Gene dysregulation as a driver of acquired temporal lobe epilepsy: A Literature Review
Introduction: Temporal lobe epilepsy (TLE) is the commonest focal epilepsy. Acquired TLE is considered to occur as the result of a 3-phase process called epileptogenesis. Firstly, an ‘epileptogenic event’ occurs, for example traumatic brain injury. Next follows a latent period whereby hyperexcitable networks form and lower the seizure threshold. Finally, TLE emerges. The objective of this review is to investigate how gene dysregulation drives hyperexcitability during epileptogenesis.
Methods: Searches were conducted using keywords and medical subject headings on bibliographic databases and complemented by Google searches and manual revision of reference lists of retrieved articles.
Results: Multiple pathogenic processes occur during the latent phase of epileptogenesis, before acquired TLE is diagnosed. These are hippocampal sclerosis, synaptic reorganisation including mossy fibre sprouting, neuroinflammation, aberrant neurogenesis and astrogliosis. Furthermore, epigenetic signalling pathways including DNA methylation, histone modifications, transcriptional and post-transcriptional dysregulation drive these pathogenic brain changes.
Discussion: The epigenetic pathways that drive pathogenic brain changes following epileptogenic events are potential therapeutic targets for novel antiepileptic drugs. Targeting molecular pathways could prevent many cases of acquired TLE by halting epileptogenesis in the latent phase, meaning new therapies for acquired TLE have the potential to be antiepileptogenic rather than simply anticonvulsant.
Epilepsy a disorder whereby abnormal brain activity results in unprovoked seizures, altered behaviour, abnormal sensations, or loss of awareness1. Epilepsy is among the commonest neurological conditions, with a worldwide prevalence of 50 million people2. Globally, an estimated five million people are diagnosed with epilepsy every year3. Epilepsy is not a single entity, rather a spectrum of disorders4. The International League Against Epilepsy (ILAE) classified epileptic seizures into 3 groups depending on if they are focal or generalised5. Generalised seizures affect both brain hemispheres, focal seizures start in a single side, and unknown onset seizures is a category used this information is not known5.
Temporal lobe epilepsy (TLE), meaning seizures involving the temporal lobes, is the commonest focal epilepsy (60% of cases)6. TLE is classified by the ILAE as mesial TLE, arising in medial structures including the hippocampus and amygdala, and lateral TLE, arising in temporal lobe neocortex7,8. TLE is diagnosed using clinical features and electroencephalogram findings9.
TLE seizures are classified as focal unaware automatisms10, involuntary motor activities that are normally accompanied by impaired consciousness and amnesia11. Common TLE automatisms involve the hands (fumbling/fidgeting) or mouth (chewing/swallowing)11. An aura often precedes TLE seizures, which can range from epigastric pain to déjà vu10. Autonomic phenomena can precede these seizures, including salivation, palpitations, or urges to urinate/defaecate10. Postictally, confusion and aphasia are common11.
Current first line treatments for acquired TLE are anti-epileptic drugs (AEDs)6, which 20-40% of cases are refractory to12. AEDs are defined as agents which decrease the frequency and/or severity of epileptic seizures13. In cases refractory to AEDs, surgery, usually resective procedures, are considered6. If surgery is not possible or unsuccessful, devices including vagus nerve stimulation may control seizures6.
The primary cause of TLE is neuronal hyperexcitability in the temporal lobe14. Factors causing this imbalance are genetic or acquired, most likely a combination14. Although there are families with familial monogenic TLE such as Autosomal Dominant Lateral TLE, and Familial Mesial TLE14, typically TLE is not associated with Mendelian inheritance.
Environmental factors can be involved in acquired TLE’s aetiology, including traumatic brain injury (TBI), previous infections including encephalitis/meningitis, brain arteriovenous malformations, strokes and brain tumours15. The process linking these factors to the development of epilepsy is termed epileptogenesis16. This process has three phases: firstly, occurrence of an ‘epileptogenic event’. Next, a latent period during which changes in gene expression occur in affected neurons and result in hyperexcitable networks and a lowered seizure threshold. The third and final stage is emergence of epilepsy16.
However, often none of these factors are evident in a patient’s history, therefore the aetiology of TLE is complex, likely involving dysregulation in various susceptibility genes along with environmental factors, making TLE a heterogenous polygenic condition14.
This review’s objective is to investigate how gene dysregulation drives acquired TLE. Furthering knowledge is a crucial first step in developing novel AEDs targeting gene dysregulation during the latent period of epileptogenesis rather than simply suppressing seizures symptomatically. Effective early treatment of TLE in this manner may prevent years of unnecessary seizures and the long-term consequences, including cognitive impairment17. Moreover, epigenetic factors regulate multiple pathways, therefore targeting one of these molecules has the potential to influence many pathological changes that take place in the epileptic brain. Current AEDs target just one type of pathway, and recent trials which target just one channel have failed to prevent epilepsy development18,19. Targeting a single pathway is insufficient to halt epileptogenesis, and targeting these “master-regulators” could be a better approach.
To obtain relevant published literature, searches using keywords and medical subject headings (MeSH) relating to gene dysregulation and acquired TLE were conducted on the following bibliographic databases: Embase, PubMed and Ovid MEDLINE. The keywords/MeSH terms used were the following: Epigenetics, epigenomics, epileptogenesis, temporal lobe epilepsy, acquired epilepsy, partial epilepsy. Searches were complemented by Google searches using similar keyword strategies, and manual revision of reference lists of retrieved articles.
Review of retrieved literature revealed multiple pathological processes function in the development of acquired TLE.
- Cell loss/Sclerosis
Hippocampal sclerosis (HS) is a common pathology in epilepsy20, detected in 65-70% of cases of medically intractable TLE21. The hippocampus is an extension of cortex functioning in learning, memory, navigation, and emotional regulation22. The histopathologic hallmark of HS is segmental pyramidal cell loss23. In 2013 the ILAE classified HS into three types, distinguishable by visual examination of surgical specimens23. Type 1 is the commonest, exhibiting cell loss in CA4 and CA1 sectors. Type 2 is a rarer subtype with in CA1-dominant cell loss23. Type 3 is another rare variant showing CA4-predominant cell loss23.
The aetiology of HS remains controversial, but is likely a multifactorial sporadic condition24. HS is considered an acquired pathology, e.g. prolonged childhood febrile seizures24. Genetic susceptibility determinants to HS are not yet clearly defined, but likely exist24.
- Synaptic Reorganisation & Mossy Fibre Sprouting (MFS)
In response to HS-related damage, hippocampal pathways undergo different synaptic rearrangements25. Structural changes occur in the hippocampus of patients with acquired TLE, including loss of inhibitory interneurons, hypertrophy of surviving interneurons, GABAergic axon sprouting, dispersion of granule cells to ectopic locations, excessive development of hilar basal dendrites on granule cells and MFS26. MFS is a form of long-lasting synaptic reorganisation whereby granule cell axons grow into their own dendritic field in the inner molecular layer, creating recurrent excitatory circuits27. Despite much investigation, the role of MFS in epileptogenesis remains controversial26. While MFS is one of the most consistent pathological findings in acquired TLE and there is data supporting MFS drives recurrent seizure activity28, many researchers found that blocking MFS does not reduce seizure frequency29.
- Chronic Neuroinflammation
Evidence suggests inflammation plays a role in HS-associated TLE30. Gales et al30 evaluated tissue of surgical patients with refractory TLE and found 41% of specimens displayed lymphocytes in the perivascular and parenchymal regions. Furthermore, cases with chronic inflammation were more likely to experience post-operative seizure recurrences30, supporting neuroinflammation as a driver of TLE.
Reactive oxygen species and other cytotoxins produced following epileptogenic events mediate neuroinflammation31. They activate microglia, resulting in pro-inflammatory cytokines being released31. Most research focused on IL-1β, IL-6 and TNFα, which demonstrate pro-convulsive properties in animal studies32. However, difficulty extrapolating these results to human epilepsies remains, hence further research is required to investigate to what extent cytokines are relevant in epileptogenesis32.
Interestingly, a well-documented association exists between epilepsy and systemic inflammatory conditions including systemic lupus erythematous, Hashimoto’s thyroiditis, and Rheumatoid arthritis33. While our CNS is normally protected against peripheral inflammation by the blood-brain-barrier, epileptogenic events cause transient changes in its permeability, possibly allowing peripheral inflammation to trigger central inflammation and thus contribute to epileptogenesis33.
- Aberrant Neurogenesis
Hippocampal neurogenesis (HN) is a physiological process occurring throughout life34. Adult HN describes the generation of novel dentate gyrus cells from adult neural stem cells which integrate into existing neural circuits, providing structural and functional plasticity35. Many roles for adult HN have been proposed, including pattern separation, learning and memory35.
Interest in HN has developed due to evidence that aberrant neurogenesis occurs following epileptogenic events36, creating new pathways for recurrent excitation. This aberrant HN occurring alongside other methods of synaptic reorganisation in the latent period of acquired TLE may explain the co-existence of cognitive impairment associated with the condition37. Researchers used pharmacological and genetic strategies in animal models to alter neurogenesis rates and ablate pathological dentate gyrus cells37. Despite many studies demonstrating that ceasing aberrant neurogenesis has disease modifying effects in epilepsy37, other researchers found that reducing aberrant neurogenesis does not mitigate epilepsy development or reduce seizure frequency38. Our understanding of HN in epileptogenesis is still in early stages.
The term reactive astrogliosis describes the response of astrocytes to CNS insults including TBI and stroke39. Changes seen depend on the injury severity, and include altered molecular expression, cellular hypertrophy and scar formation40. This process restores homeostasis and restricts tissue damage39.
However, if persistent, reactive astrogliosis becomes maladaptive, counteracting regeneration and limiting functional recovery39. Sustained reactive astrogliosis is commonly observed during epileptogenesis and is associated with chronic spontaneous seizures in animal models and human epileptogenic foci41. Evidence exists that reactive astrogliosis drives neuronal hyperexcitability, possibly due to impaired control of extracellular potassium ions42, rather than simply being a bystander phenomenon of brain insults41.
As well as understanding the mechanisms of the pathogenic processes listed above, there is much research describing how gene dysregulation drives these pathways in epileptogenesis. Upon examining the literature, four epigenetic processes were found to be potential drivers of acquired TLE.
- DNA methylation
DNA methylation is an epigenetic signalling tool catalysed by the DNA methyltransferase (DNMT) enzyme family, which is used to “silence” genes43. DNMT3a and DNMT3b add methyl groups to the fifth carbon of the cytosine DNA base, and this is maintained throughout cell division by DNMT144. This is a critical process in gene expression, hence errors can result in devastating consequences, including malignancy following tumour suppressor gene methylation43, and neuropsychiatric diseases including Alzheimer’s, Parkinson’s, and schizophrenia45.
Long et al45 compared DNA methylation patterns in mesial TLE to neurotypical controls, and found that the groups displayed different methylation at 216 sites, largely related to anion binding, growth regulation, skeletal development and drug metabolism45. Other researchers have reported similar findings46,47.
Interestingly, disorders arising from mutations in DNA methylation genes often have epileptic phenotypes48. Rett syndrome is a neurodevelopmental disorder with a typical natural history of normal development in the first year of life, followed by rapid regression of speech and motor skills, microcephaly, seizures and autism49. 80% of cases are associated with sporadic mutations in the MECP2 gene49, which codes for the Methyl-CpG binding protein 250. This protein binds methylated DNA and regulates its transcription50. 70% of Rett syndrome patients suffer from epilepsy51, supporting changes in DNA methylation status being significant in epileptogenesis.
- Histone modifications
DNA is packaged into basic structures called nucleosomes by histone octamers48. Histones consist of eight basic proteins: H2A, H2B, H3, and H448. Their long tails contain sites for post-translational modifications (PTMs) including acetylation, methylation, phosphorylation, and ubiquitination, which influence gene expression48,52. Following extensive research, PTMs are known to drive epileptogenesis.
- Transcriptional dysregulation
Evidence suggests that many of the alterations in gene transcription associated with epilepsy are mediated via the Repressor Element-1 Silencing Transcription factor (REST), also called the Neuron-Restrictive Silencer Factor (NRSF). REST is a zinc finger repressor transcription factor53 which enables many histone modifications by recruiting lysine-modifying enzymes via multiple corepressors54.
Spencer et al analysed REST expression in multiple seizure models, and found overexpression of a truncated REST protein55. McClelland et al reported similar results56,57. Studies in human epileptic brains also conclude that REST drives epileptogenesis. Navarrete-Modesto et al found REST overexpression in hippocampal biopsies of 28 patients with pharmacoresistant TLE compared to controls53.
- Post-transcriptional dysregulation
Regulating gene expression is not confined to the transcriptional level. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit translation of specific messenger RNA (mRNA) strands58. This is an example of regulating gene expression at the post-transcriptional level.
Research has demonstrated differential miRNA expression in the hippocampus of humans with acquired TLE and in animal models59,60,61. Gorter et al reported dynamic changes in hippocampal miRNA expression during epileptogenesis in the post-SE TLE model in rats62. They found that miRNAs were consistently differentially expressed in the three different hippocampal regions they examined - CA1, the dentate gyrus and the parahippocampal cortex, and also expression of different miRNAs in these regions varied in the acute, latent and chronic stages of acquired TLE development62. Due to mounting interest in miRNAs driving epileptogenesis, EpimiRBase, a database of miRNA-epilepsy associations, was a created in 201663.
Based on these findings, researchers hypothesised that miRNA inhibition may alter the pathologic electrical brain activity associated with TLE development. The first study supporting this was by Jimenez-Mateos et al in 201264. They found that silencing miR-134 in mice suppressed seizures and the pathologic hallmarks of epilepsy such as increased CA3 dendritic spine density64.
Other researchers proposed that miRNAs could be used to diagnose TLE. Raoof et al profiled miRNA levels in cerebrospinal fluid from TLE patients and compared to controls, and found that altered levels of miRNAs such as miR-19b-3p can support a TLE diagnosis65, concluding that miRNAs could be use as TLE biomarkers65.
This review’s aim was establishing how gene dysregulation drives acquired TLE through epigenetic signalling. Analysing the literature revealed altered DNA methylation, histone modifications, transcription, and translation drives the pathogenic processes during the latent phase of epileptogenesis, namely HS, synaptic reorganisation, neuroinflammation, HN and astrogliosis.
Understanding the role epigenetics plays in epileptogenesis is important in developing novel AEDs which are antiepileptogenic rather than anticonvulsant. Administering conventional AEDs following epileptogenic events fails to prevent epilepsy onset66. Hence, researchers are attempting to identify drugs that inhibit changes occurring in the latent period of epileptogenesis, in an effort to prevent the occurrence of acquired TLE, with some success.
Jung et al found that celecoxib, a cyclooxygenase-2 inhibitor, inhibits HN and neuroinflammation following pilocarpine-induced status epilepticus, which resulted in reduced seizure frequency67. However, human clinical trials in antiepileptogenesis have been few and universally unsuccessful68. To date, despite great progress understanding epigenetic changes that drive TLE, our therapeutic strategies at preventing epileptogenesis are lacking. Some of the many challenges trailing novel potentially antiepileptogenic agents on humans pose include selecting an appropriate patient population, as well as the expenses and increased non-compliance and loss-to-follow-up associated with long trial durations68. Coordinated efforts and valid trials are necessary to develop antiepileptogenic drugs and bring them to market69.
In conclusion, identifying epigenetic pathways that drive the pathogenic brain changes occurring after an epileptogenic event occurs are potential therapeutic targets for novel antiepileptogenic drugs. Targeting molecular pathways could prevent many cases of acquired TLE by halting epileptogenesis in the latent phase.
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