Peripherally restricted acute phase response to a viral mimic alters hippocampal gene expression

Abstract

We have previously shown that peripherally restricted acute phase response (APR) elicited by intraperitoneal (i.p.) injection of a viral mimic, polyinosinic-polycytidylic acid (PIC), renders the brain hypersusceptible to excitotoxic insult as seen from profoundly exacerbated kainic acid (KA)-induced seizures. In the present study, we found that this hypersusceptibility was protracted for up to 72 h. RT-PCR profiling of hippocampal gene expression revealed rapid upregulation of 23 genes encoding cytokines, chemokines and chemokine receptors generally within 6 h after PIC challenge. The expression of most of these genes decreased by 24 h. However, two chemokine genes, i.e., Ccl19 and Cxcl13 genes, as well as two chemokine receptor genes, Ccr1 and Ccr7, remained upregulated for 72 h suggesting their possible involvement in the induction and sustenance of seizure hypersusceptibility. Also, 12 genes encoding proteins related to glutamatergic and GABAergic neurotransmission featured initial upregulation or downregulation followed by gradual normalization. The upregulation of the Gabrr3 gene remained upregulated at 72 h, congruent with its plausible role in the hypersusceptible phenotype. Moreover, the expression of ten microRNAs (miRs) was rapidly affected by PIC challenge, but their levels generally exhibited oscillating profiles over the time course of seizure hypersusceptibility. These results indicate that protracted seizure susceptibility following peripheral APR is associated with a robust polygenic response in the hippocampus.

Cerebral Response to Peripheral Challenge with a Viral Mimetic

“…At 48 h after LPS challenge, 71 genes were found dysregulated (25), while 260 genes were dysregulated by PIC (26). Only 23 genes were commonly affected by both inflammagens, whereas 48 and 237 genes were dysregulated exclusively by LPS and PIC, respectively.…”

“…We have recently shown that the rearing activity of mice challenged with PIC is equally reduced at 6 h (26). In contrast to the burrowing test that is rather intricate and time-consuming (2 h testing time), the rearing test is a simple procedure that can be completed within 15 min.…”

“…This is manifested as a transient elevation of blood levels of interferon β (IFNβ), interleukin 6 (IL-6), tumor necrosis factor α (TNFα) and IL1β (26, 27). Blood levels of these cytokines peak at 3 h post-injection, rapidly decline by 6 h and gradually dwindle to the basal level.…”

“…However, a plethora of genes related to neurotransmission were also dysregulated. Moreover, ten microRNAs that modulate both neural and immune functions or are associated with seizure pathology also featured differential expression following PIC challenge (26). Altogether, these results indicate an extensive genomic reprogramming in the hippocampal cells instigated by peripheral antiviral response.…”

“…Intraperitoneal PIC injection also increases the vulnerability of the brain to excitotoxic insults as seen from hypersusceptibility to kainic acid (KA)-induced seizures (26, 94). This hypersusceptibility manifests as a robust increase in both the severity and protracted duration of status epilepticus as compared to saline-injected mice.…”