Persistent hippocampal neurogenesis and epilepsy
Article first published online: 2 JUN 2008
© 2008 International League Against Epilepsy
Special Issue: Persistent Hippocampal Neurogenesis
Volume 49, Issue Supplement s5, pages 1–2, June 2008
How to Cite
Parent, J. M. (2008), Persistent hippocampal neurogenesis and epilepsy. Epilepsia, 49: 1–2. doi: 10.1111/j.1528-1167.2008.01631.x
- Issue published online: 2 JUN 2008
- Article first published online: 2 JUN 2008
The dogma of no neuronal production, or neurogenesis, in the adult mammalian brain slowly has been laid to rest over the past five decades. Resounding experimental evidence indicates that neural stem cells and neurogenesis persist in at least two regions of the adult mammalian brain, the hippocampal dentate gryus and striatal subventricular zone of the lateral ventricles (Ming & Song, 2005). In the adult mammalian dentate gyrus, neural stem cells in a proliferative zone under the granule cell layer give rise to dentate granule cells (DGCs) throughout life. Although important questions about the biological function of adult neurogenesis remain unanswered, a growing body of data suggests that adult neurogenesis adds an additional layer of plasticity into the hippocampal circuitry (Bruel-Jungerman et al., 2007). This plasticity likely plays a role in specific forms of hippocampus-dependent learning and memory.
The recognition of persistent neurogenesis in the adult mammalian brain has led to studies of how injury influences neurogenesis. Interestingly, nearly all types of brain insults appear to stimulate neurogenesis in the adult neurogenic zones (Parent, 2003). These findings have led to two distinct areas of inquiry with respect to epileptogenic brain injuries. The more obvious question is the following: Are neural stem cells that persist in the adult capable of repairing the injured brain if stimulated appropriately? If so, do they accomplish this through compensatory effects on neural networks or by replacing lost cells? General interest and advances in neural stem cell biology have led to related investigations of whether transplanted neural progenitors may serve similar therapeutic functions. The other main question regarding postnatal or adult hippocampal neurogenesis and epilepsy involves the idea that abnormally occurring neurogenesis is critically involved in aberrant plasticity during epileptogenesis. Simply stated, if new neurons integrate abnormally into existing circuits after an epileptogenic insult, do they contribute to the development of epilepsy or associated morbidities such as memory dysfunction or depression? These ideas relate to both acute changes in neurogenesis after injury and chronic dysfunction of the neural stem cell niche or environment.
The purpose of this supplement is to provide an overview of adult hippocampal neurogenesis and its dysregulation in the epileptic brain. The reviews are intended to provide the reader with an up-to-date understanding of how neurogenesis is altered in the epileptic brain, addressing cutting edge questions related to the role neurogenesis plays in epileptogenesis (either causative or compensatory), and describing state-of-the-art techniques being used to address these questions. How do the differentiating cells integrate in the normal brain and in the epileptic dentate gyrus? What is their morphology? Why do many cells migrate ectopically and end up in improper locations after an epileptogenic insult? What is the functional significance of these adult-born neurons in the intact versus epileptic hippocampal formation? These are just some of the questions that will be examined.
The importance of several ideas and hypotheses that need to be addressed in the area of neurogenesis and epilepsy is underscored by their discussion in several of the papers in this supplement. For example, does the loss of neurogenesis in the chronically epileptic hippocampus contribute to learning and memory dysfunction? This issue is addressed head-on in the review by Wojtowicz, and is also discussed in the articles by Hattiangady and Shetty, and Siebzehnrubl and Blumcke. Do the abnormal locations and connections of adult born-neurons play a role in seizure generation or propagation? Reviews by Zhao and Overstreet-Wadiche, Shapiro et al., and Parent and Murphy touch on this aspect.
Several difficulties and counterintuitive findings in the field are highlighted. For example, why is DGC neurogenesis decreased, rather than increased, by seizures in neonatal animals at a time when DGC neurogenesis is so robust? Why does this reverse in young adult animals, and then decline again in chronic epileptic or senescent animals? Brenda Porter provides a discussion of these issues. In terms of human mesial temporal lobe epilepsy, the controversy as to whether neurogenesis is increased or decreased continues unabated and is reviewed by Siebzehnrubl and Blumcke. Another controversy involves the etiology of granule cell layer dispersion and the ectopic locations of DGCs, and whether these two phenomena are related. Many of the reviews touch on this controversy.
One aim of this supplement is to stimulate further investigation into the function of adult neurogenesis in the intact or epileptic brain. Future work that sheds light on the biological role of persistent neurogenesis will have important implications for understanding whether and how its alteration in the setting of epilepsy contributes to disease pathophysiology. Moreover, new insights into the normal regulation and reparative potential of adult-born neurons or transplanted neural progenitor cells no doubt will critically impact potential neural stem cell therapies for epilepsy and a host of other brain disorders. A last but equally important goal of this supplement is to convince epilepsy researchers who study the hippocampus, both young and old, to routinely consider neurogenesis as an integral form of plasticity influenced by seizures or epileptogenic insults.
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