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In collaboration with Dr. Martin Weinand, we have studied alterations in gene expression in brain samples from patients with temporal lobe epilepsy (TLE). We performed RNA-seq on hippocampal tissue resected from 12 medically intractable TLE patients with pre-surgery seizure frequencies ranging from 0.33 to 120 seizures per month. We then performed differential expression (DE) analysis comparing a group patients with an average of 4 seizures per month (LSF) with a second group with an average of 60 seizures per month (HSF).  A total of 979 genes with ≥2-fold change in transcript abundance distinguished these groups. When compared with post-mortem hippocampal controls, a total of 1,676 genes were found to be significantly downregulated in HSF patients compared with only 399 downregulated genes in LSF patients.

 

Pathway analysis revealed >50 significantly deactivated or activated signaling pathways, with Signal Transduction as the central hub in the pathway network. While neuroinflammation pathways were activated in both seizure frequency groups, the HSF group systematically deactivated several key signaling pathways, including calcium, CREB and Opioid signaling.

 

We also infer that increased expression of the immediate early gene, NPAS4, and a signaling cascade promoting synaptic scaling via AMPA receptors, may have played a key role in maintaining a higher seizure threshold in the LSF cohort. These results suggest that therapeutic approaches targeting synaptic scaling pathways may aid in the treatment of seizures in TLE