AIOLOS/IKZF3 REGULATES THE COMPLEMENT SYSTEM IN THE BRAIN: IMPLICATIONS FOR SCHIZOPHRENIA

Schizophrenia is a multifactorial disorder whose pathogenesis increasingly appears to involve immune dysregulation. Here, we explore Aiolos/IKZF3, a zinc-finger transcription factor best known in immune cells but also expressed in the brain, as a potential molecular bridge between neuroinflammation and SCZ-relevant phenotypes. We hypothesize that dysregulated Aiolos in the brain modulates neuroinflammatory pathways, consequently contributing to behavioral alterations relevant to SCZ.
We first explored the expression pattern of Aiolos in adult and developing brain. We found that Aiolos levels are high at early stages and subsequently decrease to a stable adult level. Furthermore, Aiolos is not only predominantly localized to the nucleus of principal neurons but also in the cytosol of some astrocyte in the hippocampus. We then explored Aiolos levels in samples from patients with Schizophrenia and found that its levels are increased in both, PBMCs and postmortem hippocampal samples from patients compared with matched controls. In order to mimick this condition. we then overexpressed Aiolos in mice hippocampi using AAV-based technology. Mice with Aiolos overexpression exhibit schizophrenia-like phenotypes, with cognitive impairments being the most prominent. Proteomic analyses of these hippocampi further link Aiolos to immune proteins, particularly the complement system and neuroinflammatory pathways.
Overall, our findings identify Aiolos as a key neuroimmune regulator. This work provides a mechanistic framework connecting immune dysregulation, hippocampal dysfunction, and cognitive symptoms in schizophrenia.