Dentate Granule Cell Neurogenesis Is Increased by Seizures and Contributes to Aberrant Network Reorganization in the Adult Rat Hippocampus

Abstract

The dentate granule cell layer of the rodent hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. In both human temporal lobe epilepsy and rodent models of limbic epilepsy, this same neuronal population undergoes extensive remodeling, including reorganization of mossy fibers, dispersion of the granule cell layer, and the appearance of granule cells in ectopic locations within the dentate gyrus. The mechanistic basis of these abnormalities, as well as their potential relationship to dentate granule cell neurogenesis, is unknown. We used a systemic chemoconvulsant model of temporal lobe epilepsy and bromodeoxyuridine (BrdU) labeling to investigate the effects of prolonged seizures on dentate granule cell neurogenesis in adult rats, and to examine the contribution of newly differentiated dentate granule cells to the network changes seen in this model. Pilocarpine-induced status epilepticus caused a dramatic and prolonged increase in cell proliferation in the dentate subgranular proliferative zone (SGZ), an area known to contain neuronal precursor cells. Colocalization of BrdU-immunolabeled cells with the neuron-specific markers turned on after division, 64 kDa, class III ␤-tubulin, or microtubule-associated protein-2 showed that the vast majority of these mitotically active cells differentiated into neurons in the granule cell layer. Newly generated dentate granule cells also appeared in ectopic locations in the hilus and inner molecular layer of the dentate gyrus. Furthermore, developing granule cells projected axons aberrantly to both the CA3 pyramidal cell region and the dentate inner molecular layer. Induction of hippocampal seizure activity by perforant path stimulation resulted in an increase in SGZ mitotic activity similar to that seen with pilocarpine administration. These observations indicate that prolonged seizure discharges stimulate dentate granule cell neurogenesis, and that hippocampal network plasticity associated with epileptogenesis may arise from aberrant connections formed by newly born dentate granule cells.

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

“…Acute seizures have been demonstrated to dramatically induce precursor proliferation in the DG [45][46][47]. Additionally, a recent report from Varodayan et al [48] demonstrated that seizure leads to a shortening of the cell cycle in DG precursors, suggesting a link between G 1 phase length and seizureinduced proliferation.…”

Serotonin and Hippocampal Neurogenesis

“…First, conditions that are associated with diminished granule cell genesis, such as malnutrition (Debassio et al 1996), aging (Kuhn et al 1996;Gould et al 1999), high corticosterone (Cameron and Gould 1994), stress , and NMDA receptor activation (Cameron et al 1995), also decrease the density of 5HT fibers or 5HT1A receptors, or inhibit the release of 5HT in the dentate gyrus (Blatt et al 1994;Chalmers et al 1993;McKittrick et al 1995;Nishimura et al 1995;Meijer and deKloet 1994;Watanabe et al 1993;Tao and Auerbach 1996;Whitton et al 1994;Nyakas et al 1997). Second, experimental manipulations that stimulate granule cell genesis, such as seizures (Parent et al 1997), adrenalectomy (Cameron and Gould 1994), and NMDA receptor antagonist treatment (Cameron et al 1995), also increase the density of 5HT1A receptors or the release of 5HT in the dentate gyrus (Hayakawa et al 1994;Burnet et al 1995;Whitton et al 1994;Kuroda et al 1994). Third, our preliminary evidence indicates that pharmacological manipulations that elevate 5HT levels in the hippocampus (fenfluramine) or stimulate 5TH1A receptors (8-OH-DPAT) increase the rate of proliferation of granule cell precursors (Jacobs et al 1998).…”

Progressive changes in hippocampal cytoarchitecture in a neurodevelopmental rat model of epilepsy: implications for understanding presymptomatic epileptogenesis, predictive diagnosis, and targeted treatments

“…6c) consistent with the notion of cell loss in the granule layer stimulating neurogenesis. Ectopic granule cells have been demonstrated to contribute to abnormal granule cell circuitry (recurrent excitatory feedback loops) in other models of TLE [43]. It is hypothesized that this abnormal circuitry contributes to seizure activity in TLE.…”