Peripheral immune challenges elicit differential up-regulation of hippocampal cytokine and chemokine mRNA expression in a mouse model of the 15q13.3 microdeletion syndrome.

Abstract

The human heterozygous 15q13.3 microdeletion is associated with neuropathological disorders, most prominently with epilepsy and intellectual disability. The 1.5Mb deletion encompasses six genes (FAN1 [MTMR15], MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7); all but one (TRPM1) are expressed in the brain. The 15q13.3 microdeletion causes highly variable neurological symptoms, and confounding factors may contribute to a more severe phenotype. CHRNA7 and KLF13 are involved in immune system regulation and altered immune responses may contribute to neurological deficits. We used the Df[h15q13]/+ transgenic mouse model with a heterozygous deletion of the orthologous region (Het) to test the hypothesis that the microdeletion increases innate immune responses compared to wild type (WT). Male and female mice were acutely challenged with the bacteriomimetic lipopolysaccharide (LPS, 0.1mg/kg, i.p.) or the viral mimetic polyinosinic:polycytidylic acid (Poly(I:C), 5mg/kg). Hippocampal mRNA expression of pro-inflammatory cytokines and chemokines were determined three hours after injection using quantitative PCR analysis. In controls, expression was not affected by sex or genotype. LPS and Poly(I:C) resulted in significantly increased hippocampal expression of cytokines, chemokines, and interferon-γ (IFNγ), with more robust increases for TNF-α, IL-6, IL-1β, CXCL1, and CCL2 by LPS, higher induction of IFNγ by Poly(I:C), and similar increases of CCL4 and CCL5 by both agents. Generally, Hets exhibited stronger responses than WT mice, and significant effects of genotype or genotype×treatment interactions were detected for CXCL1 and CCL5, and IL-6, IL-1β, and CCL4, respectively, after LPS. Sex differences were detected for some targets. LPS but not Poly(I:C), reduced overnight burrowing independent of sex or genotype, suggesting that LPS induced sickness behavior. Thus, mice carrying the microdeletion have an increased innate immune response following a LPS challenge, but further studies will have to determine the extent and mechanisms of altered immune activation and subsequent contributions to 15q13.3 microdeletion associated deficits.