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Epilepsy

Disease Pathophysiology Research Report

2025-12-17
Falcon MONDO:0005027 Model: Edison Scientific Literature 37 citations

Disease Pathophysiology Research Report

Target Disease

  • Disease Name: Epilepsy
  • MONDO ID: MONDO:0005151
  • Category: Complex

Pathophysiology description (current understanding, 2023–2024 updates)

Epilepsy arises from converging molecular and cellular mechanisms that increase network excitability and synchrony. Core drivers include: (i) excitation–inhibition (E/I) imbalance due to ion channelopathies (e.g., SCN1A, KCNQ2/3, multiple Kv genes) and impaired GABAergic synaptic inhibition; (ii) glial mechanisms of neuroinflammation (microglia, astrocytes), including TLR/NF-κB and inflammasome-related signaling; (iii) blood–brain barrier (BBB) dysfunction with extravasation of serum proteins (e.g., albumin) and downstream TGF-β–astrocytic signaling; (iv) mTORC1 hyperactivation in “mTORopathies” (e.g., DEPDC5-related focal cortical dysplasia) with aberrant neuronal growth and synaptic function; (v) epigenetic dysregulation interacting with inflammatory and synaptic pathways; and (vi) mitochondrial/oxidative stress that lowers seizure threshold and perpetuates injury–inflammation cycles. Recent human studies have mapped altered E/I and gene expression to cognitive outcomes (TLE), demonstrated BBB causal roles and druggable stabilization strategies, and advanced precision therapies including SCN1A antisense oligonucleotides (ASOs) and senolytics for mTOR-related dysmorphic neurons (2022–2024) (duma2024excitationinhibitionbalancerelates pages 1-3, han2024unveilingthehidden pages 1-2, greene2022microvascularstabilizationvia pages 1-2, yuan2024asorestoresexcitability pages 1-2, ribierre2024targetingpathologicalcells pages 1-2).

URLs: - E/I mapping in TLE (Brain Communications, 2024): https://doi.org/10.1093/braincomms/fcae231 (duma2024excitationinhibitionbalancerelates pages 1-3) - BBB and epilepsy (Frontiers in Neurology, 2024): https://doi.org/10.3389/fneur.2024.1413023 (han2024unveilingthehidden pages 1-2) - BBB stabilization prevents seizures (Nature Communications, 2022): https://doi.org/10.1038/s41467-022-29657-y (greene2022microvascularstabilizationvia pages 1-2) - SCN1A ASO in Dravet model (Brain, 2024): https://doi.org/10.1093/brain/awad349 (yuan2024asorestoresexcitability pages 1-2) - Senolytics in mTOR-related epilepsy (Nature Neuroscience, 2024): https://doi.org/10.1038/s41593-024-01634-2 (ribierre2024targetingpathologicalcells pages 1-2)

1. Core Pathophysiology

  • E/I imbalance and ion channelopathies: In TLE, noninvasive EEG aperiodic exponent mapping identified regional E/I shifts that correlate with cognitive deficits and cortical expression of GABRA1, GRIN2A, GABRD, GABRG2, KCNA2, and PDYN, directly linking E/I to molecular architecture (Brain Communications 2024) (duma2024excitationinhibitionbalancerelates pages 1-3). Genetic epilepsies involve loss-/gain-of-function in voltage-gated potassium channels (KCNA1/2, KCNB1, KCNC1, KCND2, KCNQ2/3, KCNH1/5) that alter repolarization and network excitability (Frontiers in Neurology 2024) (zheng2024voltagegatedpotassiumchannels pages 1-2).
  • Glial neuroinflammation: Reactive astrocytes and microglia, activated by DAMPs (e.g., HMGB1), propagate cytokine signaling (IL-1, IL-6, TNF) via TLR/NF-κB and related pathways; sustained inflammation feeds seizure propensity and drug resistance (IJMS 2024) (sanz2024neuroinflammationandepilepsy pages 1-2).
  • BBB dysfunction and albumin–TGF-β–astrocyte signaling: Reviews and translational studies converge that BBB breakdown increases permeability, leads to albumin uptake by astrocytes, weakens junctions, perturbs ionic homeostasis, and contributes to epileptogenesis; BBB changes also limit drug penetration (Frontiers in Neurology 2024) (han2024unveilingthehidden pages 1-2). Human surgical tissue and mouse models show claudin-5 loss, albumin/IgG extravasation, and neuroinflammation; claudin-5 knockdown induces spontaneous seizures, whereas RepSox restores claudin-5 and prevents seizures (Nature Communications 2022) (greene2022microvascularstabilizationvia pages 1-2).
  • mTOR/DEPDC5 and cortical malformations: Brain somatic mosaicism of mTORC1 pathway genes (MTOR, RHEB) or loss of repressors (DEPDC5/GATOR1, TSC1, PTEN) in cortical progenitors causes focal malformations (FCD/HME), shared pyramidal neuron morphological and excitability abnormalities, and gene-specific synaptic changes (eLife 2024) (nguyen2024themtorpathway pages 1-2). DEPDC5 loss hyperactivates mTORC1; rapamycin rescues biochemical and survival phenotypes in Depdc5 neuronal KO mice (HMG 2019) (yuskaitis2019chronicmtorc1inhibition pages 2-3).
  • Epigenetic regulation: Epileptogenesis involves epigenetic dysregulation affecting inflammatory and synaptic genes; antiepileptogenic strategies targeting epigenetic and inflammatory processes are under study (Health Science Reports 2024) (shariff2024advancesinunderstanding pages 5-6, shariff2024advancesinunderstanding pages 4-5).
  • Mitochondrial/oxidative stress: Oxidative stress and mitochondrial dysfunction (e.g., ROS, mtDNA injury) contribute to neuronal hyperexcitability and amplify inflammatory cascades, reinforcing epileptogenesis (Health Science Reports 2024) (shariff2024advancesinunderstanding pages 5-6).

2. Key Molecular Players

3. Biological Processes (GO terms; disrupted in epilepsy)

4. Cellular Components (GO)

5. Disease Progression (sequence of events)

6. Phenotypic Manifestations (HPO) and links to mechanisms

Key evidence items with PMIDs/DOIs, URLs, dates (quotes where available)

Current applications and real-world implementations

Expert perspectives (authoritative sources)

Relevant statistics and data

  • TLE patients displayed significantly larger EEG aperiodic exponent values (inhibition-directed E/I), with regional exponents correlating with worse verbal memory (quantitative correlation) and with expression of GABRA1, GRIN2A, GABRD, GABRG2, KCNA2, PDYN (duma2024excitationinhibitionbalancerelates pages 1-3).
  • Human TLE resections show significantly reduced claudin-5 protein and widespread BBB leakage by DCE-MRI; inducible claudin-5 knockdown in mice induces spontaneous recurrent seizures (greene2022microvascularstabilizationvia pages 1-2).
  • In human FCDII slices, epileptiform activity correlated with dysmorphic neuron density (e.g., ≈54 vs 12 DNs/mm² between hyperactive vs quieter areas); senolytics reduced seizure frequency in MtorS2215F mice (ribierre2024targetingpathologicalcells pages 1-2).

Gene/protein annotations with ontology terms (selected)

Table (click to expand)
HGNC symbol Full name Primary mechanism in epilepsy (1–2 lines) Pathway(s) GO Biological Process (examples) GO Cellular Component (examples) Key cell types (CL names) Key anatomy (UBERON names) Anchor citations
SCN1A Sodium voltage-gated channel alpha subunit 1 Haploinsufficiency/LOF in GABAergic interneurons → reduced inhibition, network hyperexcitability Voltage-gated sodium channel / action potential generation Regulation of membrane potential; action potential; sodium ion transmembrane transport Axon initial segment; plasma membrane; voltage-gated sodium channel complex GABAergic interneurons (parvalbumin-positive, somatostatin-positive) Cerebral cortex; hippocampus (yuan2024asorestoresexcitability pages 1-2, zhang2025dravetsyndromenovel pages 15-16)
GABRA1 GABA A receptor alpha1 subunit LOF/reduced surface expression → impaired inhibitory synaptic currents and reduced GABAergic tone GABAergic synaptic transmission Inhibitory synaptic transmission; chloride transport; synaptic transmission Postsynaptic membrane; GABA-A receptor complex; synapse Pyramidal neuron postsynaptic sites; interneuron synapses Cortex; hippocampus (duma2024excitationinhibitionbalancerelates pages 1-3, sanz2024neuroinflammationandepilepsy pages 1-2)
GABRG2 GABA A receptor gamma2 subunit Mutations impair receptor biogenesis/clustering → decreased synaptic inhibition and DEE phenotypes GABA-A receptor assembly and synaptic localization Inhibitory synaptic transmission; receptor trafficking Postsynaptic density; plasma membrane; GABA-A receptor complex GABAergic synapses; interneuron→pyramidal neuron synapses Cortex; hippocampus (duma2024excitationinhibitionbalancerelates pages 1-3, sanz2024neuroinflammationandepilepsy pages 1-2)
KCNQ2 Potassium voltage-gated channel subfamily Q member 2 (Kv7.2) Loss-of-function reduces M-current → neonatal hyperexcitability, developmental impairment Kv7 (M-current) / neuronal excitability control Potassium ion transmembrane transport; regulation of neuronal excitability Plasma membrane; axon initial segment; potassium channel complex Excitatory neurons; developing cortical neurons Cortex; hippocampus (zheng2024voltagegatedpotassiumchannels pages 1-2, liu2024excitatoryneuronsand pages 1-3)
KCNQ3 Potassium voltage-gated channel subfamily Q member 3 (Kv7.3) Partners with KCNQ2 in M-current; variants modulate channel function and excitability Kv7 (M-current) / heteromeric KCNQ2/3 channels Regulation of membrane potential; potassium ion transport Plasma membrane; axon initial segment Excitatory neurons; developing neurons Cortex; hippocampus (zheng2024voltagegatedpotassiumchannels pages 1-2, liu2024excitatoryneuronsand pages 1-3)
KCNA2 Potassium voltage-gated channel subfamily A member 2 (Kv1.2) Kv channel dysfunction (LOF/GOF) alters repolarization → network hyperexcitability or aberrant firing Kv1 family / action potential repolarization Potassium ion transmembrane transport; regulation of action potential Plasma membrane; presynaptic terminal; ion channel complex Excitatory neurons; inhibitory interneurons Cortex; hippocampus (duma2024excitationinhibitionbalancerelates pages 1-3, zheng2024voltagegatedpotassiumchannels pages 1-2)
DEPDC5 DEP domain containing 5 (GATOR1 complex subunit) LOF → loss of GATOR1 repression → mTORC1 hyperactivation; somatic/germline variants cause FCD and focal epilepsy GATOR1 → mTORC1 regulation Regulation of mTOR signaling; cell growth; autophagy regulation Cytosol; lysosomal membrane (mTORC1 localization) Excitatory neuronal progenitors / cortical neurons Focal cortex (cortical malformations, FCD) (yuskaitis2019chronicmtorc1inhibition pages 2-3, nguyen2024themtorpathway pages 1-2, ribierre2024targetingpathologicalcells pages 1-2)
MTOR Mechanistic target of rapamycin kinase mTORC1 hyperactivation → abnormal neuronal growth/plasticity, epileptogenesis in mTORopathies mTORC1 signaling / protein synthesis and growth Regulation of translation; cell growth; synaptic plasticity Cytosol; lysosomal membrane; mTORC1 complex Neurons (excitatory), progenitors, glia Cortex (FCD), hippocampus (nguyen2024themtorpathway pages 1-2, yuskaitis2019chronicmtorc1inhibition pages 2-3)
RHEB Ras homolog enriched in brain Small GTPase activator of mTORC1; gain-of-function → mTORC1 activation in cortical development mTORC1 activation via Rheb-GTP Positive regulation of mTOR signaling; regulation of cell growth Cytosol; lysosomal membrane Neuronal progenitors; excitatory neurons Cortex; developing telencephalon (nguyen2024themtorpathway pages 1-2)
PTEN Phosphatase and tensin homolog Loss reduces PI3K/AKT inhibition → increased mTOR signaling and altered neuronal morphology/excitability PI3K-AKT- mTOR pathway regulation Negative regulation of PI3K signaling; cell growth control Cytosol; plasma membrane; nucleus Neurons; glia; progenitors Cortex; hippocampus (nguyen2024themtorpathway pages 1-2)
TSC1 Tuberous sclerosis 1 Part of TSC1/TSC2 complex suppressing mTORC1; loss → mTORC1-driven cortical dysplasia and seizures TSC complex → mTORC1 inhibition Negative regulation of mTOR signaling; cell growth; autophagy Cytosol; lysosomal membrane Neuronal progenitors; neurons Cortex (tuberous sclerosis lesions), hippocampus (yuskaitis2019chronicmtorc1inhibition pages 2-3, nguyen2024themtorpathway pages 1-2)
CLDN5 Claudin-5 Tight junction protein; decreased expression → BBB leakage, albumin extravasation and seizure susceptibility Tight junction / BBB integrity Establishment of blood–brain barrier; cell–cell adhesion Tight junction; endothelial cell membrane Brain endothelial cells; pericytes; astrocyte end-feet Cerebral microvasculature; hippocampus (greene2022microvascularstabilizationvia pages 1-2)
HMGB1 High mobility group box 1 Damage-associated molecular pattern (DAMP) released after injury/seizures → activates innate immunity and promotes epileptogenesis DAMP signaling → TLR/NF-κB / inflammasome activation Release of DAMPs; positive regulation of inflammatory response; cytokine production Nucleus (normal); extracellular space (released DAMP) Microglia; astrocytes; neurons Hippocampus; cortex (sanz2024neuroinflammationandepilepsy pages 1-2)
TLR4 Toll-like receptor 4 Pattern recognition receptor sensing HMGB1/LPS → NF-κB activation, cytokine release, neuroinflammation linked to seizure propagation TLR signaling → NF-κB / inflammasome pathways Innate immune response; cytokine-mediated signaling; inflammatory response Plasma membrane; endosome (signaling) Microglia; astrocytes; endothelial cells Hippocampus; cortex (sanz2024neuroinflammationandepilepsy pages 1-2)

Table: Concise ontology-ready table mapping 14 epilepsy-relevant genes/proteins to mechanisms, pathways, GO processes/components, cell types, anatomical sites and anchor citations; useful for knowledgebase annotations and GO/ontology curation.

Phenotype associations (HPO), Cell types (CL), Anatomy (UBERON), Chemicals (ChEBI)

Single-cell/spatial transcriptomics in human epilepsy

  • Multimodal single-nucleus RNA/ATAC profiling of human FCD IIIa temporal neocortex revealed selective dysregulation of excitatory neurons (including a DAB1high subpopulation with immune signatures) and activated OPCs, with aberrant EN–OPC communication validated by protein assays (Clinical and Translational Medicine, 2024-10-15; https://doi.org/10.1002/ctm2.70072) (liu2024excitatoryneuronsand pages 1-3).

Precision therapeutics—summary of opportunities

Evidence list (citable items)

References

  1. (duma2024excitationinhibitionbalancerelates pages 1-3): Gian Marco Duma, Simone Cuozzo, Luc Wilson, Alberto Danieli, Paolo Bonanni, and Giovanni Pellegrino. Excitation/inhibition balance relates to cognitive function and gene expression in temporal lobe epilepsy: a high density eeg assessment with aperiodic exponent. Brain Communications, Feb 2024. URL: https://doi.org/10.1093/braincomms/fcae231, doi:10.1093/braincomms/fcae231. This article has 25 citations and is from a peer-reviewed journal.

  2. (han2024unveilingthehidden pages 1-2): Jinkun Han, Ying Wang, Penghu Wei, Di Lu, and Yongzhi Shan. Unveiling the hidden connection: the blood-brain barrier’s role in epilepsy. Frontiers in Neurology, Aug 2024. URL: https://doi.org/10.3389/fneur.2024.1413023, doi:10.3389/fneur.2024.1413023. This article has 6 citations and is from a peer-reviewed journal.

  3. (greene2022microvascularstabilizationvia pages 1-2): Chris Greene, Nicole Hanley, Cristina R. Reschke, Avril Reddy, Maarja A. Mäe, Ruairi Connolly, Claire Behan, Eoin O’Keeffe, Isobel Bolger, Natalie Hudson, Conor Delaney, Michael A. Farrell, Donncha F. O’Brien, Jane Cryan, Francesca M. Brett, Alan Beausang, Christer Betsholtz, David C. Henshall, Colin P. Doherty, and Matthew Campbell. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity. Nature Communications, Apr 2022. URL: https://doi.org/10.1038/s41467-022-29657-y, doi:10.1038/s41467-022-29657-y. This article has 145 citations and is from a highest quality peer-reviewed journal.

  4. (yuan2024asorestoresexcitability pages 1-2): Yukun Yuan, Luis Lopez-Santiago, Nicholas Denomme, Chunling Chen, Heather A O'Malley, Samantha L Hodges, Sophina Ji, Zhou Han, Anne Christiansen, and Lori L Isom. Aso restores excitability, gaba signalling and sodium current density in a model of dravet syndrome. Brain : a journal of neurology, 147:1231-1246, Oct 2024. URL: https://doi.org/10.1093/brain/awad349, doi:10.1093/brain/awad349. This article has 36 citations.

  5. (ribierre2024targetingpathologicalcells pages 1-2): Théo Ribierre, Alexandre Bacq, Florian Donneger, Marion Doladilhe, Marina Maletic, Delphine Roussel, Isabelle Le Roux, Francine Chassoux, Bertrand Devaux, Homa Adle-Biassette, Sarah Ferrand-Sorbets, Georg Dorfmüller, Mathilde Chipaux, Sara Baldassari, Jean-Christophe Poncer, and Stéphanie Baulac. Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mtor-related epilepsy. Nature Neuroscience, 27:1125-1136, May 2024. URL: https://doi.org/10.1038/s41593-024-01634-2, doi:10.1038/s41593-024-01634-2. This article has 35 citations and is from a highest quality peer-reviewed journal.

  6. (zheng2024voltagegatedpotassiumchannels pages 1-2): Yiting Zheng and Jing Chen. Voltage-gated potassium channels and genetic epilepsy. Frontiers in Neurology, Oct 2024. URL: https://doi.org/10.3389/fneur.2024.1466075, doi:10.3389/fneur.2024.1466075. This article has 22 citations and is from a peer-reviewed journal.

  7. (sanz2024neuroinflammationandepilepsy pages 1-2): Pascual Sanz, Teresa Rubio, and Maria Adelaida Garcia-Gimeno. Neuroinflammation and epilepsy: from pathophysiology to therapies based on repurposing drugs. International Journal of Molecular Sciences, 25:4161, Apr 2024. URL: https://doi.org/10.3390/ijms25084161, doi:10.3390/ijms25084161. This article has 62 citations and is from a poor quality or predatory journal.

  8. (nguyen2024themtorpathway pages 1-2): Lena H Nguyen, Youfen Xu, Maanasi Nair, and Angelique Bordey. The mtor pathway genes mtor, rheb, depdc5, pten, and tsc1 have convergent and divergent impacts on cortical neuron development and function. eLife, Feb 2024. URL: https://doi.org/10.7554/elife.91010.3, doi:10.7554/elife.91010.3. This article has 33 citations and is from a domain leading peer-reviewed journal.

  9. (yuskaitis2019chronicmtorc1inhibition pages 2-3): Christopher J Yuskaitis, Leigh-Ana Rossitto, Sarika Gurnani, Elizabeth Bainbridge, Annapurna Poduri, and Mustafa Sahin. Chronic mtorc1 inhibition rescues behavioral and biochemical deficits resulting from neuronal depdc5 loss in mice. Human molecular genetics, 28:2952-2964, May 2019. URL: https://doi.org/10.1093/hmg/ddz123, doi:10.1093/hmg/ddz123. This article has 58 citations and is from a domain leading peer-reviewed journal.

  10. (shariff2024advancesinunderstanding pages 5-6): Sanobar Shariff, Halah A. Nouh, Samuel Inshutiyimana, Charbel Kachouh, Maya M. Abdelwahab, Abubakar Nazir, Magda Wojtara, and Olivier Uwishema. Advances in understanding the pathogenesis of epilepsy: unraveling the molecular mechanisms: a cross‐sectional study. Health Science Reports, Feb 2024. URL: https://doi.org/10.1002/hsr2.1896, doi:10.1002/hsr2.1896. This article has 21 citations and is from a peer-reviewed journal.

  11. (shariff2024advancesinunderstanding pages 4-5): Sanobar Shariff, Halah A. Nouh, Samuel Inshutiyimana, Charbel Kachouh, Maya M. Abdelwahab, Abubakar Nazir, Magda Wojtara, and Olivier Uwishema. Advances in understanding the pathogenesis of epilepsy: unraveling the molecular mechanisms: a cross‐sectional study. Health Science Reports, Feb 2024. URL: https://doi.org/10.1002/hsr2.1896, doi:10.1002/hsr2.1896. This article has 21 citations and is from a peer-reviewed journal.

  12. (li2025progressingenetic pages 3-4): Yang Li, Xiaojie Hu, Xueqing Chen, Yawei Cheng, Yanhong Jiang, and Xingchen Wang. Progress in genetic mechanisms and precise treatment of neurocutaneous syndrome-related epilepsy. Frontiers in Neurology, Sep 2025. URL: https://doi.org/10.3389/fneur.2025.1642299, doi:10.3389/fneur.2025.1642299. This article has 0 citations and is from a peer-reviewed journal.

  13. (zhang2025dravetsyndromenovel pages 15-16): Guirui Zhang, Shupeng Huang, Mingzhen Wei, Yongmo Wu, Zhengyi Xie, and Jin Wang. Dravet syndrome: novel insights into scn1a-mediated epileptic neurodevelopmental disorders within the molecular diagnostic-therapeutic framework. Frontiers in Neuroscience, Jul 2025. URL: https://doi.org/10.3389/fnins.2025.1634718, doi:10.3389/fnins.2025.1634718. This article has 3 citations and is from a peer-reviewed journal.

  14. (liu2024excitatoryneuronsand pages 1-3): Yingying Liu, Yinchao Li, Yaqian Zhang, Yubao Fang, Lei Lei, Jiabin Yu, Hongping Tan, Lisen Sui, Qiang Guo, and Liemin Zhou. Excitatory neurons and oligodendrocyte precursor cells are vulnerable to focal cortical dysplasia type iiia as suggested by single‐nucleus multiomics. Clinical and Translational Medicine, Oct 2024. URL: https://doi.org/10.1002/ctm2.70072, doi:10.1002/ctm2.70072. This article has 3 citations and is from a peer-reviewed journal.