Review
Depression, stress, epilepsy and adult neurogenesis

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Abstract

Epilepsy and depression share an unusually high coincidence suggestive of a common etiology. Disrupted production of adult-born hippocampal granule cells in both disorders may contribute to this high coincidence. Chronic stress and depression are associated with decreased granule cell neurogenesis. Epilepsy is associated with increased production – but aberrant integration – of new cells early in the disease and decreased production late in the disease. In both cases, the literature suggests these changes in neurogenesis play important roles in their respective diseases. Aberrant integration of adult-generated cells during the development of epilepsy may impair the ability of the dentate gyrus to prevent excess excitatory activity from reaching hippocampal pyramidal cells, thereby promoting seizures. Effective treatment of a subset of depressive symptoms, on the other hand, may require increased granule cell neurogenesis, indicating that adult-generated granule cells can modulate mood and affect. Given the robust changes in adult neurogenesis evident in both disorders, competing effects on brain structure are likely. Changes in relative risk, disease course or response to treatment seem probable, but complex and changing patterns of neurogenesis in both conditions will require sophisticated experimental designs to test these ideas. Despite the challenges, this area of research is critical for understanding and improving treatment for patients suffering from these disorders.

Introduction

Unambiguous evidence of ongoing neurogenesis in mammals has revolutionized views of neuroplasticity in the adult brain. Neurogenesis is a natural feature of the mature brain, persisting into old age in both animals (Altman and Das, 1965, Kaplan and Hinds, 1977, van Praag et al., 2002) and humans (Eriksson et al., 1998). Ongoing production of hippocampal dentate granule cells has received much attention because of the role of the hippocampus in learning, memory and cognition (for review see Lisman, 1999, Knierim et al., 2006, Rolls and Kesner, 2006). Although it will take years of study to fully elucidate the purpose of these new cells, multiple lines of evidence indicate they are important for these key hippocampal functions (for review see Deng et al., 2010). In addition, emerging research implicates dysregulation of granule cell neurogenesis in several diseases, including depression and epilepsy.

Epilepsy is a multifarious and debilitating disease affecting 1–2% of the population. Epilepsy is defined clinically by the occurrence of two or more unprovoked seizures. Seizures can originate from different regions of the brain, depending on the type of epilepsy syndrome. The present review focuses on temporal lobe epilepsy, a common and difficult to treat form of the disease with consistent hippocampal involvement. While seizures are the defining feature of epilepsy, the disease is frequently associated with other disorders, including cognitive problems, memory disturbances, anxiety and depression. Only recently, however, have these co-morbidities been targeted as an important area of research in epilepsy (National Institute of Health, Epilepsy Research Benchmarks, 2007). Intriguingly, the relationship between epilepsy and depression is bidirectional, with a history of depression associated with increased risk for developing epilepsy (Forsgren and Nyström, 1990, Hesdorffer et al., 2006, Hesdorffer et al., 2007). The mechanisms underpinning this relationship remain to be discovered. Disrupted granule cell neurogenesis, however, may be a potential common factor. In the present article, this idea is explored further following a review of the literature describing key features of disrupted granule cell neurogenesis in temporal lobe epilepsy, chronic stress and depression.

Section snippets

Adult hippocampal granule cell neurogenesis is disrupted in temporal lobe epilepsy

Basic research in temporal lobe epilepsy has relied on a variety of animal models, such as kindling and status epilepticus. In the kindling model, repeated electrical stimulation of the brain leads to a persistent lowering of the seizure threshold (Goddard et al., 1969), although animals do not exhibit spontaneous seizures unless kindling stimulations are repeated over a prolonged period (Sayin et al., 2003). In commonly-used status epilepticus models, animals receive a precipitating injury to

Part II: Co-morbidity between depression and epilepsy

Epidemiological studies have revealed an unusually high co-morbidity between depression and epilepsy. Patients with epilepsy are at high risk for major depression relative to the general population (O'Donoghue et al., 1999, Tellez-Zenteno et al., 2007). Individuals with a history of major depression and/or suicide attempts are at increased risk for developing new onset epilepsy (Forsgren and Nyström, 1990, Hesdorffer et al., 2006, Hesdorffer et al., 2007). The incidence of depression is 5–20

Granule cell neurogenesis is reduced by stress and increased by treatments that mitigate stress

Among the many effects of stress, one that emerges as a potential disease modifier is altered neurogenesis. Stressful stimuli such as sleep deprivation (Mirescu et al., 2006), subordination to a dominant animal (Gould et al., 1997, Kozorovitskiy and Gould, 2004), social isolation (Stranahan et al., 2006) and exposure to predator odor (Tanapat et al., 2001) all reduce granule cell neurogenesis, although not necessarily by the same mechanisms (for review see Duman, 2004, Lucassen et al., 2010,

Functional role of adult-generated granule cells

Chronic stress, depression and epilepsy are all associated with disrupted adult neurogenesis. Given the frequent coincidence of these conditions, their relative effects on neurogenesis almost certainly interact. The significance of these interactions, however, will largely depend on the functional role of adult-generated granule cells, an area of considerable uncertainty. In perhaps the simplest view, the primary function of adult neurogenesis is to replace older granule cells as they senesce.

Conclusions

Patients with epilepsy are at increased risk for depression, and prior history of depression increases the risk for new-onset epilepsy. Disrupted adult neurogenesis is a common feature of both disorders, raising the possibility that altered neurogenesis might contribute to this bidirectional relationship. Chronic reductions in neurogenesis following stress and depression would reduce the number of normal granule cells present in the dentate gyrus. A relative paucity of normal granule cells

Acknowledgments

This work was supported by the Charles L. Shor Foundation for Epilepsy Research and the National Institute of Neurological Disorders and Stroke (SCD, Award Numbers R01NS065020 and R01NS062806). The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. I would also like to thank Keri Kaeding and Dr. Raymund Pun for helpful comments on earlier

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