Control and recruitment of hippocampal precursor cells after seizures

Control and recruitment of hipppcampal precursor cells after seizures The birth of new neurons, neurogenesis, is sustained throughout life in the mammalian brain including humans. It has been clearly demonstrated in two niches, including the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). Neurogenesis is regulated by a variety of physiological stimuli and affected by a wide range of pathological conditions including epilepsy. Newly-born neurons are believed to be important for certain types of learning and memory as well as mood control. Hippocampal learning increases neurogenesis, and blockade of neurogenesis disrupts learning. Status epilepticus (SE) transiently enhances neurogenesis; however, patients with chronic epilepsy suffer from learning and cognitive impairments which are associated with a decline in neurogenesis. Kainate is an excitotoxin and often used to model SE and hippocampal damage. Kainate-induced seizures and SE alter hippocampal neurogenesis and coincide with cognitive impairment and mood disorders. Kainate-induced SE is also associated with abnormal morphology and integration of new neurons, which starts immediately after the insult and is long lasting. However, the triggers and the altered proliferation kinetics of precursor cells after SE are poorly understood. To gain further insight into the mechanisms underlying control of neural precursors immediately after SE, we examined the acute effects of Kainate on hippocampal precursor cells in vitro and on pre-labelled and un-labelled 'clones' of proliferating hippocampal precursors in vivo. In vitro, we found that Kainate increased symmetric and asymmetric proliferation rate of nestin-positive precursors, via AMPA receptors. It also enhanced the survival of nestin and TuJl positive cells with a proportional increase in neurogenesis in a mechanism involving AMPA receptors. Furthermore, Kainate selectively targeted quiescent and highly amplifying precursor cells. Consistently, Kainate/seizures in vivo increased cell proliferation of both pre-labelled and un-labelled 'clones' of precursors in the SGZ with increased cell cycle re-entry of the pre-labelled 'clone' and with a tendency to reduce numbers of postmitotic cells. In the granule cell layer (GCL), there was an increased preferential proliferation of the pre-labelled 'clone' without enhancing cell death. The increased proliferation of the pre-labelled 'clone' in the combined SGZ and GCL indicated an enhanced cell cycle re-entry. Furthermore, Kainate/seizures increased doublecortin positive cells in the GCL by 72 h. We conclude that Kainate/seizure enhances hippocampal precursor proliferation via activation of AMPA receptors without increasing cell death, and that it has a differential effect on the proliferation kinetics and fate choice of precursors in the SGZ and GCL. We also identify proliferating precursor cells at the time of seizure-induction as a possible target to control the generation of abnormal neurons.