RNAseq data for FACS sorted glial cells KPNA4 KO mice for Importin a4 deficiency induces psychiatric disorder-related behavioral deficits and neuroinflammation in mice.

Importin a4, which is encoded by the Kpna4 gene, is a well characterized nuclear-cytoplasmic transport factor known to mediate transport of transcription factors including NF-?B. Here, we report that Kpna4 knock-out (KO) mice exhibit psychiatric disorder-related behavioral abnormalities such as anxiety-related behaviors, deceased social interaction and sensorimotor gating deficits. Contrary to a previous study predicting attenuated NF-?B activity as a result of Kpna4 deficiency, we observed a significant increase in expression levels of NF-?B genes and pro-inflammatory cytokines such as TNFa, Il1ß or Il-6 in the Prefrontal Cortex or Basolateral Amygdala of the KO mice. Moreover, examination of inflammatory responses in primary cells revealed that Kpna4 deficient cells have an increased inflammatory response, which was rescued by addition of not only full-length, but also a nuclear transport deficient truncation mutant of importin a4, suggesting contribution of its non-transport functions. Furthermore, RNAseq of sorted adult Microglia and Astrocytes and subsequent transcription factor analysis suggested increases in Polycomb repressor complex 2 (PRC2) activity in Kpna4 KO cells. Taken together, importin a4 deficiency induces psychiatric disorder-related behavioral deficits in mice, along with an increased inflammatory response and possible alteration of PRC2 activity in glial cells. Overall design: To investigate the molecular alterations behind the unexpected increase in proinflammatory activation induced by Kpna4 deficiency, we examined individual glial cell types to understand gene expression profiles in response to a proinflammatory stimulus. We applied a tissue disassociation-cell sorting strategy utilizing florescence activated cell sorting (FACS), to isolate both microglial (MG) and AST populations from mice administered LPS to stimulate inflammation. 20 hours before dissection, 1mg,/kg of LPS (L2880; Sigma-Aldrich, St. Louis, MO, USA) was intraperitoneally injected into 8 to 9 week-old WT and KPNA4 KO mice as an inflammatory stimulus. Animals were deeply anesthetized with isoflurane and used for subsequent cell collection and FACS experiments