Verbal memory dysfunction is associated with alterations in brain transcriptome in dominant temporal lobe epilepsy

Abstract

Objective: Memory dysfunction is prevalent in many neurological disorders and can have a significant negative impact on quality of life. The genetic contributions to memory impairment in epilepsy, particularly temporal lobe epilepsy (TLE), remain poorly understood. Here, we compare the brain transcriptome between TLE patients with and without verbal memory impairments to identify genes and signaling networks important for episodic memory.

Methods: Brain tissues were resected from 23 adults who underwent dominant temporal lobectomy for treatment of pharmacoresistant epilepsy. To control for potential effects of APOE on memory, only those homozygous for the APOE ε3 allele were included. A battery of memory tests was performed, and patients were stratified into two groups based on preoperative memory performance. The groups were well matched on demographic and disease-related variables. Total RNA-Seq and small RNA-Seq were performed on RNA extracted from the brain tissues. Pathway and integrative analyses were subsequently performed.

Results: We identified 1092 differentially expressed transcripts (DETs), with the majority (71%) being underexpressed in brain tissues from patients with impaired memory compared to those from patients with intact memory. Enrichment analysis revealed overrepresentation of genes in pathways pertaining to brain-related neurological dysfunction, including a subset associated with neurodegenerative diseases, memory, and cognition (APP, MAPT, PINK1). Despite including patients with identical APOE genotypes, we identify APOE as a differentially expressed gene associated with memory status. Small RNA-Seq identified four differentially expressed microRNAs (miRNAs) that were predicted to target a subset (22%) of all DETs. Integrative analysis showed that these miRNA-predicted DET targets impact brain-related pathways and biological processes also pertinent to memory and cognition.

Significance: TLE-associated memory status may be influenced by differences in gene expression profiles within the temporal lobe. Upstream processes influencing differential expression signatures, such as miRNAs, could serve as biomarkers and potential treatment targets for memory impairment in TLE.

Keywords: RNA-Seq; epilepsy surgery; memory; temporal lobe epilepsy; transcriptome.

Figure 1.. Differentially expressed genes between brains from patients with and without verbal memory impairments converge on brain-related pathways and processes.

(A) Top 20 canonical pathways impacted by DETs. Colors correspond to activation z-scores as predicted through IPA (NA, no activity pattern available). Color intensities reflect significance (-log10 adjusted P values). (B) Multiple differentially expressed genes converge on ‘Memory’ as predicted through IPA. (C) Enrichment analysis depicting top 10 gene ontology (GO) biological processes predicted to be impacted by the DETs. (D) Enrichment analysis depicting top 10 mammalian phenotypes predicted to be impacted by the DETs.

Figure 2.. Enrichment analysis for the four differentially expressed miRNAs.

Pathways and processes were derived from miRPathDB 2.0 for (A) hsa-miR-1237–5p, (B) hsa-miR-3939, (C) hsa-miR-6805–5p, and (D) hsa-miR-6750–5p. Top five pathways are depicted for each miRNA for each of Reactome pathways, KEGG pathways, GO cellular components, and GO biological pathways.

Figure 3.. mRNA-miRNA integrative analysis.

(A) Predicted miRNA targets that also represent DETs in brains from patients with and without verbal memory impairments were extracted from IPA. Unique and shared predicted DET targets exist for each differentially expressed miRNA. (B) Canonical pathways impacted by DETs predicted to be targeted by the four differentially expressed miRNAs. Colors correspond to activation z-scores as predicted through IPA (NA, no activity pattern available). Color intensities reflect significance (-log10 adjusted P values). (C) Multiple target DETs converge on ‘Memory’ as predicted through IPA. (D) Multiple target DETs converge on ‘Cognition’ as predicted through IPA.