kainic acid

JAK/STAT regulation of the transcriptomic response during epileptogenesis

Temporal lobe epilepsy (TLE) is a progressive disorder mediated by pathological changes in molecular cascades and neural circuit remodeling in the hippocampus resulting in increased susceptibility to spontaneous seizures and cognitive dysfunction. Targeting these cascades could prevent or reverse symptom progression and has the potential to provide viable disease-modifying treatments that could reduce the portion of TLE patients (>30%) not responsive to current medical therapies. Changes in GABA(A) receptor subunit expression have been implicated in the pathogenesis of TLE, and the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has been shown to be a key regulator of these changes. The JAK/STAT pathway is known to be involved in inflammation and immunity, and to be critical for neuronal functions such as synaptic plasticity and synaptogenesis. Our laboratories have shown that a STAT3 inhibitor, WP1066, could greatly reduce the number of spontaneous recurrent seizures (SRS) in an animal model of pilocarpine-induced status epilepticus (SE). This suggests promise for JAK/STAT inhibitors as disease-modifying therapies, however, the potential adverse effects of systemic or global CNS pathway inhibition limits their use. Development of more targeted therapeutics will require a detailed understanding of JAK/STAT-induced epileptogenic responses in different cell types. To this end, we have developed a new transgenic line where dimer-dependent STAT3 signaling is functionally knocked out (fKO) by tamoxifen-induced Cre expression specifically in forebrain excitatory neurons (eNs) via the Calcium/Calmodulin Dependent Protein Kinase II alpha (CamK2a) promoter. Most recently, we have demonstrated that STAT3 KO in excitatory neurons (eNSTAT3fKO) markedly reduces the progression of epilepsy (SRS frequency) in the intrahippocampal kainate (IHKA) TLE model and protects mice from kainic acid (KA)-induced memory deficits as assessed by Contextual Fear Conditioning. Using data from bulk hippocampal tissue RNA-sequencing, we further discovered a transcriptomic signature for the IHKA model that contains a substantial number of genes, particularly in synaptic plasticity and inflammatory gene networks, that are down-regulated after KA-induced SE in wild-type but not eNSTAT3fKO mice. Finally, we will review data from other models of brain injury that lead to epilepsy, such as TBI, that implicate activation of the JAK/STAT pathway that may contribute to epilepsy development.

Characterization of the antiapoptotic and neuroprotective effect of dapsone in a model of status epilepticus induced with kainic acid in rats

Antiepileptogenic effects of trilostane in the kainic acid model of temporal lobe epilepsy

Behavioral, cannabinoid CB1 receptor and astrocytic changes in a kainic acid model of temporal lobe epilepsy

Dapsone prevents hypermetabolic effect of kainic acid in rats: An 18FDG-PET study

Deletion of the background potassium channel TWIK-1 increases susceptibility to kainic acid-induced seizure

Chemogenetic modulation of CX3CR1+ microglia in the intrahippocampal kainic acid mouse model of drug-resistant temporal lobe epilepsy

FENS Forum 2024

Identification of kainic acid-mediated concentration-dependent responses on human cortical neuronal networks in vitro

FENS Forum 2024

The kainic acid induced status epilepticus: Comparative study of the hippocampus ultrastructure in Wistar rats

FENS Forum 2024

Modulation of vagus nerve activity during spontaneous recurrent seizures in the kainic acid model of temporal lobe epilepsy

FENS Forum 2024