Biology subjects

Sichlinger, L.

Publications and source records attributed to Sichlinger, L..

3 recordsLinked to original sources

bioRxiv2022

Acute IL-6 exposure triggers canonical IL-6R signalling in hiPSC microglia, but not neural progenitor cells.

BackgroundExposure to elevated interleukin (IL)-6 levels in utero is consistently associated with increased risk for psychiatric disorders with a putative neurodevelopmental origin, such as schizophrenia (SZ) and autism spectrum condition (ASC). Although rodent models provide causal evidence for this association, we lack a detailed understanding of the cellular and molecular mechanisms in human model systems. To close this gap, we characterised the response of hiPSC-derived microglia-like cells (MGL) and neural progenitor cells (NPCs) to IL-6 in monoculture. ResultsWe observed that human forebrain NPCs did not respond to acute IL-6 exposure in monoculture at both a protein and transcript level due to the absence of IL-6Ra expression and sIL-6Ra secretion. By contrast, acute IL-6 exposure resulted in STAT3 phosphorylation and increased IL-6, JMJD3 and IL-10 expression in MGL, confirming activation of canonical IL-6R signalling. Bulk RNAseq identified 156 upregulated genes (FDR <0.05) in MGL following acute IL-6 exposure, including IRF8, REL, HSPA1A/B and OXTR, which significantly overlapped with an upregulated gene set from post-mortem brain tissue from individuals with schizophrenia. Acute IL-6 stimulation significantly increased MGL motility suggestive of a gain of surveillance function, consistent with gene ontology pathways highlighted from the RNAseq data. Finally, MGLs displayed elevated CCL1, CXCL1, MIP-1A/B, IL-8, IL-13, IL-16, IL-18, MIF and Serpin-E1 secretion post 3h and 24h IL-6 exposure. ConclusionOur data provide evidence for cell specific effects of acute IL-6 exposure in a human model system and strongly suggest microglia-NPC co-culture models are required to study how IL-6 influences human cortical neural progenitor cell development in vitro.

neuroscience↗

bioRxiv2021

Interferon-γ Exposure of Human iPSC-derived Neurons Alters Major Histocompatibility Complex I and Synapsin I Protein Expression

Human epidemiological data links maternal immune activation during gestation with increased risk for neurodevelopmental disorders including schizophrenia. Animal models of maternal immune activation (MIA) provide causal evidence for this association and strongly suggest that inflammatory cytokines act is a critical link between maternal infection and aberrant offspring brain and behavior development. This includes evidence for reduced synapse formation, consistent with post-mortem and in vivo evidence of reduced synaptic density in schizophrenia. However, to what extent specific cytokines are necessary and sufficient for these effects remains unclear. Using a human cellular model, we recently demonstrated that acute exposure to interferon-{square} (IFN{square}) recapitulates molecular and cellular phenotypes associated with neurodevelopmental disorders. Here, we extend this work to test whether IFN{square} affects synapse formation in an induced neuron model that generates forebrain glutamatergic neurons. Using immunocytochemistry and quantitative PCR, we demonstrate that acute IFN{square} exposure results in significantly increased MHCI expression at the mRNA and protein level. Furthermore, acute IFN{square} exposure decreases synapsin I protein in neurons but does not affect synaptic gene mRNA levels. Interestingly, complement component 4A (C4A) mRNA is also significantly increased following acute IFN{square} exposure. This study builds on our previous work by showing that IFN{square}-mediated disruption of relevant synaptic proteins can occur at early stages of synapse formation, potentially contributing to neurodevelopmental disorder phenotypes such as schizophrenia.

neuroscience↗

bioRxiv2021

Schizophrenia Risk Proteins ZNF804A and NT5C2 Interact at Synapses

The zinc finger protein 804A (ZNF804A) and the 5'-nucleotidase cytosolic II (NT5C2) genes have been identified as robust susceptibility genes in large-scale genome-wide association studies of schizophrenia. The ZNF804A and NT5C2 proteins are highly expressed in developing and mature cortical neurons. ZNF804A has been implicated in regulating the development of neuronal morphology; it localises to synapses and is required for activity-dependent modifications of dendritic spines. NT5C2 has been shown to regulate 5' adenosine monophosphate-activated protein kinase activity and implicated in influencing protein synthesis in neural progenitor cells. But despite these findings, a better understanding of the role these proteins play in regulating neuronal function is needed. A recent yeast two-hybrid screen has identified ZNF804A and NT5C2 as potential interacting proteins, but whether this occurs in situ; and moreover, in cortical neurons, is unknown. Here we show that ZNF804A and Nt5C2 colocalise and interact in hEK293T cells. Furthermore, their rodent homolouges, ZFP804A and NT5C2, specifically colocalise at synapses and form a protein complex in cortical neurons. Knockdown of Zfp804A or Nt5c2 resulted in a significant decrease in synaptic expression of both proteins, suggesting that both proteins are required for the synaptic targeting of each other. Taken together, these data indicate that ZNF804A/ZFP804A and NT5C2 interact together in cortical neurons and indicate that these GWAS risk factors may function as a complex to regulate neuronal function.

neuroscience↗