SUR1-TRPM4 is expressed in human epilepsy and promotes neuron hyperactivity and seizures in rodents Moyer MB, Ivanova S, Keledjian K, Kreinbrink M, Langbein J, Yang P, McAfee D, Boddeti U, Khan Z, Olu-Owotade J, Zhang T, Benavides DR, Diamond J, Zaghloul K, Bachani M, Gerzanich V, Simard JM, Ksendzovsky A. Brain. 2026 Jun 3;149(6):2124-2138. doi: 10.1093/brain/awaf435. PMID: 41239869; PMCID: PMC13232044. One-third of epilepsy patients do not achieve sufficient seizure freedom with current standard anti-seizure medications. Better understanding of the pathological mechanisms contributing to epileptogenesis is thus necessary to improve current therapies. SUR1-TRPM4 is a depolarizing ion channel minimally expressed in a healthy brain that is upregulated de novo in neurons and glia after epileptogenic CNS injuries such as traumatic brain injury and stroke. However, its role in epilepsy is not well understood. Here, we demonstrate using immunofluorescent microscopy that SUR1-TRPM4 expression is elevated in neurons within an electrographically sorted human epileptic brain compared with a non-epileptic brain obtained after resection from six drug-resistant temporal lobe epilepsy patients. Additionally, we utilized immunofluorescence and co-immunoprecipitation to observe that SUR1-TRPM4 is upregulated within the hippocampus and temporal cortex in mice after pentylenetetrazol (PTZ) kindling, a chronic model of rodent epilepsy. Pharmacologic inhibition of SUR1-TRPM4 using either the US Food and Drug Administration (FDA)-approved drug glyburide or 9-phenanthrol, as well as either constitutive or neuron-specific knockout of this channel, attenuated chronic seizure development in this model. Exogenous overexpression of SUR1-TRPM4 by plasmid transfection in neurons in vitro increased neuronal hyperexcitability in response to low Mg2 + stimulation, while pharmacologic inhibition of endogenous TRPM4 attenuated neuronal population hyperexcitation. Collectively, our results reveal that elevated SUR1-TRPM4 expression found in human and rodent epileptic neurons promotes chronic seizures by increasing neuronal excitation. These findings directly support clinical investigation of SUR1- TRPM4 inhibitors as potential anti-seizure therapies in epilepsy patients and suggest further investigations into the contribution of SUR1-TRPM4 to seizures induced by specific epileptogenic insults, such as traumatic brain injury (TBI), are warranted.
Rapid advances in disease-modifying therapies (DMTs) for epilepsy, including gene-based therapies, antisense oligonucleotides, and stem cell-derived approaches, are reshaping the treatment landscape. As these therapies move through clinical trials and toward regulatory review, they introduce complex clinical, operational, ethical, and equity considerations that extend well beyond traditional antiseizure medication management. Successful integration will require careful attention to patient selection, genetic and biomarker testing, multidisciplinary care models, infrastructure readiness, referral pathways, long-term safety monitoring, informed consent for novel and potentially irreversible interventions, access to clinical trials, and cost and reimbursement challenges. Significant investments in personnel, systems, and facilities may be necessary, raising important questions about implementation across diverse practice settings and the risk of widening disparities in care. Here, we review the evolving therapeutic pipeline and outline key considerations for safe, ethical, and equitable implementation.
Epilepsy-associated digenic variants affecting an actin/mitochondria/glutamate pathway promote seizure susceptibility. Lu S, Ma M, Hannan SB, Deng M, Chen H, Yu Z, Goodman LD, Kim H, Zhao Y, Dubey SK, Lin WW, Pan X, Dutta D, Cuddapah VA, Rosenfeld JA, Luo X, Liu Z, Shulman JM, Bellen HJ. J Clin Invest. 2026 Jul 16;136(17):e198696. doi:10.1172/JCI198696. PMID: 42461707; PMCID: PMC13528942. Epilepsy affects approximately 50 million people worldwide, yet more than half of individuals with a presumed genetic cause still lack a molecular diagnosis despite the identification of over 1000 monogenic epilepsy genes. This diagnostic gap is unlikely to be resolved by improved variant detection alone, suggesting that variants affecting the same biological pathway may combine to cause disease. By studying epilepsy-associated actin regulatory genes, we identified a conserved actin/mitochondria/glutamate (AMG) pathway. We demonstrate that reduced actin polymerization promoted DRP1-mediated mitochondrial fission, increased ROS levels, and enhanced glutamatergic transmission, leading to seizures. The glial innate immune pathway, a recently recognized contributor to epilepsy, is activated when the AMG pathway is affected. Reducing mitochondrial fission with the mitochondria division inhibitor (Mdivi-1), or suppressing ROS with N-acetyl-l-cysteine amide (NACA), significantly alleviated seizures. Importantly, digenic heterozygous loss-of-function variants in AMG pathway genes combined to cause seizures, and individuals with epilepsy of unknown etiology showed an increased burden of such variants when compared with the controls. Modeling patient-specific digenic combinations in Drosophila confirmed that many combinations promote seizure susceptibility. Together, these findings establish the AMG pathway as a mechanistic framework for identifying digenic etiologies in epilepsy and highlight potential therapeutic targets.
AKT is necessary for neuronal hypertrophy and epilepsy caused by Pten knockout. Prina ML, Goyette AR, Abdulkareem AF, Tariq K, Burgess N, Su J, Wang W, Li M, Drucker LL, Seo HH, Desmet NM, Overstreet-Wadiche L, Shafit-Zagardo B, Weston MC and Luikart BW. Brain 2026. Phosphatase and tensin homolog on chromosome 10 (PTEN) is a key negative regulator of the AKT/mTOR signaling pathway. Mutations in PTEN are highly implicated in Autism Spectrum Disorder (ASD), epilepsy, congenital hydrocephaly, and macrocephaly. While the conditional genetic knockout of Pten in murine neurons results in hypertrophy, increased migration, excitatory synaptogenesis, hyperexcitability, and epileptiform activity, the specific downstream signalling mediators of these pathologies remain to be fully elucidated. Using retroviral-mediated genetic manipulation of individual neurons within the Cre-lox system, we have analyzed pathway outputs in response to the manipulation of various genes using immunohistochemistry, confocal microscopy, and extensive morphological analyses, alongside whole-cell patch-clamp electrophysiology and 120-h video-EEG monitoring for seizure assessment. Here, we demonstrate that signaling through AKT is necessary for the development of neuronal overgrowth, increased excitatory synapse formation, excessive migration, and hyperexcitability fueled by the loss of PTEN function. Notably, the concurrent deletion of Akt1 and Akt3 isoforms was sufficient to effectively rescue hypertrophic neuronal morphology and physiology. These findings establish AKT as the essential mediator through which PTEN deficiency manifests, providing a transformative therapeutic target to correct the morphological and functional defects central to PTEN-related neurodevelopmental disorders.
This practice guideline from the American Epilepsy Society (AES) and the Congress of Neurological Surgeons (CNS) provides evidence-based recommendations for surgical treatment of epilepsy for adults and children. It is an update to previous practice parameters published by the Academy of Neurology in 2003. The multidisciplinary panel addressed resective procedures for mesial temporal epilepsy (MTLE), neocortical epilepsy, and resection/disconnection of hypothalamic hamartoma. It also examined evidence for callosotomy in developmental and epileptic encephalopathies. It did not intentionally address neurostimulation treatment. A comprehensive literature review was conducted using the Grading of Recommendations Assessment, Development and Education (GRADE) methodology, and GRADE was also used for decision-making. This guideline considers not only seizure outcomes but also other critical and important outcomes. Seizures, quality of life, mortality, adverse events, and verbal memory loss were considered critical outcomes, while other neuropsychological deficits besides verbal memory loss (ie, naming, fluency), neuropsychiatric, and social outcomes were considered important outcomes. Following the GRADE process, the following strong recommendation was made based on a moderate level of evidence: (1) anterior temporal lobectomy (ATL) is recommended for people with MTLE at low risk for cognitive decline. Due to very low to low certainty of evidence the panel suggested the following conditional recommendations: (1) ATL for people with MTLE at high risk for cognitive decline, (2) selective amygdalo-hippocampectomy (SAH) in MTLE, (3) laser interstitial thermal therapy (LITT) in MTLE, (4) neocortical resection in neocortical epilepsy, and (5) callosotomy in people with drop attacks, Lennox-Gastaut Syndrome (LGS) or developmental and epileptic encephalopathies. The panel recognized that conditional recommendations need to account for individual patient circumstances and mandate shared decision-making to ensure that decisions align with each person's values and preferences. For hypothalamic hamartoma, the panel strongly recommended LITT despite low levels of evidence due to a paradigmatic situation where open surgery has significant risks that outweigh the benefits. If LITT is not available, the panel suggested radiosurgery for hypothalamic hamartoma (conditional recommendation). The panel highlighted that every person with drug-resistant epilepsy should have access to a tertiary epilepsy care center that performs surgical procedures and advanced epilepsy diagnostics (good practice statement).
