Role of fractalkine–CX3CR1 pathway in seizure-induced microglial activation, neurodegeneration, and neuroblast production in the adult rat brain

Abstract

Temporal lobe seizures lead to an acute inflammatory response in the brain primarily characterized by activation of parenchymal microglial cells. Simultaneously, degeneration of pyramidal cells and interneurons is evident together with a seizure-induced increase in the production of new neurons within the dentate gyrus of the hippocampus. We have previously shown a negative correlation between the acute seizure-induced inflammation and the survival of newborn hippocampal neurons. Here, we aimed to evaluate the role of the fractalkine-CX3CR1 pathway for these acute events. Fractalkine is a chemokine expressed by both neurons and glia, while its receptor, CX3CR1 is primarily expressed on microglia. Electrically-induced partial status epilepticus (SE) was induced in adult rats through stereotaxically implanted electrodes in the hippocampus. Recombinant rat fractalkine or CX3CR1 antibody was infused intraventricularly during one week post-SE. A significant increase in the expression of CX3CR1, but not fractalkine, was observed in the dentate gyrus at one week. CX3CR1 antibody treatment resulted in a reduction in microglial activation, neurodegeneration, as well as neuroblast production. In contrast, fractalkine treatment had only minor effects. This study provides evidence for a role of the fractalkine-CX3CR1 signaling pathway in seizure-induced microglial activation and suggests that neuroblast production following seizures may partly occur as a result of microglial activation.

Coupled Oscillators Model of Hyperexcitable Neuroglial Networks

“…Following seizures, changes in the morphological characteristics of microglia, such as increased numbers, increased cell body size, fewer processes, and decreased process branching have been reported [69]. In addition, increased expression of certain proteins, such as fractalkine receptors, have been observed in epileptic patients [79]. (Fractalkine receptors are selectively expressed on microglia and the fractalkine chemokine is expressed by neurons, facilitating a privileged interaction between the two populations [80]).…”

“…On the other hand, there is evidence for a harmful neurodegenerative role for microglia in epilepsy. 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].…”

Spatiotemporal expression and inhibition of prolyl oligopeptidase contradict its involvement in key pathologic mechanisms of kainic acid–induced temporal lobe epilepsy in rats

“…3,10,[34][35][36][37] For Ox-42 staining, images of ROIs were taken at 4× magnification with an AxioCam Erc5s (ZEISS, Germany) and converted into 8-bit images in ImageJ. ROI included the entire hippocampal cornu ammonis (CA)1, CA3, CA4, hilar sub-regions, and piriform cortex (PC).…”

“…3 The cells were counted in 3 sections and the average number of cells per section was recorded. ROIs were delineated for each hippocampal subregion and piriform cortex.…”

“…1,2 A proinflammatory response can contribute to cell death, 3,4 network excitability, 5,6 and synaptic reorganization. Current antiepileptic drugs are only symptomatic and around one-third of patients do not respond to treatment, highlighting the need to explore new therapies.…”