Ballasch Iván, López-Molina Laura, Galán-Ganga Marcos, Sancho-Balsells Anna, Rodríguez-Navarro Irene, Borràs-Pernas Sara, Rabadan M Angeles, Chen Wanqi, Pastó-Pellicer Carlota, Flotta Francesca, Maoyu Wang, Fernández-Irigoyen Joaquín, Santamaría Enrique, Aguilar Ruth, Dobaño Carlota, Egri Natalia, Hernandez Carla, Alfonso Miqueu, Juan Manel, Alberch Jordi, Del Toro Daniel, Arranz Belén, Canals Josep M, Giralt Albert
Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, 08036, Barcelona, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain.
J Neuroinflammation. 2024 Dec 18;21(1):326. doi: 10.1186/s12974-024-03320-3.
Schizophrenia is a complex multifactorial disorder and increasing evidence suggests the involvement of immune dysregulations in its pathogenesis. We observed that IKZF1 and IKZF2, classic immune-related transcription factors (TFs), were both downregulated in patients' peripheral blood mononuclear cells (PBMCs) but not in their brain. We generated a new mutant mouse model with a reduction in Ikzf1 and Ikzf2 to study the impact of those changes. Such mice developed deficits in the three dimensions (positive-negative-cognitive) of schizophrenia-like phenotypes associated with alterations in structural synaptic plasticity. We then studied the secretomes of cultured PBMCs obtained from patients and identified potentially secreted molecules, which depended on IKZF1 and IKZF2 mRNA levels, and that in turn have an impact on neural synchrony, structural synaptic plasticity and schizophrenia-like symptoms in in vivo and in vitro models. Our results point out that IKZF1-IKZF2-dependent immune signals negatively impact on essential neural circuits involved in schizophrenia.
精神分裂症是一种复杂的多因素疾病，越来越多的证据表明免疫失调参与了其发病机制。我们观察到，经典的免疫相关转录因子IKZF1和IKZF2在患者外周血单核细胞（PBMC）中均下调，但在其大脑中未下调。我们构建了一种新的Ikzf1和Ikzf2表达降低的突变小鼠模型，以研究这些变化的影响。此类小鼠在精神分裂症样表型的三个维度（阳性-阴性-认知）上出现缺陷，并伴有结构突触可塑性的改变。然后，我们研究了从患者获取的培养PBMC的分泌蛋白质组，并鉴定了潜在的分泌分子，这些分子依赖于IKZF1和IKZF2的mRNA水平，进而在体内和体外模型中对神经同步性、结构突触可塑性和精神分裂症样症状产生影响。我们的结果指出，依赖IKZF1-IKZF2的免疫信号对精神分裂症相关的关键神经回路产生负面影响。
