Doctoral defence: Fangling Xuan „Regulation of stress response in first episode schizophrenia by monocytes and microglia“

On May 17th Fangling Xuan will defend her thesis „Regulation of stress response in first episode schizophrenia by monocytes and microglia”.

Supervisors:
Professor Li Tian 
Professor Claudio Rivera Baeza, University of Helsinki (Finland)
Professor  Eero Vasar, University of Tartu
Research fellow Kersti Lilleväli, Centre of Estonian Rural Research and Knowledge

Opponent: 
Professor Pentti Tienari, University of Helsinki (Finland)

Summary
Schizophrenia, a complex neuropsychiatric disorder, affects approximately 1% of the global population and poses significant challenges in understanding its pathobiological mechanisms. This thesis aims to unravel the role of monocytes and microglia in neuroinflammatory processes in schizophrenia, particularly in the context of stress. Our investigations focused on first episode schizophrenia (FES) patients and animal stress models to elucidate molecular mechanisms mediated by these immune cells. In FES patients, alterations in monocyte-related transcriptomic profiles were found, notably in nonclassical and intermediate monocytic subsets. Besides, FES patients who exhibited higher stress sensitivity had smaller hippocampal structures and altered gene expression related to immune development. Microglial renewal partially mitigated psychiatric-like behavioral deficits induced by chronic unpredictable stress (CUS) in mice, via affecting brain transcriptomics involved in developmental processes, such as axonal and synaptic formation. Furthermore, FES patients with lower stress traits had smaller amygdala and higher PLXNB2 expression, which was negatively correlated with perceived stress severity. In mice, CUS led to a downregulation of Plxnb2 expression, and blocking Plxnb2 induced anxiety, amygdaloid enlargement, and microglial ramification. These findings suggest that while monocytic subsets and their genes can be detrimental for brain function and cognition in healthy individuals, they may develop maladaptive inflammation-related mechanisms to alleviate brain and cognitive deficits in FES. Microglial reprogramming might offer benefits in schizophrenia, particularly in stress perception. Furthermore, amygdaloid microglial activation, potentially modulated by Plxnb2, highlights a novel cellular and molecular mechanism underlying different stress traits associated with schizophrenia. This research provides valuable insights into the complex interplay between stress, monocytes/microglia function, and neuronal outcomes in schizophrenia, paving the way for future research and potential therapeutic interventions.