Roles of astrocytes and microglia in seizure‐induced aberrant neurogenesis in the hippocampus of adult rats

Abstract

Recent evidence showed that epileptic seizures increase hippocampal neurogenesis in the adult rat, but prolonged seizures result in the aberrant hippocampal neurogenesis that often leads to a recurrent excitatory circuitry and thus contributes to epileptogenesis. However, the mechanism underlying the aberrant neurogenesis after prolonged seizures remains largely unclear. In this study, we examined the role of activated astrocytes and microglia in the aberrant hippocampal neurogenesis induced by status epilepticus. Using a lithium-pilocarpine model to mimic human temporal lobe epilepsy, we found that status epilepticus induced a prominent activation of astrocytes and microglia in the dentate gyrus 3, 7, 14, and 20 days after the initial seizures. Then, we injected fluorocitrate stereotaxicly into the dentate hilus to inhibit astrocytic metabolism and found that fluorocitrate failed to prevent the seizure-induced formation of ectopic hilar basal dendrites but instead promoted the degeneration of dentate granule cells after seizures. In contrast, a selective inhibitor of microglia activation, minocycline, inhibited the aberrant migration of newborn neurons at 14 days after status epilepticus. Furthermore, with stereotaxic injection of lipopolysaccharide into the intact dentate hilus to activate local microglia, we found that lipopolysaccharide promoted the development of ectopic hilar basal dendrites in the hippocampus. These results indicate that the activated microglia in the epileptic hilus may guide the aberrant migration of newborn neurons and that minocycline could be a potential drug to impede seizure-induced aberrant migration of newborn neurons.

Coupled Oscillators Model of Hyperexcitable Neuroglial Networks

“…Ali et al, for example, found that the inhibition of fractalkine signaling reduced neurodegeneration in the hippocampus [79]. In addition, microglia may contribute to seizure-induced aberrant neurogenesis [84].…”

A Functional Role for Microglia in Epilepsy

“…A recent study confirmed the presence both of activated microglial and also immunoreactive leukocytes in tissue resected from patents with intractable medial temporal lobe epilepsy, and in kainic acid (KA) treated mice, either associated with blood vessels or distributed intraparenchymally in the CA1-CA3, hillus, and to a lesser extent, dentate gyrus (Zattoni et al, 2011). Following pilocarpine induced seizures in mice, microgliosis persists for at least 3-31 days in regions of neuronal loss such as the hippocampus and amygdala (Borges et al, 2003, Yang et al, 2010a. However, we have shown that during KA excitotoxicity, microglia activation is associated with tPA release from injured neurons, and thus is a consequence rather than a cause of neurodegeneration, but overall this microglia activation can further exacerbate the injury (Siao et al, 2003).…”

“…Given the plethora of molecules microglia release, one can easily imagine numerous potential outcomes. For instance, it has been proposed that microglia activation may contribute to spontaneous recurrent seizures (SRS) by facilitating aberrant migration of newborn neurons in the DG (Yang et al, 2010a). This study showed that LPS injected directly into the DG promoted the development of ectopic hilar basal dendrites in the hippocampus, while addition of minocycline that blocked microglia activation, prevented it.…”

“…There are a few examples in the literature where preconditioning microglia with LPS modulates seizures including our own, and this will be discussed in more detail in the next section (Sayyah et al, 2003, Akarsu et al, 2006, Arican et al, 2006, Dmowska et al, 2010, Mirrione et al, 2010, Yang et al, 2010a. One mechanism that may contribute to the positive effects attributed to LPS preconditioning is through enhanced neurotrophin release (Nakajima et al, 2001a).…”

Transient extracellular application of gold nanostars increases hippocampal neuronal activity

“…It is not known whether this increase in firing rate could cause pathological conditions that involve the hippocampus, such as epilepsy [16]. Increases in neuronal activity in isolated preparations could be compensated by network dynamics [17]. Oscillations in the brain are common [18]; therefore, nanoparticle induced increases in firing rate could occur without a behavioral effect.…”