TY - JOUR
T1 - Interferon-γ exposure of human iPSC-derived neurons alters major histocompatibility complex I and synapsin protein expression
AU - Pavlinek, Adam
AU - Matuleviciute, Rugile
AU - Sichlinger, Laura
AU - Dutan Polit, Lucia
AU - Armeniakos, Nikolaos
AU - Vernon, Anthony Christopher
AU - Srivastava, Deepak Prakash
N1 - Funding Information:
The authors thank Daniel Beglin for his insightful comments on image analysis. The authors also thank the Wohl Cellular Imaging Centre (WCIC) at the IoPPN, Kings College, London, for help with microscopy.
Funding Information:
DS and AV: conception and design, literature searching, manuscript writing and editing, project supervision, and financial support. AP, RM, LS, LD, and NA: carried out experiments. AP: manuscript writing and editing. All authors approved the final manuscript.
Publisher Copyright:
Copyright © 2022 Pavlinek, Matuleviciute, Sichlinger, Dutan Polit, Armeniakos, Vernon and Srivastava.
PY - 2022/9/14
Y1 - 2022/9/14
N2 - Human epidemiological data links maternal immune activation (MIA) during gestation with increased risk for psychiatric disorders with a putative neurodevelopmental origin, including schizophrenia and autism. Animal models of MIA provide evidence for this association and suggest that inflammatory cytokines represent one critical link between maternal infection and any potential impact on offspring brain and behavior development. However, to what extent specific cytokines are necessary and sufficient for these effects remains unclear. It is also unclear how specific cytokines may impact the development of specific cell types. Using a human cellular model, we recently demonstrated that acute exposure to interferon-γ (IFNγ) recapitulates molecular and cellular phenotypes associated with neurodevelopmental disorders. Here, we extend this work to test whether IFNγ can impact the development of immature glutamatergic neurons using an induced neuronal cellular system. We find that acute exposure to IFNγ activates a signal transducer and activator of transcription 1 (STAT1)-pathway in immature neurons, and results in significantly increased major histocompatibility complex I (MHCI) expression at the mRNA and protein level. Furthermore, acute IFNγ exposure decreased synapsin I/II protein in neurons but did not affect the expression of synaptic genes. Interestingly, complement component 4A (C4A) gene expression was significantly increased following acute IFNγ exposure. This study builds on our previous work by showing that IFNγ-mediated disruption of relevant synaptic proteins can occur at early stages of neuronal development, potentially contributing to neurodevelopmental disorder phenotypes.
AB - Human epidemiological data links maternal immune activation (MIA) during gestation with increased risk for psychiatric disorders with a putative neurodevelopmental origin, including schizophrenia and autism. Animal models of MIA provide evidence for this association and suggest that inflammatory cytokines represent one critical link between maternal infection and any potential impact on offspring brain and behavior development. However, to what extent specific cytokines are necessary and sufficient for these effects remains unclear. It is also unclear how specific cytokines may impact the development of specific cell types. Using a human cellular model, we recently demonstrated that acute exposure to interferon-γ (IFNγ) recapitulates molecular and cellular phenotypes associated with neurodevelopmental disorders. Here, we extend this work to test whether IFNγ can impact the development of immature glutamatergic neurons using an induced neuronal cellular system. We find that acute exposure to IFNγ activates a signal transducer and activator of transcription 1 (STAT1)-pathway in immature neurons, and results in significantly increased major histocompatibility complex I (MHCI) expression at the mRNA and protein level. Furthermore, acute IFNγ exposure decreased synapsin I/II protein in neurons but did not affect the expression of synaptic genes. Interestingly, complement component 4A (C4A) gene expression was significantly increased following acute IFNγ exposure. This study builds on our previous work by showing that IFNγ-mediated disruption of relevant synaptic proteins can occur at early stages of neuronal development, potentially contributing to neurodevelopmental disorder phenotypes.
KW - C4A
KW - inflammation
KW - interferon-γ
KW - iPSC
KW - maternal immune activation
KW - MHCI
KW - schizophrenia
KW - synapsin
UR - http://www.scopus.com/inward/record.url?scp=85139104587&partnerID=8YFLogxK
U2 - 10.3389/fpsyt.2022.836217
DO - 10.3389/fpsyt.2022.836217
M3 - Article
AN - SCOPUS:85139104587
SN - 1664-0640
VL - 13
JO - Frontiers in Psychiatry
JF - Frontiers in Psychiatry
M1 - 836217
ER -