Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline

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Abstract

Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.

Abstract

Aberrant hippocampal neurogenesis often occurs after acute seizures that produce epilepsy and cognitive impairment but the role of neurogenesis in the development of epilepsy is unclear. Here the authors suppress adult neurogenesis in mice preceding seizures and show that it reduces subsequent chronic seizure frequency and epilepsy-associated cognitive decline.

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Adult hippocampal neurogenesis buffers stress responses and depressive behavior

Jason Snyder, Amélie Soumier, Michelle Brewer … (2011)

Summary Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness 1, 2 . In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis 3 . Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking 4, 5 . Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioral components of the stress response. Using transgenic and radiation methods to specifically inhibit adult neurogenesis, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice compared with intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis 6, 7 . Relative to controls, neurogenesis-deficient mice showed increased food avoidance in a novel environment after acute stress, increased behavioral despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

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When is the hippocampus involved in recognition memory?

Gareth Barker, Elizabeth Warburton (2011)

The role of the hippocampus in recognition memory is controversial. Recognition memory judgments may be made using different types of information, including object familiarity, an object's spatial location, or when an object was encountered. Experiment 1 examined the role of the hippocampus in recognition memory tasks that required the animals to use these different types of mnemonic information. Rats with bilateral cytotoxic lesions in the hippocampus or perirhinal or prefrontal cortex were tested on a battery of spontaneous object recognition tasks requiring the animals to make recognition memory judgments using familiarity (novel object preference); object-place information (object-in-place memory), or recency information (temporal order memory). Experiment 2 examined whether, when using different types of recognition memory information, the hippocampus interacts with either the perirhinal or prefrontal cortex. Thus, groups of rats were prepared with a unilateral cytotoxic lesion in the hippocampus combined with a lesion in either the contralateral perirhinal or prefrontal cortex. Rats were then tested in a series of object recognition memory tasks. Experiment 1 revealed that the hippocampus was crucial for object location, object-in-place, and recency recognition memory, but not for the novel object preference task. Experiment 2 revealed that object-in-place and recency recognition memory performance depended on a functional interaction between the hippocampus and either the perirhinal or medial prefrontal cortices. Thus, the hippocampus plays a role in recognition memory when such memory involves remembering that a particular stimulus occurred in a particular place or when the memory contains a temporal or object recency component.

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Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus.

Michael Geschwind, Robert Sloviter, T Yu … (1997)

The dentate granule cell layer of the rodent hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. In both human temporal lobe epilepsy and rodent models of limbic epilepsy, this same neuronal population undergoes extensive remodeling, including reorganization of mossy fibers, dispersion of the granule cell layer, and the appearance of granule cells in ectopic locations within the dentate gyrus. The mechanistic basis of these abnormalities, as well as their potential relationship to dentate granule cell neurogenesis, is unknown. We used a systemic chemoconvulsant model of temporal lobe epilepsy and bromodeoxyuridine (BrdU) labeling to investigate the effects of prolonged seizures on dentate granule cell neurogenesis in adult rats, and to examine the contribution of newly differentiated dentate granule cells to the network changes seen in this model. Pilocarpine-induced status epilepticus caused a dramatic and prolonged increase in cell proliferation in the dentate subgranular proliferative zone (SGZ), an area known to contain neuronal precursor cells. Colocalization of BrdU-immunolabeled cells with the neuron-specific markers turned on after division, 64 kDa, class III beta-tubulin, or microtubule-associated protein-2 showed that the vast majority of these mitotically active cells differentiated into neurons in the granule cell layer. Newly generated dentate granule cells also appeared in ectopic locations in the hilus and inner molecular layer of the dentate gyrus. Furthermore, developing granule cells projected axons aberrantly to both the CA3 pyramidal cell region and the dentate inner molecular layer. Induction of hippocampal seizure activity by perforant path stimulation resulted in an increase in SGZ mitotic activity similar to that seen with pilocarpine administration. These observations indicate that prolonged seizure discharges stimulate dentate granule cell neurogenesis, and that hippocampal network plasticity associated with epileptogenesis may arise from aberrant connections formed by newly born dentate granule cells.

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Author and article information

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Pub. Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 26 March 2015

Volume: 6

Electronic Location Identifier: 6606

Affiliations

[1 ]Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center , Dallas, Texas 75390, USA

[2 ]Department of Pharmacology, School of Medicine, The Catholic University of Korea , Seoul 137-701, South Korea

[3 ]Department of Psychiatry, UT Southwestern Medical Center , Dallas, Texas 75390, USA

[4 ]Department of Clinical Research, Oriental Medicine Research Center, Kitasato University , Tokyo 108-8641, Japan

[5 ]Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center , Dallas, Texas 75390, USA

[6 ]Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and Baylor College of Medicine , Houston, Texas 77030, USA

[7 ]Department of Pediatrics, Columbia University , New York, New York 10027, USA

[8 ]The Nathan Kline Institute for Psychiatric Research and NYU Langone Medical Center , Orangeburg, New York 10962, USA

Author notes

[a ] Jenny.Hsieh@ 123456UTSouthwestern.edu

[*]

These authors equally contributed to this work

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Publisher Item ID: ncomms7606

DOI: 10.1038/ncomms7606

PMC ID: 4375780

PubMed ID: 25808087

SO-VID: fdfa3aca-191e-43ea-b0c6-2933392461b4

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Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline

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Most cited references 46

Adult hippocampal neurogenesis buffers stress responses and depressive behavior

When is the hippocampus involved in recognition memory?

Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus.

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