Brain single cell transcriptomic profiles in episodic memory phenotypes associated with temporal lobe epilepsy

Abstract

Memory dysfunction is prevalent in temporal lobe epilepsy (TLE), but little is known about the underlying molecular etiologies. Single-nucleus RNA sequencing technology was used to examine differences in cellular heterogeneity among left (language-dominant) temporal neocortical tissues from patients with TLE with (n = 4) or without (n = 2) impairment in verbal episodic memory. We observed marked cell heterogeneity between memory phenotypes and identified numerous differentially expressed genes across all brain cell types. The most notable differences were observed in glutamatergic (excitatory) and GABAergic (inhibitory) neurons with an overrepresentation of genes associated with long-term potentiation, long-term depression, and MAPK signaling, processes known to be essential for episodic memory formation.

Fig. 1. Histogram demonstrating clusters of nuclei by cell type and by patient.

Plots of cells from temporal lobe tissue of individual patients with and without memory impairment by (a) percent and (b) number of each cell type.

Fig. 2. Pathway enrichment analysis of differentially expressed genes from glutamatergic and GABAergic neurons.

A machine learning algorithm implemented through Ingenuity Pathway Analysis (IPA) agnostically identifies pathways and molecules relevant to memory function in (a) glutamatergic and (b) GABAergic neurons. Note that the legend may include predicted events not observed within the constructed networks.

Fig. 3. Diseases and functions associated with the differentially expressed genes from glutamatergic and GABAergic neurons.

Differentially expressed genes between brains from patients with and without memory impairment converge on memory-related processes as predicted through IPA in both (a) glutamatergic and (b) GABAergic neurons.