The Developmental Stage of Dentate Granule Cells Dictates Their Contribution to Seizure-Induced Plasticity

Abstract

Dentate granule cell (DGC) neurogenesis persists throughout life in the hippocampal dentate gyrus. In rodent temporal lobe epilepsy models, status epilepticus (SE) stimulates neurogenesis, but many newborn DGCs integrate aberrantly and are hyperexcitable, whereas others may integrate normally and restore inhibition. The overall influence of altered neurogenesis on epileptogenesis is therefore unclear. To better understand the role DGC neurogenesis plays in seizure-induced plasticity, we injected retroviral (RV) reporters to label dividing DGC progenitors at specific times before or after SE, or used x-irradiation to suppress neurogenesis. RV injections 7 weeks before SE to mark DGCs that had matured by the time of SE labeled cells with normal placement and morphology 4 weeks after SE. RV injections 2 or 4 weeks before seizure induction to label cells still developing during SE revealed normally located DGCs exhibiting hilar basal dendrites and mossy fiber sprouting (MFS) when observed 4 weeks after SE. Cells labeled by injecting RV after SE displayed hilar basal dendrites and ectopic migration, but not sprouting, at 28 d after SE; when examined 10 weeks after SE, however, these cells showed robust MFS. Eliminating cohorts of newborn DGCs by focal brain irradiation at specific times before or after SE decreased MFS or hilar ectopic DGCs, supporting the RV labeling results. These findings indicate that developing DGCs exhibit maturation-dependent vulnerability to SE, indicating that abnormal DGC plasticity derives exclusively from aberrantly developing DGCs. Treatments that restore normal DGC development after epileptogenic insults may therefore ameliorate epileptogenic network dysfunction and associated morbidities.

Abnormal neuronal patterning occurs during early postnatal brain development of Scn1b -null mice and precedes hyperexcitability

“…7B). These data suggest that Prox1+ hilar ectopic DGCs are increased in Scn1b nulls; however, in contrast to previous studies (22), this occurs before seizure onset, as assessed by c-fos activation. As expected, at P16, levels of hilar Prox1+ nuclei in WT mice decreased compared with P5 levels (Fig.…”

“…In agreement with this, the density of Prox1+ hilar ectopic DGCs was increased in null mice. Hilar ectopic DGCs increase following status epilepticus (22). However, our data suggest that in Scn1b-null mice, Prox1+ hilar ectopic DGCs increase before behavioral seizure onset.…”

“…7 A, i and ii). Prox1+ hilar ectopic DGCs arise from progenitors following status epilepticus (SE) (22). Hilar Prox1+ nuclei increased by 1.6-fold in nulls (P < 0.01; Fig.…”

Long-Lasting Plasticity of Hippocampal Adult-Born Neurons

“…These results might seem surprising in the light of the abundant literature showing that learning influences the dendritic tree and synaptic density in other brain areas (Bailey and Kandel, 1993;Moser et al, 1994;Kleim et al, 1997;Rusakov et al, 1997;Moser, 1999;Leuner et al, 2003). Interestingly it has been recently shown that developmentally generated neurons (born at P7) are resistant to status epilepticus-induced remodeling, whereas adult-generated ones are vulnerable (Kron et al, 2010). To date, the degree of functional connectivity and plasticity of naive 2-month-old adult-generated neurons has been reported similar to that of neurons generated during development (Laplagne et al, 2006).…”

Neurogenesis and epilepsy

“…Accumulating evidence suggests, however, that altered neurogenesis contributes to several well-characterized cellular abnormalities seen in human and experimental mTLE. These abnormalities include mossy fiber sprouting, DGC layer dispersion, and the appearance of DGCs in ectopic locations or with abnormal hilar basal dendrites (Kron et al, 2010). In contrast, other work suggests that adult-born DGCs that integrate normally during epileptogenesis may serve a compensatory role to restore inhibition (Jakubs et al, 2006).…”