Effects of minocycline on dendrites, dendritic spines, and microglia in immature mouse brains after kainic acid‐induced status epilepticus

Abstract

PurposeThis study aimed to investigate whether minocycline could influence alterations of microglial subtypes, the morphology of dendrites and dendritic spines, the microstructures of synapses and synaptic proteins, or even cognition outcomes in immature male mice following status epilepticus (SE) induced by kainic acid.MethodsGolgi staining was performed to visualize the dendrites and dendritic spines of neurons of the hippocampus. The microstructures of synapses and synaptic proteins were observed using transmission electron microscopy and western blotting analysis, respectively. Microglial reactivation and their markers were evaluated using flow cytometry. The Morris water maze (MWM) test was used to analyze spatial learning and memory ability.ResultsSignificant partial spines increase (predominate in thin spines) was observed in the dendrites of neurons after acute SE and partial loss (mainly in thin spines) was presented by days 14 and 28 post‐SE. The postsynaptic ultrastructure was impaired on the 7th and 14th days after SE. The proportion of M1 microglia increased significantly only after acute SE Similarly, the proportion of M2 microglia increased in the acute stage with high expression levels of all surface markers. In contrast, a decrease in M2 microglia and their markers was noted by day 14 post‐SE. Minocycline could reverse the changes in dendrites and synaptic proteins caused by SE, and increase the levels of synaptic proteins. Meanwhile, minocycline could inhibit the reactivation of M1 microglia and the expression of their markers, except for promoting CD200R. In addition, treatment with minocycline could regulate the expression of M2 microglia and their surface markers, as well as ameliorating the impaired spatial learning and memory on the 28th day after SE.ConclusionsDendritic spines and microglia are dynamically changed after SE. Minocycline could ameliorate the impaired cognition in the kainic acid‐induced mouse model by decreasing the damage to dendrites and altering microglial reactivation.

Exploring Dendritic and Spine Structural Profiles in Epilepsy: Insights From Human Studies and Experimental Animal Models

“…22 In line with these findings, a time course analysis performed between 1 and 3 weeks after ELS induced with the chemoconvulsant kainic acid (KA) in P14 mice revealed an initial rise in GC dendritic branching and spine density along with a persistent reduction in dendritic branching within CA1 and CA3 cells. 21 Additionally, an increased abundance of thin-shaped spines coupled with a decreased density of stubby-shape spines in CA1 dendrites was observed between 1-and 4-weeks following hypoxia-induced seizures in P10 rats 19 as well as following KA in immature mice. 21 Given that short CA1 dendrites, arborized GC dendrites, and thin-shaped spines are indicative of an immature state, 17 it is possible that ELS may disrupt the maturation of dendritic architectures.…”

“…21 Additionally, an increased abundance of thin-shaped spines coupled with a decreased density of stubby-shape spines in CA1 dendrites was observed between 1-and 4-weeks following hypoxia-induced seizures in P10 rats 19 as well as following KA in immature mice. 21 Given that short CA1 dendrites, arborized GC dendrites, and thin-shaped spines are indicative of an immature state, 17 it is possible that ELS may disrupt the maturation of dendritic architectures.…”

“…1,15,16 However, events such as early-life seizures (ELS) can disrupt these processes and harm the proper network connectivity and function of the developing brain. 17 Experimental models of ELS occurring between the first and second weeks of postnatal development are associated with long-lasting alterations of hippocampal dendritic architectures [18][19][20][21][22] and hippocampal-dependent spatial learning and memory dysfunctions. 17,18,20,21 Dendritic structural alterations in CA1 pyramidal cells and dentate granule cells (GCs) have been consistently reported in studies utilizing different models of ELS induced by the volatile convulsant flurothyl, 20 hyperthermia, 18,22 chemoconvulsants, 21 or hypoxia.…”

“…17 Experimental models of ELS occurring between the first and second weeks of postnatal development are associated with long-lasting alterations of hippocampal dendritic architectures [18][19][20][21][22] and hippocampal-dependent spatial learning and memory dysfunctions. 17,18,20,21 Dendritic structural alterations in CA1 pyramidal cells and dentate granule cells (GCs) have been consistently reported in studies utilizing different models of ELS induced by the volatile convulsant flurothyl, 20 hyperthermia, 18,22 chemoconvulsants, 21 or hypoxia. 19 Seizures triggered with flurothyl inhalation during postnatal days (P) 7 to 11 in mice resulted in decreased basal dendrite length and branching of CA1 neurons and impaired spatial learning and memory functions 6 weeks later.…”

“…Underlying mechanisms may be related to impaired growth or excessive pruning of CA1 dendrites or amplified growth or inadequate pruning of GCs, potentially involving signaling cascades such as neuron-restrictive silencer factor (NRSF), 18 calcineurin, 24 immune complement molecules, 8,14 microglia, 21 and the mTOR pathway (discussed next). It is noteworthy that treatments involving minocycline 21 and NRSF signaling inhibitors 18 attenuated some of the dendritic pathology and improved hippocampal-dependent functions. This finding suggests that ELS may contribute to the development of behavioral and/or cognitive impairments later in life.…”