Converging early responses to brain injury pave the road to epileptogenesis

Abstract

Epilepsy, characterized by recurrent seizures and abnormal electrical activity in the brain, is one of the most prevalent brain disorders. Over two million people in the United States have been diagnosed with epilepsy and 3% of the general population will be diagnosed with it at some point in their lives. While most developmental epilepsies occur due to genetic predisposition, a class of "acquired" epilepsies results from a variety of brain insults. A leading etiological factor for epilepsy that is currently on the rise is traumatic brain injury (TBI), which accounts for up to 20% of all symptomatic epilepsies. Remarkably, the presence of an identified early insult that constitutes a risk for development of epilepsy provides a therapeutic window in which the pathological processes associated with brain injury can be manipulated to limit the subsequent development of recurrent seizure activity and epilepsy. Recent studies have revealed diverse pathologies, including enhanced excitability, activated immune signaling, cell death, and enhanced neurogenesis within a week after injury, suggesting a period of heightened adaptive and maladaptive plasticity. An integrated understanding of these processes and their cellular and molecular underpinnings could lead to novel targets to arrest epileptogenesis after trauma. This review attempts to highlight and relate the diverse early changes after trauma and their role in development of epilepsy and suggests potential strategies to limit neurological complications in the injured brain.

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

“…In 30-to 40-hour simultaneous video and surface EEG recordings from rats 12 to 15 weeks after sham or FPI, none of the sham rats (n = 9) showed electrographic seizures, but spontaneous electrographic and behavioral seizures were observed in 8 of 13 FPI rats (~62%; Fig 4). In rats with spontaneous seizures, the average seizure severity was Racine score 3.37 AE 0.18 (range, [3][4], and average seizure duration was 97.88 AE 10.20 seconds (range, 50-140 seconds), confirming the risk for post-traumatic epileptogenesis in the experimental model. It is possible that strain differences, use of younger juvenile rats, which are more susceptible to adverse effects of brain injury, 40 implementation of injury on the day after surgery to minimize neuroprotection due to surgical anesthesia, and inclusion criteria based on apnea duration contributed to greater proportion of rats developing spontaneous seizures compared to earlier studies.…”

“…Although early increases in dentate excitability after brain injury have been proposed to contribute to epileptogenesis, a convincing demonstration of a causal association has been lacking. We recently showed that suppressing post‐traumatic increases in neurogenesis reduced dentate excitability and epileptogenesis in parallel, supporting the association between excitability and epileptogenesis .…”

“…and contribute to epileptogenesis. [3][4][5][6][7][8][9] However, the interaction between neurophysiological and inflammatory responses to injury and the underlying mechanisms are not fully understood. 10 Activation of the innate immune receptor Toll-like receptor 4 (TLR4) by its ligand high mobility group box chromosomal protein 1 (HMGB1), which is released during neuronal damage, is thought to play a critical role in the inflammatory responses to seizures and brain injury.…”

“…The divergent effect of TLR4 on network excitability underscores the need to identify the effectors and mechanisms underlying these disparate responses. Simultaneously, differential TLR4‐mediated effects present an unparalleled opportunity to address the long‐standing question concerning the role for altered network excitability in post‐traumatic epileptogenesis and to discriminate between the roles for neuronal and classical inflammatory effectors in injury‐induced epileptogenesis.…”

Distinct cellular mediators drive the Janus Faces of Toll-like Receptor 4 regulation of network excitability which impacts working memory performance after brain Injury

“…Activation of glial inflammatory signals including TNFα and purinergic receptors have been shown to impact synaptic plasticity and hippocampal memory function (Beattie et al, 2002;Belarbi et al, 2012;Pascual et al, 2012;Pribiag and Stellwagen, 2014). Increases in neuronal excitability and immune activation are hallmarks of traumatic brain injury and present a condition in which neuroimmune interactions are potentially accentuated (Chiu et al, 2016;Neuberger et al, 2017a). While post-traumatic inflammatory responses are implicated in neurodegeneration, and immunosuppressants can improve neurological outcomes after brain injury (Saletti et al, 2019), mechanisms underlying immune regulation of neuronal function and behaviors are not fully understood.…”