Seizure-Associated, Abberent Neurogenesis in Adult Rats Characterized with Retrovirus-Mediate Cell Labeling

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2007; 27(35):9400-7. DOI: 10.1523/JNEUROSCI.2002-07.2007
Source: PubMed


Seizure activity within the hippocampal circuitry not only affects pre-existing structures, but also dramatically increases the number of newborn granule cells. A retroviral strategy was used to label dividing cells and their progeny in the adult dentate gyrus and to analyze the impact of epileptic activity on adult-generated cells labeled before or after seizures. We show that epileptic activity led to dramatic changes in the neuronal polarity, migration, and integration pattern of newborn granule cells, depending on the time of birth in relation to the epileptic insult. Aberrant neurons were stably integrated into the dentate circuitry, and the consequences on hippocampal neurogenesis were long lasting. The data presented characterized the consequences of seizure-associated plasticity on adult neurogenesis leading to long-term structural changes in the hippocampal circuitry that might represent a pivotal component of the epileptic disease process.

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    • "These newly generated cells migrate to ectopic locations in the hilus, develop aberrant basal dendrites, contribute to mossy fiber sprouting, and exhibit changes in apical dendrite structure and dendritic spine number (Santos et al., 2011). Using retroviral labeling to visualize newborn neurons, Jessberger et al. described, in a seminal work, a significant number of these cells with aberrant morphology comprising additional basal dendrites directed into the hilus and an ectopic positioning of the cells after seizures (Jessberger et al., 2007). In addition, Cho et al. demonstrated that ablation of neurogenesis is sufficient to alleviate the cognitive decline produced by seizure activity and to prevent the development of subsequent seizures for at least 1 year. "
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    ABSTRACT: Newborn neurons are continuously added to the hippocampal dentate gyrus throughout adulthood. In this review, we analyze the maturational stages that newborn granule neurons go through, with a focus on their unique morphological features during each stage under both physiological and pathological circumstances. In addition, the influence of deleterious (such as schizophrenia, stress, Alzheimer’s disease, seizures, stroke, inflammation, dietary deficiencies, or the consumption of drugs of abuse or toxic substances) and neuroprotective (physical exercise and environmental enrichment) stimuli on the maturation of these cells will be examined. Finally, the regulation of this process by proteins involved in neurodegenerative and neurological disorders (such as Glycogen synthase kinase 3β, Disrupted in Schizophrenia 1 (DISC-1), Glucocorticoid receptor, pro-inflammatory mediators, Presenilin-1, Amyloid precursor protein, Cyclin-dependent kinase 5 (CDK5), among others, will be evaluated. Given the recently acquired relevance of the dendritic branch as a functional synaptic unit required for memory storage, a full understanding of the morphological alterations observed in newborn neurons may have important consequences for the prevention and treatment of the cognitive and affective alterations that evolve in conjunction with impaired adult hippocampal neurogenesis.
    Full-text · Article · Jan 2016 · Frontiers in Neuroscience
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    • "Not every DGC contributes to MFS (Buckmaster and Dudek, 1999), and it is not known what influences the likelihood to contribute. DGC birthdate is one potential factor because of the well-documented role of adult-born DGCs in seizure-related plasticity (Jessberger et al., 2007, Kron et al., 2010, Walter et al., 2007). Previous work suggested that DGCs developing during or after an epileptogenic insult are responsible for most, if not all, MFS in the IML (Kron et al., 2010). "
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    ABSTRACT: Dentate granule cell (DGC) mossy fiber sprouting (MFS) in mesial temporal lobe epilepsy (mTLE) is thought to underlie the creation of aberrant circuitry which promotes the generation or spread of spontaneous seizure activity. Understanding the extent to which populations of DGCs participate in this circuitry could help determine how it develops and potentially identify therapeutic targets for regulating aberrant network activity. In this study, we investigated how DGC birthdate influences participation in MFS and other aspects of axonal plasticity using the rat pilocarpine-induced status epilepticus (SE) model of mTLE. We injected a retrovirus (RV) carrying a synaptophysin-yellow fluorescent protein (syp-YFP) fusion construct to birthdate DGCs and brightly label their axon terminals, and compared DGCs born during the neonatal period with those generated in adulthood. We found that both neonatal and adult-born DGC populations participate, to a similar extent, in SE-induced MFS within the dentate gyrus inner molecular layer (IML). SE did not alter hilar MF bouton density compared to sham-treated controls, but adult-born DGC bouton density was greater in the IML than in the hilus after SE. Interestingly, we also observed MF axonal reorganization in area CA2 in epileptic rats, and these changes arose from DGCs generated both neonatally and in adulthood. These data indicate that both neonatal and adult-generated DGCs contribute to axonal reorganization in the rat pilocarpine mTLE model, and indicate a more complex relationship between DGC age and participation in seizure-related plasticity than was previously thought.
    Full-text · Article · Nov 2015 · Neurobiology of Disease
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    • "ostnatal and adult hippocampal neurogenesis support hippocampal dependent learning and memory under physiological conditions (Dupret et al., 2007; Gould et al., 1999; Leuner et al., 2006; Shors et al., 2001; Winocur et al., 2006; Zhang et al., 2008). Furthermore, altered neurogenesis has been implicated in cognitive and mood impairment in temporal lobe epilepsy (Barkas et al., 2012; Kuruba et al., 2009), depression, and certain neurodegenerative diseases (Jessberger et al., 2007; Jin et al., 2004; Kempermann, 2002; Malberg et al., 2000; Parent et al., 1997; Rockenstein et al., 2007), suggesting that hippocampal neurogenesis may be an appropriate therapeutic target for these conditions. All these conditions have an important neuroinflammatory component to their pathogenesis, and the innate and adaptive immune systems are increasingly recognized as important control systems for hippocampal neurogenesis under both physiological and pathological conditions. "
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    ABSTRACT: Neurogenesis, the production of new neurons from neural stem/progenitor cells (NSPCs), occurs throughout adulthood in the dentate gyrus of the hippocampus, where it supports learning and memory. The innate and adaptive immune systems are increasingly recognized as important modulators of hippocampal neurogenesis under both physiological and pathological conditions. However, the mechanisms by which the immune system regulates hippocampal neurogenesis are incompletely understood. In particular, the role of microglia, the brains resident immune cell is complex, as they have been reported to both positively and negatively regulate neurogenesis. Interestingly, neuronal activity can also regulate the function of the immune system. Here, we show that depleting microglia from hippocampal cultures reduces NSPC survival and proliferation. Furthermore, addition of purified hippocampal microglia, or their conditioned media, is trophic and proliferative to NSPCs. VIP, a neuropeptide released by dentate gyrus interneurons, enhances the proliferative and pro-neurogenic effect of microglia via the VPAC1 receptor. This VIP-induced enhancement is mediated by IL-4 release, which directly targets NSPCs. This demonstrates a potential neuro-immuno-neurogenic pathway, disruption of which may have significant implications in conditions where combined cognitive impairments, interneuron loss, and immune system activation occurs, such as temporal lobe epilepsy and Alzheimer's disease. GLIA 2014
    Full-text · Article · Aug 2014 · Glia
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