Alterations of the IKZF1-IKZF2 tandem in immune cells of schizophrenia patients regulate associated phenotypes
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.
Authors
- Albert Giralt (ORCID: https://orcid.org/0000-0001-5334-0963)
- Daniel del Toro (ORCID: https://orcid.org/0000-0002-7416-2155)
- M. Angeles Rabadán (ORCID: https://orcid.org/0000-0003-0060-144X)
- Sara Borràs‐Pernas
- Marcos Galán-Ganga (ORCID: https://orcid.org/0009-0005-1399-2058)
- Natalia Egri (ORCID: https://orcid.org/0000-0001-7698-0672)
- Wanqi Chen (ORCID: https://orcid.org/0000-0001-5990-3691)
- Jordi Alberch (ORCID: https://orcid.org/0000-0002-8684-2721)
- Josep M. Canals (ORCID: https://orcid.org/0000-0001-6829-7670)
- Anna Sancho‐Balsells (ORCID: https://orcid.org/0000-0003-2053-7211)
- Belén Arranz (ORCID: https://orcid.org/0000-0003-3927-8803)
- Laura López-Molina (ORCID: https://orcid.org/0000-0002-6121-0779)
- Iván Ballasch (ORCID: https://orcid.org/0000-0001-9625-5144)
- Ruth Aguilar (ORCID: https://orcid.org/0000-0003-3277-3107)
- Manel Juan (ORCID: https://orcid.org/0000-0002-3064-1648)
- Enrique Santamaría (ORCID: https://orcid.org/0000-0001-8046-8102)
- Joaquín Fernández‐Irigoyen (ORCID: https://orcid.org/0000-0001-5072-4099)
- Carlota Dobaño (ORCID: https://orcid.org/0000-0002-6751-4060)
- Miqueu Alfonso (ORCID: https://orcid.org/0000-0002-0297-2351)
- Irene Rodríguez-Navarro (ORCID: https://orcid.org/0000-0002-1863-2124)
- Carlota Pastó-Pellicer
- Francesca Flotta
- Carla Hernández
- Wang Maoyu
Institutions
- Universidad Pública de Navarra (UPNA) (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Centro de Investigación Biomédica en Red de Salud Mental (ES)
- Centro de Investigación en Red en Enfermedades Cardiovasculares (ES)
- Navarrabiomed (ES)
- ZeClinics (Spain) (ES)
- Parc Sanitari Sant Joan de Déu (ES)
- Barcelona Institute for Global Health (ES)
- Fundació Clínic per a la Recerca Biomèdica (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Journal of Neuroinflammation
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1186/s12974-024-03320-3
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministerio de Ciencia e Innovación
- Universitat de Barcelona
- Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación