Postnatal Systemic Inflammation Exacerbates Impairment of Hippocampal Synaptic Plasticity in an Animal Seizure Model

Abstract

Objective: To investigate the effects of systemic inflammation in the critical postnatal stages on neurophysiological actions of immune processes and neural plasticity in adult rats after kainic acid (KA)-induced seizures. Methods: To determine changes in hippocampal synaptic plasticity after postnatal central nervous system inflammatory responses and seizure attacks, we performed intraperitoneal injections of lipopolysaccharide (LPS) in postnatal Sprague Dawley rats on day 14 (P14) to induce central nervous system inflammation. We then used a KA tail vein injection on P35 to induce seizure attacks. We compared the variability in synaptic plasticity in the hippocampal Schaffer collateral-CA1 region of seizure animals with or without LPS-induced inflammation preconditioning. Results: P14 injection of LPS increased susceptibility to seizures, while treatment with KA on P35 induced seizures. Long-term potentiation (LTP) of the Schaffer collateral-CA1 region was impaired in seizure animals, and this effect was more pronounced in the P14 LPS injection group. Fluoro-Jade staining revealed an increase in degenerated hippocampal CA1 pyramidal cells in the P14 LPS injection group. Cytokine expression in the hippocampus in the pre-, peri- and postictus periods was greater in P14 LPS rats than in saline-treated rats. Conclusions: Intraperitoneal LPS injection on P14 induces higher cytokine secretion after KA-induced seizures, enhancing neuronal excitability, shortening seizure onset time and exacerbating neuronal degeneration and impairment of LTP formation in the hippocampal Schaffer collateral-CA1 region. Central nervous system inflammation during critical stages of childhood development could disrupt the balance needed for neurophysiological actions of immune processes, producing direct, pernicious effects on memory, neural plasticity and neurogenesis into adulthood.

Increased interleukin-6 and high-sensitivity C-reactive protein levels in pediatric epilepsy patients with frequent, refractory generalized motor seizures

“…Experimental evidence indicates significant roles for inflammatory and immune mediators in the initiation of seizures and epileptogenesis. [15][16][17][18][19][20][21][22][23][24][25][26][27][28] In particular, cytokines including IL-1b, IL-6, and TNF-a, and Toll-like receptor 4 have been shown to contribute to seizure generation and epileptogenesis. 28,29 In addition to experimental studies using animal models, human clinical studies have demonstrated alterations in the levels of IL-6 in samples from patients with epilepsy.…”

Inhibition of long-term potentiation in the schaffer-CA1 pathway by repetitive high-intensity sound stimulation

“…Several lines of evidence suggest that seizures can have a profound impact in hippocampal synaptic plasticity (Reid and Stewart, 1997). For instance, recurrent seizures reduce hippocampal LTP and function in rats (Zhou et al, 2007;Chen et al, 2013) whereas febrile seizures in early life enhance hippocampal LTP and decrease LTD) (Notenboom et al, 2010). Additionally, sustained Status Epilepticus (SE) induced by pilocarpine enhances LTP in hippocampal CA1 neurons of rats (Mu¨ller et al, 2013).…”

Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis?

“…Transient cytokine release (including IL-1b, TNFb, and IL-6; see Table 1), microglial priming, and astrocyte reactivity are all mechanisms by which early life immune challenges can yield long-lasting effects on seizure threshold. Several other cytokines, chemokines, and (Heida and Pittman, 2005;Vezzani et al, 2008;Chen et al, 2013) Preterm (Dube et al, 2005;Dube et al, 2010;Fukuda et al, 2014;Fukuda et al, 2015;Patterson et al, 2015) Status epilepticus KA kindling; lithiumpilocarpine Rat, p9-15 • Upregulated IL-1b and IL-1R acutely and chronically (to 8 weeks), associated with glial activation (Holmes and Thompson, 1988;Rizzi et al, 2003;Omran et al, 2012 (Fukuda et al, 2007) Viral infection (MIA) Systemic or intracerebral poly I:C administration Mouse, g12-16 • Chronic epilepsy phenotype in offspring prevented by antibodies to IL-1b and IL-6 (when combined) (Pineda et al, 2013) Prenatal (Galic et al, 2008;Chen et al, 2013;Kosonowska et al, 2015) Bacterial infection (meningitis)…”

“…This time period coincides with the developmental peak in synaptogenesis and synaptic pruning, yielding considerable changes in neuronal circuitry which likely underlies this critical window of vulnerability. This paradigm has since been used to demonstrate that LPS exposure increases susceptibility to KA-induced seizures at p35, alongside impairments in long-term potentiation and exacerbated hippocampal neurodegeneration (Chen et al, 2013), and pilocarpineinduced seizures at 2 months of age (Setkowicz et al, 2017). In another study, KA was administered simultaneously with LPS to p14 pups, revealing long-lasting molecular changes alongside increased seizure excitability by adulthood.…”