Modulation of neurogenesis by targeted hippocampal irradiation fails to affect kindling progression

Abstract

Changes in the rate of dentate granule cell neurogenesis and in the fate of newborn granule cells have been implicated in the development and progression of epilepsies. Strategies to normalize neurogenesis in chronic epilepsy models are thought to increase our understanding of the functional consequences of aberrant neurogenesis in the epileptic brain. Therefore, we modulated neurogenesis in an amygdala kindling paradigm in rats by targeted irradiation of the hippocampus using a medical linear accelerator device. Selective irradiation normalized the hippocampal cell proliferation rate in kindled animals. Both, in kindled and nonkindled rats the number of BrdU/NeuN-labeled newborn neurons was reduced in response to irradiation. Whereas kindling resulted in a pronounced increase in the number of neuroblasts identified based on doublecortin-labeling, irradiation prevented the expansion of the neuroblast population. Moreover, irradiation counteracted the kindling-associated increase in hilar basal dendrites, and kept the fraction of cells with basal dendrites at control levels. Despite the efficacious modulation of neurogenesis, irradiation did not affect the rate of kindling progression. Both, the number of stimulations as well as the cumulative afterdischarge duration to reach respective seizure stages were comparable in animals with and without irradiation. In addition, pre- and postkindling thresholds as well as seizure parameters recorded at threshold stimulation remained unaffected by irradiation. In conclusion, the fact that the efficacious modulation of neurogenesis by irradiation did not exert any effects on kindling acquisition and kindled seizures suggests that newborn neurons do not critically contribute to the hyperexcitable state in the chronic epilepsy model used.

Analysis in conditional cannabinoid 1 receptor-knockout mice reveals neuronal subpopulation-specific effects on epileptogenesis in the kindling paradigm

“…Surprisingly, in the present study, proliferation and generation of newborn neurons were induced by repeated seizures regardless of the genetic modulation of the endocannabinoid system. It has also been shown that the kindling process itself leads to increased hippocampal neurogenesis (Aguado et al, 2005;Jafari et al, 2012b;Parent et al, 1998;Pekcec et al, 2010), here pointing toward kindling associated alterations of cell proliferation. These data suggest that the endocannabinoid system plays no role in the disease-associated modulation of neurogenesis in the kindling model of temporal lobe epilepsy.…”

Reduced abnormal integration of adult-generated granule cells does not attenuate spontaneous recurrent seizures in mice

“…However, studies on whether aberrant hippocampal neurogenesis contribute to epileptogenesis have produced mixed results. Some studies using pharmacological agents (Jung et al, 2004(Jung et al, , 2006Sugaya et al, 2010) or genetic approaches (Cho et al, 2015;Hosford et al, 2016) concluded that inhibiting the newborn granule cells leaded to reduced spontaneous recurrent seizures (SRSs), while others indicated that ablation of newborn granule cells via pharmacological agents (Radley and Jacobs, 2003;Pekcec et al, 2008) or selective hippocampal irradiation (Pekcec et al, 2011) did not alleviate chronic seizures.…”

“…Papers by Jung et al (2006), Sugaya et al (2010) and Pekcec et al (2007) demonstrated a reduction in HECs after ablation of hippocampal neurogenesis, but MSF was not measured. In another study (Pekcec et al, 2011), neither the HECs nor the MFS was examined. In particular, the generation of hilar basal dendrites, another common pathological integration, was poorly assessed in these studies.…”

“…After suppression of the neurogenesis by endoN, an increased number of doublecortin (DCX) immunopositive cells with HBDs was observed (Pekcec et al, 2007). Paradoxically, an decrease was also found after selective hippocampal irradiation (Pekcec et al, 2011). Whether these antineurogenic treatments have effectively reduced HBDs in adult-generated mature granule cells was not examined.…”

After the Storm: From Windswept to Spiny Trees

“…Mixed results were obtained from studies aimed at preventing epileptogenesis by experimental reduction of neurogenesis (7,8). The complexity of the influence of newly added cells to existing circuitry was also demonstrated in early neural transplantation studies, in which new neurons transplanted into the hippocampal formation exerted either proconvulsive or anticonvulsive effects depending on the cell source used (9).…”