Numerous studies to date have documented the wide range of manipulations that can increase neurogenesis. These include exercise, altered diet, growth factors, modulation of serotoninergic systems, reproductive or adrenal steroids, as well as pathological conditions such as traumatic injury, hypoxia/ischemia, and seizure induction [for a review, see Cameron et al., 1998
; Kempermann, 2005
]. Given this long list, it is surprising that there are few reports of ectopic granule cells. One would expect that with increased adult neurogenesis, some neurons would not obtain the correct cues for migration, and migrate ectopically. The lack of reports could be due to the focus of most investigators on the granule cell layer rather than other locations, or it could be that, remarkably, most granule cells born in the adult brain are provided all the cues necessary and sufficient to support correct migration.
What experimental approaches have reported an increase in ectopic granule cells? Most of these involve growth factor delivery or increased growth factor expression. For example, infusion of insulin-like growth factor led to increased neurogenesis and evidence of numerous granule-like hilar profiles [Åberg et al., 2000
; Lichtenwalner et al., 2001
]. VEGF infusion also led to increased neurogenesis and evidence of hilar granule cells [Jin et al., 2002
], although experiments did not address directly whether the hilar cells were granule cells. BDNF infusion, which increased neurogenesis, also led to ectopic hilar granule cells [Scharfman et al., 2005
]. Developmental disorders also appear to foster ectopic granule cells. Thus, in the reeler mouse [Stanfield and Cowan, 1979
], the p35 knockout mouse [Patel et al., 2004
] and the Pcmt1 knockout mouse [Farrar et al., 2005
], there are increased ectopic granule cells.
Interestingly, seizures that are not severe, or seizures that are not continuous, could influence ectopic granule cell development, even if they are not as powerful a stimulus to produce ectopic granule cells as status epilepticus. The reason to suggest this is because the p35 knockout mouse and Pcmt1 knockout mouse have intermittent seizures, and the reeler mouse has increased excitability [Patrylo et al., 2006
]. These are the knockouts that develop ectopic granule cells, so the phenotype may depend on the developmental defect and intermittent seizures (presumably due to altered circuitry resulting from the defect). However, the role of the intermittent seizures and the role of the developmental defect are difficult to tease apart. In the adult, intermittent seizures do not
appear to initiate ectopic granule cell formation, because animals that have had numerous individual kindled seizures do not develop substantial numbers of ectopic granule cells [Scharfman and Goodman, unpublished].
It is notable that the robust ability of severe seizures to initiate ectopic granule cell formation is not as simple as one might think. There may not be a linear relationship between the severity of seizures and ectopic granule cell number. Thus, status epilepticus that is prolonged beyond 1 h appears to promote death of new neurons [Mohapel et al., 2004
]. This result suggests a balance between the ability of severe seizures to increase proliferation, and the fact that severe seizures increase death. Death of neurons appears to escalate as status epilepticus increases in duration. This may reflect a permissive influence of robust neuronal activity, balanced by the negative impact of seizure-induced energy depletion, and hypoxia.
The permissive effect of increased neuronal activity may be due to the increase in growth factor expression in the dentate gyrus, a robust effect of seizures [for a review, see Scharfman, 2006]. Status may also change the expression of the molecules thought to control migration of granule cells. One of these is reelin, normally a ‘stop’ signal for granule cells, keeping them from migrating beyond the granule cell layer [Frotscher, 1997
]. In animal models of epilepsy, as well as humans with intractable temporal lobe epilepsy, reelin expression diminishes [Haas et al., 2002]. Thus, status may facilitate neuroproliferation by increasing growth factors that normally stimulate proliferation. In addition, status may change chemotactic factors, and these changes might lead to abnormal migration of newly born cells [Bagri et al., 2002
; Lu et al., 2002
; Minami et al., 2002
; Scharfman, 2006].
Other seizure-induced changes in the dentate gyrus may also be involved in ectopic granule cell formation. Seizures have been reported to delay maturation [Overstreet-Wadiche et al., 2006
] and delay proliferation of newly born granule cells, and these delays may influence their migration. Thus, it was found that induction of seizures after treatment with the convulsant kainic acid did not alter the normal turnover of nestin-immunoreactive precursors of granule cells, but did delay the maturation of type 3 precursors, which normally express doublecortin [Jessberger et al., 2005
]. Doublecortin expression could be key, because it ordinarily is a critical element in the normal migration of cortical neurons during development. By perturbing the stage in development when doublecortin is expressed, migration may become perturbed itself. Other studies have defined alternate potential factors that could contribute to aberrant migration, such as changes in the proliferaton of radial glia [Huttmann et al., 2003
]. These could stimulate an unusual relationship with newly born granule cells, as hypothesized elsewhere [Shapiro et al., 2005
]. Proinflammatory cytokines may play a role in ectopic granule cell formation, because after seizures there is an increase in cytokines in response to seizure-induced damage, and some members of the proinflammatory cytokine family influence dentate gyrus neurogenesis [Monje et al., 2003