Faculty Bibliography

Granule cells of the mammalian dentate gyrus normally form a discrete layer, and virtually all granule cells migrate to this location. Exceptional granule cells that are positioned incorrectly, in 'ectopic' locations, are rare. Although the characteristics of such ectopic granule cells appear similar in many respects to granule cells located in the granule cell layer, their rare occurrence has limited a full evaluation of their structure and function. More information about ectopic granule cells has been obtained by studying those that develop after experimental manipulations that increase their number. For example, after severe seizures, the number of ectopic granule cells located in the hilus increases dramatically. These experimentally-induced ectopic granule cells may not be equivalent to normal ectopic granule cells necessarily, but the vastly increased numbers have allowed much more information to be obtained. Remarkably, the granule cells that are positioned ectopically develop intrinsic properties and an axonal projection that are similar to granule cells that are located normally, i.e., in the granule cell layer. However, dendritic structure and synaptic structure/function appear to differ. These studies have provided new insight into a rare type of granule cell in the dentate gyrus, and the plastic characteristics of dentate granule cells that appear to depend on the location of the cell body

Seizure induction in laboratory animals is followed by many changes in structure and function, and one of these is an increase in neurogenesis-the birth of new neurons. This phenomenon may be relevant to temporal lobe epilepsy (TLE), because one of the regions of the brain where seizure-induced neurogenesis is most robust is the dentate gyrus-an area of the brain that has been implicated in the pathophysiology of TLE. Although initial studies predicted that neurogenesis in the dentate gyrus would be important to normal functions, such as learning and memory, the new neurons that are born after seizures may not necessarily promote normal function. There appears to be a complex functional and structural relationship between the new dentate gyrus neurons and preexisting cells, both in the animal models of TLE and in tissue resected from patients with intractable TLE. These studies provide new insights into the mechanisms of TLE, and suggest novel strategies for intervention that could be used to prevent or treat TLE

The hippocampus is typically described in the context of the trisynaptic circuit, a pathway that relays information from the perforant path to the dentate gyrus, dentate to area CA3, and CA3 to area CA1. Associated with this concept is the assumption that most hippocampal information processing occurs along the trisynaptic circuit. However, the entorhinal cortex may not be the only major extrinsic input to consider, and the trisynaptic circuit may not be the only way information is processed in hippocampus. Area CA3 receives input from a variety of sources, and may be as much of an 'entry point' to hippocampus as the dentate gyrus. The axon of CA3 pyramidal cells targets diverse cell types, and has commissural projections, which together make it able to send information to much more of the hippocampus than granule cells. Therefore, CA3 pyramidal cells seem better designed to spread information through hippocampus than the granule cells. From this perspective, CA3 may be a point of entry that receives information which needs to be 'broadcasted,' whereas the dentate gyrus may be a point of entry that receives information with more selective needs for hippocampal processing. One aspect of the argument that CA3 pyramidal cells have a widespread projection is based on a part of its axonal arbor that has received relatively little attention, the collaterals that project in the opposite direction to the trisynaptic circuit, 'back' to the dentate gyrus. The evidence for this 'backprojection' to the dentate gyrus is strong, particularly in area CA3c, the region closest to the dentate gyrus, and in temporal hippocampus. The influence on granule cells is indirect, through hilar mossy cells and GABAergic neurons of the dentate gyrus, and appears to include direct projections in the case of CA3c pyramidal cells of ventral hippocampus. Physiological studies suggest that normally area CA3 does not have a robust excitatory influence on granule cells, but serves instead to inhibit it by activating dentate gyrus GABAergic neurons. Thus, GABAergic inhibition normally controls the backprojection to dentate granule cells, analogous to the way GABAergic inhibition appears to control the perforant path input to granule cells. From this perspective, the dentate gyrus has two robust glutamatergic inputs, entorhinal cortex and CA3, and two 'gates,' or inhibitory filters that reduce the efficacy of both inputs, keeping granule cells relatively quiescent. When GABAergic inhibition is reduced experimentally, or under pathological conditions, CA3 pyramidal cells activate granule cells reliably, and do so primarily by disynaptic excitation that is mediated by mossy cells. We suggest that the backprojection has important functions normally that are dynamically regulated by nonprincipal cells of the dentate gyrus. Slightly reduced GABAergic input would lead to increased polysynaptic associative processing between CA3 and the dentate gyrus. Under pathological conditions associated with loss of GABAergic interneurons, the backprojection may support reverberatory excitatory activity between CA3, mossy cells, and granule cells, possibly enhanced by mossy fiber sprouting. In this case, the backprojection could be important to seizure activity originating in hippocampus, and help explain the seizure susceptibility of ventral hippocampus

Following status epilepticus in the rat, dentate granule cell neurogenesis increases greatly, and many of the new neurons appear to develop ectopically, in the hilar region of the hippocampal formation. It has been suggested that the ectopic hilar granule cells could contribute to the spontaneous seizures that ultimately develop after status epilepticus. However, the population has never been quantified, so it is unclear whether it is substantial enough to have a strong influence on epileptogenesis. To quantify this population, the total number of ectopic hilar granule cells was estimated using unbiased stereology at different times after pilocarpine-induced status epilepticus. The number of hilar neurons immunoreactive for Prox-1, a granule-cell-specific marker, was estimated using the optical fractionator method. The results indicate that the size of the hilar ectopic granule cell population after status epilepticus is substantial, and stable over time. Interestingly, the size of the population appears to be correlated with the frequency of behavioral seizures, because animals with more ectopic granule cells in the hilus have more frequent behavioral seizures. The hilar ectopic granule cell population does not appear to vary systematically across the septotemporal axis, although it is associated with an increase in volume of the hilus. The results provide new insight into the potential role of ectopic hilar granule cells in the pilocarpine model of temporal lobe epilepsy

It is clear from both clinical observations of women, and research in laboratory animals, that gonadal hormones exert a profound influence on neuronal excitability, seizures, and epilepsy. These studies have led to a focus on two of the primary ovarian steroid hormones, estrogen and progesterone, to clarify how gonadal hormones influence seizures in women with epilepsy. The prevailing view is that estrogen is proconvulsant, whereas progesterone is anticonvulsant. However, estrogen and progesterone may not be the only reproductive hormones to consider in evaluating excitability, seizures, or epilepsy in the female. It seems unlikely that estrogen and progesterone would exert single, uniform actions given our current understanding of their complex pharmacological and physiological relationships. Their modulatory effects are likely to depend on endocrine state, relative concentration, metabolism, and many other factors. Despite the challenges these issues raise to future research, some recent advances have helped clarify past confusion in the literature. In addition, testable hypotheses have developed for complex clinical problems such as 'catamenial epilepsy.' Clinical and animal research, designed with the relevant endocrinological and neurobiological issues in mind, will help advance this field in the future

In summary, NPY is clearly an important peptide in the adult rat dentate gyrus because it has the potential to influence synaptic transmission and neurogenesis. It may even have other functions, as yet undiscovered, mediated by glia or vasculature. The remarkable plasticity of NPY puts it in a position to allow dentate gyrus function to be modified in a changing environment. The importance of this plasticity in the context of epilepsy cannot be emphasized enough. It could help explain a range of observations about epilepsy that currently is poorly understood. For example, rapid increases in NPY could mediate postictal depression, the period of depression that can last for several hours after generalized seizures. It may mediate the 'priming effect,' which is a reduction in seizure threshold following an initial period of seizures. Finally, it could contribute to the resistance of dentate granule cells to degeneration after seizures. However, despite the focus in this review on seizure-induced changes, the changes described here also appear to occur after other types of manipulations, which considerably broadens the scope of NPY's role in the brain