transcriptomic signature

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.

Examining the transcriptomic signature of the thalamus in a dual-hit rat model of schizophrenia: Insights into gender-specific alterations

FENS Forum 2024

AβPP-induced UPR transcriptomic signature of glial cells to oxidative stress as an adaptive mechanism to preserve cell function and Survival

High-throughput analysis in a fragile X syndrome mouse model after CB1 receptor targeting reveals specific transcriptomic signature sensitive to treatment

A study of the transcriptomic signatures in male and female rats exposed to maternal immune activation and THC during adolescence

Transcriptomic signature and Enriched Signaling Pathways linked to Alzheimer's Disease model induced by Tau seed pathology

Impairment of the placenta–cortex transcriptomic signature following prenatal alcohol exposure, leading to dysregulation of angiogenic pathways

FENS Forum 2024

Influence of the APOE4 risk factor on hippocampal epigenetic and transcriptomic signatures in a physiological and pathological environment indicative of dementia with Lewy bodies (DLB)

FENS Forum 2024

Normalization of the accumbal cell type-specific transcriptomic signatures and anxiety-like behaviour following treatment with a mitochondrial booster in outbred rats

FENS Forum 2024