Epilepsy and Adult Neurogenesis

Abstract

Seizure activity in the hippocampal region strongly affects stem cell-associated plasticity in the adult dentate gyrus. Here, we describe how seizures in rodent models of mesial temporal lobe epilepsy (mTLE) affect multiple steps in the developmental course from the dividing neural stem cell to the migrating and integrating newborn neuron. Furthermore, we discuss recent evidence indicating either that seizure-induced aberrant neurogenesis may contribute to the epileptic disease process or that altered neurogenesis after seizures may represent an attempt of the injured brain to repair itself. Last, we describe how dysfunction of adult neurogenesis caused by chronic seizures may play an important role in the cognitive comorbidities associated with mTLE.

Figure 1.

Pilocarpine-induced status epilepticus (SE) increases dentate gyrus cell proliferation. Dentate gyrus bromodeoxyuridine (BrdU) labeling in adult rats 35 d after pilocarpine-induced SE (right) or saline treatment in a control (left). BrdU immunoreactivity is increased markedly in the inner granule cell layer (GCL), hilus (h), and molecular layer (ML) of the animal that experienced 2 h of continuous seizure activity (right). BrdU was given on days 7–21 after pilocarpine or saline treatment. Scale bar, 100 µm.

Figure 2.

Neurogenesis following kainic acid (KA)-induced seizures is largely aberrant. Retroviral labeling reveals the highly polarized morphology with a single apical dendrite (arrow) and an axon (arrowhead) extending from newborn granule cells that were born under normal conditions (left panel). KA-induced seizures lead to the formation of a basal dendrite (blue arrow) in addition to the apical dendritic (arrow) and axonal processes (arrowhead, middle panel). Another portion of seizure-generated granule cells ectopically migrates into the hilus (right panel). Surprisingly, some ectopic granule cells morphologically appear very normal despite the aberrant localization. Scale bar, 15 µm. GCL, granule cell layer; h, hilus; ML, molecular layer.

Figure 3.

Ectopic granule cells in experimental and human mesial temporal lobe epilepsy (mTLE). (Top panels) Prox1 immunoreactivity in adult rat dentate gyrus 35 d after saline treatment (A) or pilocarpine-induced status epilepticus (SE) (B) shows many ectopic granule neurons in the epileptic rat (B) but not in the control (A). (Bottom panels) NeuN immunoreactivity in control human (C; temporal lobe tumor) and human mTLE (D) dentate gyrus shows granule cell layer (GCL) dispersion and ectopic granule-like neurons in the hilus (h) and molecular layer (ML) only in the patient with mTLE who had mesial temporal sclerosis (D). Arrowheads (C) point to larger, NeuN-immunoreactive hilar neurons in the control tissue that are not seen in the mTLE subject (D) caused by hilar cell loss, or in either rat (A,B) because Prox1 is expressed specifically in dentate granule cells. Scale bars, 100 µm (A,B); 50 µm (C,D).

Figure 4.

Aberrant integration of adult-born neurons after SE alters dentate gyrus circuitry. Top panel shows a schematic of the normal dentate gyrus with radial glia-like neural stem cells (NSCs) (green) that generate more proliferative type-2 cells (blue) that give rise to immature neurons that extend dendrites toward molecular layer (ML) and their axons (mossy fibers) toward the hilus (orange). Mature newborn neurons functionally integrate with their dendrites in the ML and send their axons to area CA3 and hilar regions (red). In experimental mesial temporal lobe epilepsy (mTLE) (bottom panel), status epilepticus (SE) increases neurogenesis and also alters the integration of differentiating neurons. Proliferation of radial glia-like cells (green) and also type-2 cells is strongly enhanced (blue). Cells born after SE extend aberrant dendrites into the hilar region (orange). Aberrant dendrites remain also on fully mature newborn granule cells (red) that may be implicated in disturbing dentate connectivity. Furthermore, mossy fiber sprouting occurs from seizure-generated (red) but also preexisting mature granule cells (not shown in this scheme). In addition to aberrant neurite extension and integration, some seizure-generated neurons migrate ectopically to reside in hilus (figure prepared by Simon Braun, University of Zurich).