Acute Microglial Responses to Single Non-Epileptogenic vs. Epileptogenic Seizures in Mouse Hippocampus
Year: 2019
Type: dissertation
Abstract: As the resident macrophage of the central nervous system, microglia are in a uniquely privileged position to both affect and be affected by neuroinflammation, neuronal activity and injury, which are all hallmarks of seizures and the epilepsies.In one of the prototypical rodent models of seizure-induced epilepsy, hippocampal microglia become activated after prolonged, damaging seizures known as Status Epilepticus (SE).However, since SE comprises both neuronal hyperactivity and injury, the specific mechanisms triggering this microglial activation remain unclear, as does its relevance to the ensuing epileptogenic processes.The present studies employed another well-established seizure model, electroconvulsive shock (ECS), to study the effect of paroxysmal/ictal neuronal hyperactivity on mouse hippocampal microglia, in the absence of concomitant neuronal degeneration.Unlike SE, ECS did not cause neuronal injury and did not alter hippocampal CA1 microglial and astrocytic density, morphology nor baseline process motility.In contrast, both ECS and SE produced a similar increase in ATP-directed microglial process motility in acute slices and similarly upregulated expression of the iv chemokine CCL2.As opposed to the general pro-inflammatory environment produced after SE (where induction of CCL2, TNF, IL-1 and IL-6 signaling among others have been reported), the acute microglial response to ECS was more selective: I found upregulated expression of Ccl2 message but unchanged transcript levels of the proinflammatory cytokine Tnf.Whole-cell patch-clamp recordings of hippocampal CA1sr microglia showed that ECS enhanced purinergic currents mediated by P2X7 receptors, in the absence of changes in passive properties or voltage-gated currents or changes in receptor expression.This differs from previously described alterations in intrinsic characteristics and purinoreceptor upregulation which coincided with enhanced purinergic currents following SE.These ECS-induced effects point to a common "seizure signature" in hippocampal microglia, characterized by functional alterations to purinergic signaling.The data herein demonstrate that ictal activity per se can drive changes in microglial physiology.These described physiological changes (which up until now have been exclusively associated with prolonged and damaging seizures) are of added interest as they may be relevant to electroconvulsive therapy which remains a gold-standard treatment for depression.v ACKNOWLEDGEMENTS "O Lord, that lends me life, lend me a heart replete with thankfulness!"-William Shakespeare, Henry VI The research and writing of this thesis are dedicated to: Karen Gale, who picked my application and called me from the hospital to propose that we submit the CONACyT fellowship that supported my work these past 5 years.Nothing would make me feel prouder than when others would comment on how she would be proud of my progress and project. My mother Cecilia and my father Alberto, their spouses and all my siblings, but especially Gua for the constant inspiration.I honestly feel that she deserved a CONACyT award more than me, and am certain she would have received one if they still existed
Author: Alberto Sepulveda‐Rodriguez
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2997055125