Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy

Abstract

The hippocampus is the most common seizure focus in people. Within the hippocampus, aberrant neurogenesis plays a critical role in the initiation and progression of epilepsy in rodent models, but it is unknown whether this also holds true in humans. To address this question, we used immunofluorescence on control healthy hippocampus and surgical resections from mesial temporal lobe epilepsy (MTLE), plus neural stem cell cultures, and multi-electrode recordings of ex vivo hippocampal slices. We found that a longer duration of epilepsy is associated with a sharp decline in neuronal production, and persistent numbers in astrogenesis. Further, immature neurons in MTLE are mostly inactive, and are not observed in cases with local epileptiform-like activity. However, immature astroglia are present in every MTLE case and their location and activity are dependent upon epileptiform-like activity. Immature astroglia, rather than newborn neurons, therefore represent a potential target to continually modulate adult human neuronal hyperactivity.

Does the plasticity of neural stem cells and neurogenesis make them biosensors of disease and damage?

“…An intriguing possibility is that symmetric division was also increased and thus the pool of NSCs could be maintained and neurogenesis kept at higher levels for longer periods. The scenario confirmed so far is the chronic impairment of neurogenesis due to accelerated depletion of NSCs (Sierra et al, 2015) and could explain recent findings that suggest that neurogenesis decreases faster over time in the hippocampus of epilepsy patients (Ammothumkandy et al, 2022).…”

“…Finally, the key question that triggered the writing of this Perspective is whether we should consider neurogenesis as another readout to better discriminate pathology and how useful it could be as a diagnosis tool. Mounting evidence suggest not only that there is continuous neurogenesis in the human dentate gyrus, but also that as found in mouse models, neurogenesis responds differently in diverse pathologies, acting as biosensor of the undergoing pathological process ( Klein et al, 2021 ; Terreros-Roncal et al, 2021 ; Ammothumkandy et al, 2022 ). The main challenge is of course, how to monitor neurogenesis, in vivo .…”

Human Adult Neurogenesis Loss Underlies Cognitive Decline During Epilepsy Progression

“…The critical period (Fig 2) coincides with the time when neurogenesis becomes undetectable in human MTLE 11 . We next determined the relationship between the loss of neurogenesis and cognitive performance in intelligence, verbal learning, and memory tests.…”

“…Therefore, the current neurogenesis findings provide a new understanding of the cellular dynamics that drive DG volume change during MTLE disease progression. Altered neurogenesis in MTLE patients may reflect many cellular mechanisms, including a decrease in neural stem cell number, proliferation, neuronal fate commitment, or neuronal survival 11,19 . Remarkably, a previous study in healthy individuals has also implied a selective role for exercise-induced neurogenesis on verbal learning using indirect measures of dentate gyrus cerebral blood volume 20 .…”

“…Our recent study on human MTLE shows the most profound decline in neurogenesis among neurological diseases to date. Neurogenesis rapidly deteriorates over the course of the disease and was not detected after 20 years of MTLE disease duration (DD) 11 . It remains unknown how the loss of neurogenesis associates with cognitive impairment.…”