Functional integration of new hippocampal neurons in adult epileptic brain is determined by characteristics of pathological environment

Laboratory of Neurogenesis and Cell Therapy, Lund University Hospital, SE-221 84 Lund, Sweden.
Experimental Neurology (Impact Factor: 4.7). 03/2011; 229(2):484-93. DOI: 10.1016/j.expneurol.2011.03.019
Source: PubMed


We have previously shown that following severe brain insults, chronic inflammation induced by lipopolysaccharide (LPS) injection, and status epilepticus, new dentate granule cells exhibit changes of excitatory and inhibitory synaptic drive indicating that they may mitigate the abnormal brain function. Major inflammatory changes in the environment encountering the new neurons were a common feature of these insults. Here, we have asked how the morphology and electrophysiology of new neurons are affected by a comparably mild pathology: repetitive seizures causing hyperexcitability but not inflammation. Rats were subjected to rapid kindling, i.e., 40 rapidly recurring, electrically-induced seizures, and subsequently exposed to stimulus-evoked seizures twice weekly. New granule cells were labeled 1 week after the initial insult with a retroviral vector encoding green fluorescent protein. After 6-8 weeks, new neurons were analyzed using confocal microscopy and whole-cell patch-clamp recordings. The new neurons exposed to the pathological environment exhibited only subtle changes in their location, orientation, dendritic arborizations, and spine morphology. In contrast to the more severe insults, the new neurons exposed to rapid kindling and stimulus-evoked seizures exhibited enhanced afferent excitatory synaptic drive which could suggest that the cells that had developed in this environment contributed to hyperexcitability. However, the new neurons showed concomitant reduction of intrinsic excitability which may counteract the propagation of this excitability to the target cells. This study provides further evidence that following insults to the adult brain, the pattern of synaptic alterations at afferent inputs to newly generated neurons is dependent on the characteristics of the pathological environment.

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Available from: James Wood, Jul 22, 2015
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    • "Morphological, electrophysiological, and functional studies aimed at exploring the influence of normotopic newborn granule cells in the development of epilepsy have reached somewhat conflicting conclusions (Bielefeld et al., 2014). Although morphological studies done in different rodent epilepsy models have found that normotopic granule cells born after SE are morphologically different from naturally born granule cells in several respects (Kron et al., 2010; Murphy et al., 2011, 2012; Hester and Danzer, 2013), electrophysiological studies have not proven that normotopic newborn granule cells are more excitable than naturally born, age-matched granule cells (Jakubs et al., 2006; Wood et al., 2011). As the adult hippocampal neurogenesis plays an important role in learning, memory formation, and mood regulation (Deng et al., 2010; Samuels and Hen, 2011), illustrating the structural and functional differences between granule cells born after SE and those born naturally would also be helpful in understanding the role of enhanced neurogenesis not only for the development of epilepsy but also for the occurrence of comorbid cognitive impairment and behavioral disturbances (Chauvière et al., 2009; Cavarsan et al., 2013). "
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    ABSTRACT: To understand the potential role of enhanced hippocampal neurogenesis after pilocarpine-induced status epilepticus (SE) in the development of epilepsy, we quantitatively analyzed the geometry of apical dendrites, synaptic transmission, and activation levels of normotopically distributed mature newborn granule cells in the rat. SE in male Sprague-Dawley rats (between 6 and 7 weeks old) lasting for more than 2 h was induced by an intraperitoneal injection of pilocarpine. The complexity, spine density, miniature post-synaptic currents, and activity-regulated cytoskeleton-associated protein (Arc) expression of granule cells born 5 days after SE were studied between 10 and 17 weeks after CAG-GFP retroviral vector-mediated labeling. Mature granule cells born after SE had dendritic complexity similar to that of granule cells born naturally, but with denser mushroom-like spines in dendritic segments located in the outer molecular layer. Miniature inhibitory post-synaptic currents (mIPSCs) were similar between the controls and rats subjected to SE; however, smaller miniature excitatory post-synaptic current (mEPSC) amplitude with a trend toward less frequent was found in mature granule cells born after SE. After maturation, granule cells born after SE did not show denser Arc expression in the resting condition or 2 h after being activated by pentylenetetrazol-induced transient seizure activity than vicinal GFP-unlabeled granule cells. Thus our results suggest that normotopic granule cells born after pilocarpine-induced SE are no more active when mature than age-matched, naturally born granule cells.
    Frontiers in Cellular Neuroscience 10/2015; 9. DOI:10.3389/fncel.2015.00384 · 4.29 Impact Factor
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    • "Acute microglial activation following epileptic seizures is detrimental to the survival of newly formed neurons (Ekdahl et al., 2003). Both seizure-induced pathology and lipopolysaccharide-induced brain inflammation alter the functional properties and the expression of synaptic proteins, including adhesion molecules and scaffolding proteins, of adult born hippocampal neurons (Jakubs et al., 2006; Wood et al., 2011; Jackson et al., 2012; Chugh et al., 2013). In addition, it has been speculated that microglia may regulate synaptic pruning and transmission in adult born neurons (Ekdahl, 2012). "
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    ABSTRACT: Temporal lobe seizures lead to an acute inflammatory response in the brain primarily characterized by activation of parenchymal microglial cells. Simultaneously, degeneration of pyramidal cells and interneurons is evident together with a seizure-induced increase in the production of new neurons within the dentate gyrus of the hippocampus. We have previously shown a negative correlation between the acute seizure-induced inflammation and the survival of newborn hippocampal neurons. Here, we aimed to evaluate the role of the fractalkine-CX3CR1 pathway for these acute events. Fractalkine is a chemokine expressed by both neurons and glia, while its receptor, CX3CR1 is primarily expressed on microglia. Electrically-induced partial status epilepticus (SE) was induced in adult rats through stereotaxically implanted electrodes in the hippocampus. Recombinant rat fractalkine or CX3CR1 antibody was infused intraventricularly during one week post-SE. A significant increase in the expression of CX3CR1, but not fractalkine, was observed in the dentate gyrus at one week. CX3CR1 antibody treatment resulted in a reduction in microglial activation, neurodegeneration, as well as neuroblast production. In contrast, fractalkine treatment had only minor effects. This study provides evidence for a role of the fractalkine-CX3CR1 signaling pathway in seizure-induced microglial activation and suggests that neuroblast production following seizures may partly occur as a result of microglial activation. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Neurobiology of Disease 11/2014; 74. DOI:10.1016/j.nbd.2014.11.009 · 5.08 Impact Factor
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    • "Enhanced granule cell neurogenesis was temporally related to SE [54]–[55] but also promoted by repeated spontaneous brief seizures in absence of SE [56]. Newly generated neurons not only influenced the reorganization of hippocampal network [55] but they were also deeply affected by the pathologic conditions created by SE or repeated seizures [57]–[59]. VGLUT1 and VGAT staining demonstrated either increased GABAergic and glutamatergic input in the hippocampus after pilocarpine SE [60], or reduced GABA and increased glutamate synaptic input in the neocortex of the irradiated model of cortical dysplasia [25]. Finally, dendritic damage and reshaping and spine loss shortly following SE and seizures was demonstrated in different SE models of experimental epilepsy [22], [61]–[63]. "
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    ABSTRACT: Whether severe epilepsy could be a progressive disorder remains as yet unresolved. We previously demonstrated in a rat model of acquired focal cortical dysplasia, the methylazoxymethanol/pilocarpine - MAM/pilocarpine - rats, that the occurrence of status epilepticus (SE) and subsequent seizures fostered a pathologic process capable of modifying the morphology of cortical pyramidal neurons and NMDA receptor expression/localization. We have here extended our analysis by evaluating neocortical and hippocampal changes in MAM/pilocarpine rats at different epilepsy stages, from few days after onset up to six months of chronic epilepsy. Our findings indicate that the process triggered by SE and subsequent seizures in the malformed brain i) is steadily progressive, deeply altering neocortical and hippocampal morphology, with atrophy of neocortex and CA regions and progressive increase of granule cell layer dispersion; ii) changes dramatically the fine morphology of neurons in neocortex and hippocampus, by increasing cell size and decreasing both dendrite arborization and spine density; iii) induces reorganization of glutamatergic and GABAergic networks in both neocortex and hippocampus, favoring excitatory vs inhibitory input; iv) activates NMDA regulatory subunits. Taken together, our data indicate that, at least in experimental models of brain malformations, severe seizure activity, i.e., SE plus recurrent seizures, may lead to a widespread, steadily progressive architectural, neuronal and synaptic reorganization in the brain. They also suggest the mechanistic relevance of glutamate/NMDA hyper-activation in the seizure-related brain pathologic plasticity.
    PLoS ONE 02/2014; 9(2):e89898. DOI:10.1371/journal.pone.0089898 · 3.23 Impact Factor
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