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Published on: November 20, 2015
Postnatal inflammation increases seizure susceptibility in adult rats
Michael A Galic1, Kiarash Riazi, James G Heida
1Epilepsy and Brain Circuits Program, Hotchkiss Brain Institute, Department of Neuroscience, University of Calgary, Calgary, Alberta, Canada. magalic@ucalgary.ca
Insights
Early life immune challenges, like lipopolysaccharide (LPS) exposure, can increase adult seizure susceptibility. This effect, mediated by tumor necrosis factor alpha (TNFα), occurs during critical postnatal periods.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Postnatal development is a critical window where early insults can lead to long-lasting physiological changes.
- Immune system activation during this period may impact brain development and function, potentially influencing neurological disorders.
Purpose of the Study:
- To investigate if an immune challenge during early postnatal development alters neuronal excitability and seizure susceptibility in adult rats.
- To determine the critical postnatal period for LPS-induced changes in seizure susceptibility.
- To elucidate the role of tumor necrosis factor alpha (TNFα) in mediating these long-term effects.
Main Methods:
- Postnatal day 14 (P14) Sprague Dawley rats were injected with lipopolysaccharide (LPS) or saline.
- Neuronal excitability was assessed via extracellular recordings in hippocampal slices.
- Seizure susceptibility was evaluated using lithium-pilocarpine, kainic acid, and pentylenetetrazol challenges.
- The role of TNFα was investigated using antibody blockade and recombinant protein administration.
Main Results:
- Postnatal LPS injection significantly increased adult seizure susceptibility to various convulsants.
- LPS exposure during a critical window (P7-P14) induced persistent increases in seizure susceptibility.
- Increased cytokine release and hippocampal neuronal degeneration were observed post-seizure.
- TNFα blockade prevented LPS-induced seizures, while TNFα administration mimicked the effect.
- Astrocyte numbers slightly increased, but microglial activity and cytokine levels were not permanently altered.
Conclusions:
- A single LPS injection during a critical postnatal period induces long-lasting increases in seizure susceptibility.
- Tumor necrosis factor alpha (TNFα) plays a crucial role in mediating this LPS-induced increase in seizure susceptibility.
- These findings highlight the vulnerability of the developing brain to immune challenges and suggest potential therapeutic targets.
Abstract:
There are critical postnatal periods during which even subtle interventions can have long-lasting effects on adult physiology. We asked whether an immune challenge during early postnatal development can alter neuronal excitability and seizure susceptibility in adults. Postnatal day 14 (P14) male Sprague Dawley rats were injected with the bacterial endotoxin lipopolysaccharide (LPS), and control animals received sterile saline. Three weeks later, extracellular recordings from hippocampal slices revealed enhanced field EPSP slopes after Schaffer collateral stimulation and increased epileptiform burst-firing activity in CA1 after 4-aminopyridine application. Six to 8 weeks after postnatal LPS injection, seizure susceptibility was assessed in response to lithium-pilocarpine, kainic acid, and pentylenetetrazol. Rats treated with LPS showed significantly greater adult seizure susceptibility to all convulsants, as well as increased cytokine release and enhanced neuronal degeneration within the hippocampus after limbic seizures. These persistent increases in seizure susceptibility occurred only when LPS was given during a critical postnatal period (P7 and P14) and not before (P1) or after (P20). This early effect of LPS on adult seizures was blocked by concurrent intracerebroventricular administration of a tumor necrosis factor alpha (TNFalpha) antibody and mimicked by intracerebroventricular injection of rat recombinant TNFalpha. Postnatal LPS injection did not result in permanent changes in microglial (Iba1) activity or hippocampal cytokine [IL-1beta (interleukin-1beta) and TNFalpha] levels, but caused a slight increase in astrocyte (GFAP) numbers. These novel results indicate that a single LPS injection during a critical postnatal period causes a long-lasting increase in seizure susceptibility that is strongly dependent on TNFalpha.
