Radiation of the Rat Brain Suppresses Seizure‐Induced Neurogenesis and Transiently Enhances Excitability during Kindling Acquisition

Abstract

Summary:Purpose: Adult hippocampal neurogenesis is enhanced in several models for temporal lobe epilepsy (TLE). In this study, we used low-dose whole brain radiation to suppress hippocampal neurogenesis and then studied the effect of this treatment on epileptogenesis in a kindling model for TLE.Methods: Half of the rats were exposed to a radiation dose of 8 Gy one day before the initiation of a rapid kindling protocol. Afterdischarge threshold (ADT), afterdischarge duration (ADD), clinical seizure severity, and inflammation were compared between groups. On the first and third day after radiation, rats were injected with 5 -bromo-2 -deoxyuridine (BrdU) to evaluate neurogenesis. Seven and 21 days after radiation, numbers of doublecortin (DCX) positive neuroblasts in subgranular zone and granule cell layer were compared between groups.Results: We showed that radiation significantly suppressed neurogenesis and neuroblast production during kindling acquisition. Radiation prevented an increase in ADT that became significantly lower in radiated rats. On the third and fourth kindling acquisition day radiated rats developed more severe seizures more rapidly, which resulted in a significantly higher mean severity score on these days. Differences in ADD could not be demonstrated.Discussion: Our results demonstrate that brain radiation with a relatively low dose effectively suppressed the generation of new granule cells and transiently enhanced excitability during kindling acquisition. Although seizure-induced neurogenesis was lower in the radiated rats we could not detect a strong effect on the final establishment of the permanent fully kindled state, which argues against a prominent role of seizure-induced neurogenesis in epileptogenesis.

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

“…In line with our present data, targeting epileptogenesis-associated induction of neurogenesis by enzymatic depolysialylation of NCAM failed to impact epilepsy development in a post-status epilepticus model as well as the progression of seizure development in a kindling paradigm (Pekcec et al, 2008;Pekcec et al, 2007b). When drawing conclusions from the different approaches that analyzed the consequences of neurogenesis modulation in chronic epilepsy models, it needs to be considered that the different paradigms only affected the generation of new neurons in response to the seizure induction (Jung et al, 2004;Jung et al, 2006;Pekcec et al, 2007b;Raedt et al, 2007;Pekcec et al, 2008). Neuroblasts which had arisen from cell division prior to treatment were still available for aberrant integration in all approaches.…”

“…Two previous studies also modulated neurogenesis in chronic epilepsy models using an irradiation approach (Parent et al, 1999;Raedt et al, 2007). Parent et al (1999) demonstrated that whole-brain irradiation does not abolish mossy fiber sprouting in a post-status epilepticus model.…”

“…However, this study did not include EEG or video recordings in the chronic phase to evaluate seizure occurrence. In a hippocampal rapid kindling paradigm, rats were exposed to a nonselective whole brain irradiation before the first kindling stimulation (Raedt et al, 2007). The authors reported a transiently enhanced excitability during kindling acquisition at selected stimulation days.…”

“…Low-dose irradiation renders an alternate approach to modulate neurogenesis. Whole-brain irradiation has been described to transiently enhance excitability in a hippocampal kindling paradigm (Raedt et al, 2007). However, the use of irradiation has limitations since other effects such as inflammation, alterations in microvasculature, and changes in metabolic and signaling pathways in different brain regions might bias the outcome of these studies Silasi et al, 2004).…”

Status epilepticus during old age is not associated with enhanced hippocampal neurogenesis

“…Furthermore, DG neurogenesis in the young brain exhibits notable plasticity to injury through considerable upregulation in the production of new neurons (Liu et al, 1998;Jin et al, , 2004. While the latent benefits or adverse effects of increased neurogenesis after seizures or brain injury are still being examined (Parent, 2003;Jessberger et al, 2007a;Pekcec et al, 2007;Raedt et al, 2007;Scharfman and Gray, 2007;Shetty and Hattiangady 2007), studies in some brain injury models suggest that this plasticity may be valuable for diminishing impairments in cognitive functions after brain injury (Kleindienst et al, 2005;Sun et al, 2007).…”