Article

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: 4.3). 01/2009; 20(1):113-24. DOI: 10.1002/hipo.20589
Source: PubMed

ABSTRACT 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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    • "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 1:98-108. DOI:10.1111/j.1528-1167.2012.03481.x · 4.58 Impact Factor
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    • "Pilocarpine-induced status epilepticus persistently increases size and vesicular release rate of mossy fibre boutons in synaptopHluorin-expressing mice Live cell imaging of MFBs in acute hippocampal slices was done by bulk loading a group of granule cells and their axons with Alexa Fluor 594-dextran. Dye-filled excrescences (Fig. 1B) were classified as the main body of giant MFBs if they had at least a 4 mm 2 cross-sectional area (Claiborne et al., 1986; Acsady et al., 1998; Danzer et al., 2010). The mean area of MFBs 1–2 months after pilocarpine induced-status epilepticus was significantly enhanced ($21.09%, "
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    ABSTRACT: In searching for persistent seizure-induced alterations in brain function that might be causally related to epilepsy, presynaptic transmitter release has relatively been neglected. To measure directly the long-term effects of pilocarpine-induced status epilepticus on vesicular release and recycling in hippocampal mossy fibre presynaptic boutons, we used (i) two-photon imaging of FM1-43 vesicular release in rat hippocampal slices; and (ii) transgenic mice expressing the genetically encoded pH-sensitive fluorescent reporter synaptopHluorin preferentially at glutamatergic synapses. In this study we found that, 1-2 months after pilocarpine-induced status epilepticus, there were significant increases in mossy fibre bouton size, faster rates of action potential-driven vesicular release and endocytosis. We also analysed the ultrastructure of rat mossy fibre boutons using transmission electron microscopy. Pilocarpine-induced status epilepticus led to a significant increase in the number of release sites, active zone length, postsynaptic density area and number of vesicles in the readily releasable and recycling pools, all correlated with increased release probability. Our data show that presynaptic release machinery is persistently altered in structure and function by status epilepticus, which could contribute to the development of the chronic epileptic state and may represent a potential new target for antiepileptic therapies.
    Brain 03/2012; 135(Pt 3):869-85. DOI:10.1093/brain/awr341 · 10.23 Impact Factor
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    • "Pilocarpine-induced status epilepticus persistently increases size and vesicular release rate of mossy fibre boutons in synaptopHluorin-expressing mice Live cell imaging of MFBs in acute hippocampal slices was done by bulk loading a group of granule cells and their axons with Alexa Fluor 594-dextran. Dye-filled excrescences (Fig. 1B) were classified as the main body of giant MFBs if they had at least a 4 mm 2 cross-sectional area (Claiborne et al., 1986; Acsady et al., 1998; Danzer et al., 2010). The mean area of MFBs 1–2 months after pilocarpine induced-status epilepticus was significantly enhanced ($21.09%, "
    [Show abstract] [Hide abstract]
    ABSTRACT: In searching for persistent seizure-induced alterations in brain function that might be causally related to epilepsy, presynaptic transmitter release has relatively been neglected. To measure directly the long-term effects of pilocarpine-induced status epilepticus on vesicular release and recycling in hippocampal mossy fibre presynaptic boutons, we used (i) two-photon imaging of FM1-43 vesicular release in rat hippocampal slices; and (ii) transgenic mice expressing the genetically encoded pH-sensitive fluorescent reporter synaptopHluorin preferentially at glutamatergic synapses. In this study we found that, 1–2 months after pilocarpine-induced status epilepticus, there were significant increases in mossy fibre bouton size, faster rates of action potential-driven vesicular release and endocytosis. We also analysed the ultrastructure of rat mossy fibre boutons using transmission electron microscopy. Pilocarpine-induced status epilepticus led to a significant increase in the number of release sites, active zone length, postsynaptic density area and number of vesicles in the readily releasable and recycling pools, all correlated with increased release probability. Our data show that presynaptic release machinery is persistently altered in structure and function by status epilepticus, which could contribute to the development of the chronic epileptic state and may represent a potential new target for antiepileptic therapies.
    Brain 03/2012; 135(3):869-885. · 10.23 Impact Factor
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