OO248 - ROLE OF IL-1Β IN THE SYNAPTIC DYSFUNCTION INDUCED BY RECURRENT HERPES SIMPLEX VIRUS TYPE-1 REACTIVATIONS IN THE ADULT MICE BRAIN (ID 1401)
Abstract
Aims
A growing body of evidence suggests that HSV-1 infection is a risk factor for Alzheimer’s disease (AD). We recently developed a mouse model of multiple Herpes Simplex Virus Type-1 (HSV-1) replications within the brain showing typical AD hallmarks that include increased proinflammatory cytokine levels. Here, we investigated the contribution of Interleukin 1beta (IL-1β) increment to the HSV-1-induced synaptic dysfunction.
Methods
HSV-1 was inoculated via lip scarification in 1-month-old male C57/Bl6 mice. After two thermal stresses inducing virus reactivation, the AD-like phenotype was studied by electrophysiology, biochemistry, molecular biology and Real-Time PCR.
Results
In HSV-1-infected mice we found increased levels of IL-1β (20.9 ±1.1 vs. 5.8 ±2.1 pg/mg in mock-infected mice, p<0.05) that correlated with synaptic dysfunction assesses by deficits of: i) long-term potentiation (LTP) at CA3-CA1 hippocampal synapses; ii) pre- and post-synaptic proteins; iii) dendritic spine density in hippocampal neurons; iv) expression of plasticity-related genes. These effects were associated with enhanced mRNA levels of two transcriptional repressors, MeCP2 and REST (+5.5±1.4 and +3.0±0.8 fold increase vs. mock-infected mice, respectively; p<0.05). Of note, treatment of infected mice with the interleukin receptor antagonist, anakinra (30 mg/Kg i.p.): i) ameliorated LTP (78.7±12.6 vs. 58.2±7.9% without anakinra, P<0.05); ii) rescued the expression of synaptic proteins and dendritic spine density; iii) counteracted the HSV-1-induced increases in MeCP2 and REST at both mRNA and protein levels.
Conclusions
Our results suggest that IL-1β-activated pathways involving upregulation of MeCP2 and REST contribute to an AD-like phenotype in C57/Bl6 mice subjected to multiple HSV-1 reactivations in the brain.
