An interdisciplinary collaboration has deciphered the genomic cellular map associated with hippocampal sclerosis, a major histological condition of temporal lobe epilepsy.
Epilepsies are brain disorders that are characterised by enduring predisposition to seizures. They are also associated with other emotional and cognitive comorbidities. Although there have been several therapeutic advancements in the field, one-third of affected individuals remain resistant to therapies. Temporal lobe epilepsy (TLE) is the most prevalent form of pharmacoresistant epilepsy. It is also frequently linked with hippocampal sclerosis, a neuropathological condition associated with severe neuronal loss. There are various factors that influence the degree and severity of hippocampal sclerosis, including epilepsy history, age of onset and the relationship with early triggering events.
Type 1 is the most common form of hippocampal sclerosis. It shows severe neuronal loss of CA1, CA3 and CA4 pyramidal neurons and milder loss in CA2. Our understanding of the mechanisms behind why some neuronal types are more vulnerable than others remain largely unknown.
A genomic single-cell map
In a recent study, published in Cell Reports, researchers developed a transcriptional map that identified the precise genetic landscape of cell types affected in the disease. They specifically combined gene expression profiling at the single-nucleus and microdissected tissue levels with single-cell electrophysiology.
From these analyses, the team revealed that superficial CA1 pyramidal neurons were overactive in epileptic rodents. They found that more hyperexcitable neurons were located within this superficial sublayer of the hippocampal region and expressed some characteristic genes (so-called neurodegenerative signatures). The transcripts regulating other neuronal processes such as voltage channels, synaptic signalling and cell adhesion were deregulated differently.
José López-Atalaya, from the Institute of Neurosciences (CSIC-UMH), explained:
“When neurons begin to degenerate, they release some signals that can be detected by microglia, which are mediating the inflammatory and neurotoxic response. Each of these processes involve the activation or inactivation of some genetic programs defining a specific genetic signature. We identify some of these genetic signatures associated to neuronal types.”
The team also performed a disease pseudotime analysis which revealed separated trajectories from health to epilepsy across cell types.
Overall, these findings emphasise the importance of using cell type specificity to gain a better understanding of the phenotypic complexities accompanying hippocampal sclerosis in epilepsy. The researchers have now also made the data within this study accessible as a public resource through two interactive websites.
Image credit: By chaikom – canva