Structural plasticity of dentate granule cell mossy fibers during the development of limbic epilepsy

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Hippocampus (Impact Factor: 4.16). 01/2009; 20(1):113-24. DOI: 10.1002/hipo.20589
Source: PubMed


Altered granule cell>CA3 pyramidal cell synaptic connectivity may contribute to the development of limbic epilepsy. To explore this possibility, granule cell giant mossy fiber bouton plasticity was examined in the kindling and pilocarpine models of epilepsy using green fluorescent protein-expressing transgenic mice. These studies revealed significant increases in the frequency of giant boutons with satellite boutons 2 days and 1 month after pilocarpine status epilepticus, and increases in giant bouton area at 1 month. Similar increases in giant bouton area were observed shortly after kindling. Finally, both models exhibited plasticity of mossy fiber giant bouton filopodia, which contact GABAergic interneurons mediating feedforward inhibition of CA3 pyramids. In the kindling model, however, all changes were fleeting, having resolved by 1 month after the last evoked seizure. Together, these findings demonstrate striking structural plasticity of granule cell mossy fiber synaptic terminal structure in two distinct models of adult limbic epileptogenesis. We suggest that these plasticities modify local connectivities between individual mossy fiber terminals and their targets, inhibitory interneurons, and CA3 pyramidal cells potentially altering the balance of excitation and inhibition during the development of epilepsy.

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Available from: Steve C Danzer, Mar 03, 2014
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    • "Subsequent studies revealed that these sprouted axons form excitatory synaptic connections with granule cell dendrites projecting through the IML, creating recurrent loops which have been hypothesized to promote hyperexcitability (for review, see Nadler, 2003). More recently, studies using models of temporal lobe epilepsy have identified ectopic granule cells (Parent et al., 1997; Scharfman et al., 2000; Overstreet-Wadiche et al., 2006), hypertrophied granule cells (Suzuki et al., 1995; Murphy et al., 2011, 2012), granule cells with basal dendrites (Ribak et al., 2000, 2012; Overstreet-Wadiche et al., 2006; Murphy and Danzer, 2011), and granule cells with altered synaptic structure (Pierce and Milner, 2001; Danzer et al., 2010; McAuliffe et al., 2011; Upreti et al., 2012) as common pathologies of the disorder. Interestingly, the dentate gyrus is one of only two regions exhibiting persistent neurogenesis in adulthood, and a majority of the granule cells exhibiting these pathological abnormalities appear to be newborn (Parent et al., 2006; Walter et al., 2007; Kron et al., 2010; Santos et al., 2011). "
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    ABSTRACT: The phosphatidylinositol-3-kinase/phosphatase and tensin homolog (PTEN)-mammalian target of rapamycin (mTOR) pathway regulates a variety of neuronal functions, including cell proliferation, survival, growth, and plasticity. Dysregulation of the pathway is implicated in the development of both genetic and acquired epilepsies. Indeed, several causal mutations have been identified in patients with epilepsy, the most prominent of these being mutations in PTEN and tuberous sclerosis complexes 1 and 2 (TSC1, TSC2). These genes act as negative regulators of mTOR signaling, and mutations lead to hyperactivation of the pathway. Animal models deleting PTEN, TSC1, and TSC2 consistently produce epilepsy phenotypes, demonstrating that increased mTOR signaling can provoke neuronal hyperexcitability. Given the broad range of changes induced by altered mTOR signaling, however, the mechanisms underlying seizure development in these animals remain uncertain. In transgenic mice, cell populations with hyperactive mTOR have many structural abnormalities that support recurrent circuit formation, including somatic and dendritic hypertrophy, aberrant basal dendrites, and enlargement of axon tracts. At the functional level, mTOR hyperactivation is commonly, but not always, associated with enhanced synaptic transmission and plasticity. Moreover, these populations of abnormal neurons can affect the larger network, inducing secondary changes that may explain paradoxical findings reported between cell and network functioning in different models or at different developmental time points. Here, we review the animal literature examining the link between mTOR hyperactivation and epileptogenesis, emphasizing the impact of enhanced mTOR signaling on neuronal form and function.
    Frontiers in Molecular Neuroscience 03/2014; 7:18. DOI:10.3389/fnmol.2014.00018 · 4.08 Impact Factor
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    • "Indeed, studies of human epilepsy clearly indicate that some patients report stress-induced seizures, and some do not [4]. It is reasonable to think that animals might show similar variability, and although attempts were made to keep experimental animals as homogenous as possible, the pilocarpine model of epilepsy can produce very heterogeneous patterns of cell loss and plasticity [53]. No overt differences in gross brain pathology were observed between “responding” and “non-responding” animals in the present study (data not shown), but the possibility that more subtle differences are important cannot be excluded. "
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    ABSTRACT: Stress is the most commonly reported precipitating factor for seizures in patients with epilepsy. Despite compelling anecdotal evidence for stress-induced seizures, animal models of the phenomena are sparse and possible mechanisms are unclear. Here, we tested the hypothesis that increased levels of the stress-associated hormone corticosterone (CORT) would increase epileptiform activity and spontaneous seizure frequency in mice rendered epileptic following pilocarpine-induced status epilepticus. We monitored video-EEG activity in pilocarpine-treated mice 24/7 for a period of four or more weeks, during which animals were serially treated with CORT or vehicle. CORT increased the frequency and duration of epileptiform events within the first 24 hours of treatment, and this effect persisted for up to two weeks following termination of CORT injections. Interestingly, vehicle injection produced a transient spike in CORT levels - presumably due to the stress of injection - and a modest but significant increase in epileptiform activity. Neither CORT nor vehicle treatment significantly altered seizure frequency; although a small subset of animals did appear responsive. Taken together, our findings indicate that treatment of epileptic animals with exogenous CORT designed to mimic chronic stress can induce a persistent increase in interictal epileptiform activity.
    PLoS ONE 09/2012; 7(9):e46044. DOI:10.1371/journal.pone.0046044 · 3.23 Impact Factor
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    • "More recently, the formation of stable mossy fiber synapses onto sprouted HBDs from adult newborn granule cells has been suggested to play a role in the formation of epileptic recurrent excitatory circuitry (Buckmaster et al., 2002; Austin & Buckmaster, 2004; Shapiro et al., 2005; Shapiro & Ribak, 2006; Thind et al., 2008; Toni et al., 2008). Recent studies in the pilocarpine model demonstrated that periseizure born granule cells contribute the majority of mossy fiber and HBD sprouting, and are interconnected within a recurrent circuitry (Shapiro & Ribak, 2006; Shapiro et al., 2007; Danzer et al., 2010; Kron et al., 2010; McAuliffe et al., 2011; Murphy et al., 2011). "
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    ABSTRACT: Numerous animal models of epileptogenesis demonstrate neuroplastic changes in the hippocampus. These changes occur not only for the mature neurons and glia, but also for the newly generated granule cells in the dentate gyrus. One of these changes, the sprouting of mossy fiber axons, is derived predominantly from newborn granule cells in adult rats with pilocarpine-induced temporal lobe epilepsy. Newborn granule cells also mainly contribute to another neuroplastic change, hilar basal dendrites (HBDs), which are synaptically targeted by mossy fibers in the hilus. Both sprouted mossy fibers and HBDs contribute to recurrent excitatory circuitry that is hypothesized to be involved in increased seizure susceptibility and the development of spontaneous recurrent seizures (SRS) that occur following the initial pilocarpine-induced status epilepticus. Considering the putative role of these neuroplastic changes in epileptogenesis, a critical question is whether similar anatomic phenomena occur after epileptogenic insults to the immature brain, where the proportion of recently born granule cells is higher due to ongoing maturation. The current study aimed to determine if such neuroplastic changes could be observed in a standardized model of neonatal seizure-inducing hypoxia that results in development of SRS. We used immunoelectron microscopy for the immature neuronal marker doublecortin to label newborn neurons and their HBDs following neonatal hypoxia. Our goal was to determine whether synapses form on HBDs from neurons born after neonatal hypoxia. Our results show a robust synapse formation on HBDs from animals that experienced neonatal hypoxia, regardless of whether the animals experienced tonic-clonic seizures during the hypoxic event. In both cases, the axon terminals that synapse onto HBDs were identified as mossy fiber terminals, based on the appearance of dense core vesicles. No such synapses were observed on HBDs from newborn granule cells obtained from sham animals analyzed at the same time points. This aberrant circuit formation may provide an anatomic substrate for increased seizure susceptibility and the development of epilepsy.
    Epilepsia 06/2012; 53 Suppl 1(s1):98-108. DOI:10.1111/j.1528-1167.2012.03481.x · 4.57 Impact Factor
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