Faculty Bibliography

Glial cells provide energy substrates to neurons, in part from glycogen metabolism, which is influenced by glycogen phosphorylase (GP). To gain insight into the potential subfield and laminar-specific expression of GP, histochemistry can be used to evaluate active GP (GPa) or totalGP (GPa + GPb). Using this approach, we tested the hypothesis that changes in GP would occur under pathological conditions that are associated with increased energy demand, i.e. severe seizures (status epilepticus or 'status'). We also hypothesized that GP histochemistry would provide insight into changes in the days and weeks after status, particularly in the hippocampus and entorhinal cortex, where there are robust changes in structure and function. One hour after the onset of pilocarpine-induced status, GPa staining was reduced in most regions of the hippocampus and entorhinal cortex relative to saline-injected controls. One week after status, there was increased GPa and totalGP, especially in the inner molecular layer, where synaptic reorganization of granule cell mossy fibre axons occurs (mossy fibre sprouting). In addition, patches of dense GP reactivity were evident in many areas. One month after status, levels of GPa and totalGP remained elevated in some areas, suggesting an ongoing role of GP or other aspects of glycogen metabolism, possibly due to the evolution of intermittent, recurrent seizures at approximately 3-4 weeks after status. Taken together, the results suggest that GP is dynamically regulated during and after status in the adult rat, and may have an important role in the pilocarpine model of epilepsy

Epilepsy is a complex disease with diverse clinical characteristics that preclude a singular mechanism. One way to gain insight into potential mechanisms is to reduce the features of epilepsy to its basic components: seizures, epileptogenesis, and the state of recurrent unprovoked seizures that defines epilepsy itself. A common way to explain seizures in a normal individual is that a disruption has occurred in the normal balance of excitation and inhibition. The fact that multiple mechanisms exist is not surprising given the varied ways the normal nervous system controls this balance. In contrast, understanding seizures in the brain of an individual with epilepsy is more difficult because seizures are typically superimposed on an altered nervous system. The different environment includes diverse changes, making mechanistic predictions a challenge. Understanding the mechanisms of seizures in an individual with epilepsy is also more complex than understanding the mechanisms of seizures in a normal individual because epilepsy is not necessarily a static condition but can continue to evolve over the lifespan. Using temporal lobe epilepsy as an example, it is clear that genes, developmental mechanisms, and neuronal plasticity play major roles in creating a state of underlying hyperexcitability. However, the critical control points for the emergence of chronic seizures in temporal lobe epilepsy, as well as their persistence, frequency, and severity, are questions that remain unresolved

In adult female rats, robust hippocampal changes occur when estradiol rises on the morning of proestrus. Whether estradiol mediates these changes, however, remains unknown. To address this issue, we used sequential injections of estradiol to simulate two key components of the preovulatory surge: the rapid rise in estradiol on proestrous morning, and the slower rise during the preceding day, diestrus 2. Animals were examined mid-morning of simulated proestrus, and compared to vehicle-treated or intact rats. In both simulated and intact rats, CA1-evoked responses were potentiated in hippocampal slices, and presynaptic mechanisms appeared to contribute. In CA3, multiple population spikes were evoked in response to mossy fiber stimuli, and expression of brain-derived neurotrophic factor was increased. Simulation of proestrous morning also improved performance on object and place recognition tests, in comparison to vehicle treatment. Surprisingly, effects on CA1-evoked responses showed a dependence on estradiol during simulated diestrus 2, as well as a dependence on proestrous morning. Increasing estradiol above the physiological range on proestrous morning paradoxically decreased evoked responses in CA1. However, CA3 pyramidal cell activity increased further, and became synchronized. Together, the results confirm that physiological estradiol levels are sufficient to profoundly affect hippocampal function. In addition: (i) changes on proestrous morning appear to depend on slow increases in estradiol during the preceding day; (ii) effects are extremely sensitive to the peak serum level on proestrous morning; and (iii) there are striking subfield differences within the hippocampus

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

Characterizing the responses of different mouse strains to experimentally-induced seizures can provide clues to the genes that are responsible for seizure susceptibility, and factors that contribute to epilepsy. This approach is optimal when sequenced mouse strains are available. Therefore, we compared two sequenced strains, DBA/2J (DBA) and A/J. These strains were compared using the chemoconvulsant pilocarpine, because pilocarpine induces status epilepticus, a state of severe, prolonged seizures. In addition, pilocarpine-induced status is followed by changes in the brain that are associated with the pathophysiology of temporal lobe epilepsy (TLE). Therefore, pilocarpine can be used to address susceptibility to severe seizures, as well as genes that could be relevant to TLE. A/J mice had a higher incidence of status, but a longer latency to status than DBA mice. DBA mice exhibited more hippocampal pyramidal cell damage. DBA mice developed more ectopic granule cells in the hilus, a result of aberrant migration of granule cells born after status. DBA mice experienced sudden death in the weeks following status, while A/J mice exhibited the most sudden death in the initial hour after pilocarpine administration. The results support previous studies of strain differences based on responses to convulsants. They suggest caution in studies of seizure susceptibility that are based only on incidence or latency. In addition, the results provide new insight into the strain-specific characteristics of DBA and A/J mice. A/J mice provide a potential resource to examine the progression to status. The DBA mouse may be valuable to clarify genes regulating other seizure-associated phenomena, such as seizure-induced neurogenesis and sudden death

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

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