the gene encoding complement component 4 (C4) showed the strongest association with schizophrenia, and this protein is involved in complement-dependent and microglia-mediated synaptic pruning. As a matter of fact, microglia are overactive in schizophrenia, and reduced synaptic arborization, especially in the prefrontal cortex (PFC), is an established hallmark of schizophrenia, likely associated with gray matter loss, cortical thinning, hypofrontality, and deficit syndrome. The recent development of a new radioligand targeting the synaptic vesicle glycoprotein 2A (SV2A) demonstrated in vivo lower synaptic density at the PFC level in individuals with schizophrenia, corroborating the synaptic hypothesis of thedisease first proposed by Feinberg in 1982. Interestingly, robust preclinical evidence (in vitro and animal models) showed the ability of psychedelics to promote neuroplasticity and synaptogenesis, potentially counteracting the excessive synaptic loss, restoring volume loss, and possibly explaining improvements in negative and cognitive symptoms described by old clinical studies. Overall, microdoses should be explored first as a possible treatment in a selected sample of patients affected by deficit schizophrenia, followed by low and full doses if encouraging results were to emerge.
精神分裂症是一种高度多基因疾病，与该疾病相关的几个基因变异都集中在突触稳态的改变上。特别是，编码补体成分4（C4）的基因与精神分裂症的关联最为强烈，并且这种蛋白质参与补体依赖性和小胶质细胞介导的突触修剪。事实上，小胶质细胞在精神分裂症中过度活跃，而突触分支减少，尤其是在额叶前皮质（PFC），是精神分裂症已确定的一个标志，可能与灰质丢失、皮质变薄、额叶功能低下和缺陷综合征有关。最近开发的一种靶向突触囊泡糖蛋白2A（SV2A）的新型放射性配体表明，精神分裂症患者在PFC水平的体内突触密度较低，这证实了费恩伯格于1982年首次提出的该疾病的突触假说。有趣的是，有力的临床前证据（体外和动物模型）表明，迷幻药有促进神经可塑性和突触形成的能力，可能抵消过度的突触损失，恢复体积损失，并可能解释早期临床研究中描述的阴性和认知症状的改善。总体而言，应首先探索微剂量作为对受缺陷型精神分裂症影响的选定患者样本的一种可能治疗方法，如果出现令人鼓舞的结果，则随后探索低剂量和全剂量。
