A study published in the journal Brainindicates that the innate immune response to toll-like receptor 4 (TLR4) ligands, most likely involving activated microglia and release of interleukin (IL)-1, results in increased neuronal excitability sufficient to trigger experimental seizures in vivo.
An increasing body of evidence suggests that inflammatory processes may play an important role in the initiation of seizures and epileptogenesis. This includes both the generation of individual seizures and the process by which a previously normal brain might become epileptic (epileptogenesis).
Epilepsy research is mostly ‘neurocentric’, but glial cells far outnumber neurons in the forebrain and are perfectly situated to modulate neuronal function by encapsulating neuronal synapses and maintaining neurotransmitter balance. These cells have been largely ignored with respect to their potential influence on normal or abnormal electrical activity of neural circuits. With the recent reports of dynamic neuro-glial interactions the possible modulating role of glial cells in epileptogenicity has received intense interest.
Glial cells have long been thought to provide only metabolic/structural support in the cerebral cortex. Microglia are activated by central infection, trauma and ischemia. Of note, glial cells are clearly activated following seizures in experimental models of epileptic foci, and this is associated with increased local IL-1β mRNA expression.
Recent evidence indicates that chemically induced visceral inflammation is correlated with widespread activation of cortical glial cells, and decreased thresholds for generalized pentylenetetrazol (PTZ)-induced seizures that can be reversed by cortical application of the anti-inflammatory glial inhibitor minocycline. These results strongly implicate glial cells and the accompanying innate immune response in the facilitation of generalized seizures when the cortex is challenged by convulsant compounds.
This also raises the possibility that direct activation of brain innate immunity, characteristic of more commonly observed cortical insult and focal epilepsy, could participate in epileptogenesis. It is possible that innate immune responses alone, in the absence of convulsive agents and prior seizures, could independently increase cortical excitbility and serve as a source as well as potentiator of epileptogenesis.
In the Brain journal’s study Krista Rodgers and co-workers from the Department of Psychology and Neuroscience, University of Colorado, USA demonstrate that the cortical innate immune responses contribute to enhanced brain excitability resulting in focal seizures.
The authors found that the cortical application of bacterial lipopolysaccharide (LPS), binding to TLR4, produced spontaneous epileptiform discharges. Epicortical application of more concentrated LPS produced spontaneous epileptiform discharge within 10–20 min. Three animals exhibited motor characteristics of focal seizures, with extension and superimposed twitching of the tail, contralateral hindpaw and/or forepaw.
These effects are prevented by pre-application of interleukin-1 receptor antagonist (IL-1ra). Application of IL-1ra prior to LPS prevented both seizures and epileptiform spikes in tested animals, indicating the involvement of IL-1. In bilateral preparations prevention of epileptiform spiking was achieved with IL-1ra in the left hemisphere while subsequent LPS application to the untreated contralateral hemisphere resulted in substantial epileptiform discharges.
Rodgers et al. discuss that IL-1 may increase neuronal excitability through its activating effect on astrocytes, interfering with their control of glutamate homeostasis. IL-1 released by microglia and/or astrocytes may also have direct effects on neuronal channels and excitability.
In conclusion, the authors demonstrate how the innate immune response may participate in acute seizures, increasing neuronal excitability through interleukin-1 release in response to TLR4 detection of the danger signals associated with infections of the central nervous system and with brain injury.
This study suggests an important role of innate immune responses and pro-inflammatory cytokines in epileptogenesis. The findings could help prevent acquired epilepsy, which is often found in people who have suffered a brain injury or infection.