Targeting MMP-9 activation after early-life seizures reduces seizure susceptibility and memory deficits in a larval zebrafish model.

One in 26 Americans experience seizures, with a high incidence occurring in the first years of life. Chronic consequences of prolonged early-life seizures (ELS) in humans and rodent models vary, but can include the development of epilepsy (spontaneous, recurrent seizures) and cognitive impairment. Because it is not clear how seizures might lead to these consequences, no therapeutic strategy exists to prevent or predict them. Here, we optimized a larval zebrafish ELS model to assess a therapeutic approach targeting post-ELS sequelae. Using increased seizure susceptibility as a readout of the epileptogenic process and a novel object recognition task to assess memory, we found that two weeks after a three-day ELS induction paradigm, zebrafish were significantly more susceptible to seizures and showed a significant memory deficit. Therefore, we next used this model to identify and target underlying mechanisms. After observing an acute post-ELS increase in mmp9 gene expression, we pharmacologically inhibited the conversion of pro-MMP-9 to active MMP-9 after ELS using JNJ0966, and tested subsequent seizure susceptibility and memory two weeks later. Preventing formation of active MMP-9 for the first hour post-ELS was sufficient to return memory and seizure susceptibility readouts to that of clutch mate controls. This study provides novel insight into the development of ELS sequelae and presents a promising model for moving ELS research forward, demonstrating seizure susceptibility, memory assessment, therapeutic targeting, and pharmacological testing in a simplified model.

• Publication year

  2025

• Venue

  Neurobiology of Disease

• Publication date

  2025-05-29

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.nbd.2025.106978PMID 40449606
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Induction of seizures and initiation of epileptogenesis by pilocarpine in zebrafish larvae

  2024cited by this paper
• Neuroinflammation microenvironment sharpens seizure circuit.

  2023cited by this paper
• Neuronal circuitry for recognition memory of object and place in rodent models.

  2022cited by this paper
• Chloride transporters controlling neuronal excitability.

  2022cited by this paper
• Learning Deficits and Attenuated Adaptive Stress Response After Early-Life Seizures in Zebrafish

  2022influential reference
• Operational diagnosis of epilepsy in children at undetermined risk: A meta-analysis of prognostic factors for seizure recurrence.

  2021cited by this paper
• Seizures in the neonate: A review of etiologies and outcomes.

  2021cited by this paper
• Defining the latent period of epileptogenesis and epileptogenic zone in a focal cortical dysplasia type II (FCDII) rat model

  2021cited by this paper
• The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects.

  2020influential reference
• Dexamethasone after early-life seizures attenuates increased susceptibility to seizures, seizure-induced microglia activation and neuronal injury later in life.

  2020cited by this paper
• Measuring recognition memory in zebrafish larvae: issues and limitations

  2020cited by this paper
• Zebrafish model of posttraumatic epilepsy

  2020cited by this paper
• Extracellular Matrix in Neural Plasticity and Regeneration

  2020cited by this paper
• MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients

  2019cited by this paper
• Phenotypic Characterization of Larval Zebrafish (Danio rerio) with Partial Knockdown of the cacna1a Gene

  2019cited by this paper
• Susceptibility of larval zebrafish to the seizurogenic activity of GABA type A receptor antagonists.

  2019cited by this paper
• Neuroimaging Biomarkers of Experimental Epileptogenesis and Refractory Epilepsy

  2019cited by this paper
• Embryonic exposure to ethanol increases the susceptibility of larval zebrafish to chemically induced seizures

  2018cited by this paper
• Tenuous Inhibitory GABAergic Signaling in the Reticular Thalamus

  2017cited by this paper
• Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation

  2017cited by this paper
• Advancing epilepsy treatment through personalized genetic zebrafish models.

  2016cited by this paper
• Involvement of hippocampal NMDA receptors in retrieval of spontaneous object recognition memory in rats.

  2016cited by this paper
• A Novel Long-term, Multi-Channel and Non-invasive Electrophysiology Platform for Zebrafish

  2016cited by this paper
• Using visual lateralization to model learning and memory in zebrafish larvae

  2015influential reference
• NLRP1 inflammasome is activated in patients with medial temporal lobe epilepsy and contributes to neuronal pyroptosis in amygdala kindling-induced rat model

  2015cited by this paper
• EEG characteristics predict subsequent epilepsy in children with their first unprovoked seizure.

  2015cited by this paper
• Maternal immune activation increases seizure susceptibility in juvenile rat offspring.

  2015cited by this paper
• Local impermeant anions establish the neuronal chloride concentration.

  2014cited by this paper
• The zebrafish reference genome sequence and its relationship to the human genome

  2013cited by this paper
• AMPA Receptor antagonist NBQX attenuates later‐life epileptic seizures and autistic‐like social deficits following neonatal seizures

  2013cited by this paper
• Matrix metalloproteinase-9 (MMP-9) in human intractable epilepsy caused by focal cortical dysplasia.

  2013cited by this paper
• Anesthesia and euthanasia in zebrafish.

  2012cited by this paper
• Synaptic circuit remodelling by matrix metalloproteinases in health and disease

  2012cited by this paper
• Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus

  2011cited by this paper
• Development of later life spontaneous seizures in a rodent model of hypoxia‐induced neonatal seizures

  2011cited by this paper
• Hypoxia-Induced Neonatal Seizures Diminish Silent Synapses and Long-Term Potentiation in Hippocampal CA1 Neurons

  2011cited by this paper
• Epileptogenesis in the immature brain: emerging mechanisms

  2009cited by this paper
• Global cognitive function in children with epilepsy: A community‐based study

  2008cited by this paper
• Validation of a larval zebrafish locomotor assay for assessing the seizure liability of early-stage development drugs.

  2008cited by this paper
• Important role of matrix metalloproteinase 9 in epileptogenesis

  2008cited by this paper
• Autism Spectrum Disorders in Children with Seizures in the First Year of Life—A Population‐Based Study

  2007cited by this paper
• Effects of a Single Dose of Erythropoietin on Subsequent Seizure Susceptibility in Rats Exposed to Acute Hypoxia at P10

  2007cited by this paper
• Matrix Metalloproteinase-9 Is Required for Hippocampal Late-Phase Long-Term Potentiation and Memory

  2006cited by this paper
• Pentylenetetrazole induced changes in zebrafish behavior, neural activity and c-fos expression.

  2005influential reference
• Impaired SynGAP expression and long-term spatial learning and memory in hippocampal CA1 area from rats previously exposed to perinatal hypoxia-induced insults: beneficial effects of A68930.

  2004cited by this paper
• NBQX or Topiramate Treatment after Perinatal Hypoxia‐induced Seizures Prevents Later Increases in Seizure‐induced Neuronal Injury

  2004cited by this paper
• Excitatory actions of gaba during development: the nature of the nurture

  2002cited by this paper
• Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy.

  2001cited by this paper

• No citing papers are available for this paper.