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Altered patterning of dentate granule cell mossy fiber inputs onto CA3 pyramidal cells in limbic epilepsy.

ABSTRACT: Impaired gating by hippocampal dentate granule cells may promote the development of limbic epilepsy by facilitating seizure spread through the hippocampal trisynaptic circuit. The second synapse in this circuit, the dentate granule cell?CA3 pyramidal cell connection, may be of particular importance because pathological changes occurring within the dentate likely exert their principal effect on downstream CA3 pyramids. Here, we utilized GFP-expressing mice and immunolabeling for the zinc transporter ZnT-3 to reveal the pre- and postsynaptic components of granule cell?CA3 pyramidal cell synapses following pilocarpine-epileptogenesis. Confocal analyses of these terminals revealed that while granule cell presynaptic giant boutons increased in size and complexity 1 month after status epilepticus, individual thorns making up the postsynaptic thorny excrescences of the CA3 pyramidal cells were reduced in number. This reduction, however, was transient, and 3 months after status, thorn density recovered. This recovery was accompanied by a significant change in the distribution of thorns along pyramidal cells dendrites. While thorns in control animals tended to be tightly clustered, thorns in epileptic animals were more evenly distributed. Computational modeling of thorn distributions predicted an increase in the number of boutons required to cover equivalent numbers of thorns in epileptic vs. control mice. Confirming this prediction, ZnT-3 labeling of presynaptic giant boutons apposed to GFP-expressing thorns revealed a near doubling in bouton density, while the number of individual thorns per bouton was reduced by half. Together, these data provide clear evidence of novel plastic changes occurring within the epileptic hippocampus.

SUBMITTER: McAuliffe JJ

PROVIDER: S-EPMC2888689 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Altered patterning of dentate granule cell mossy fiber inputs onto CA3 pyramidal cells in limbic epilepsy.

McAuliffe John J JJ Bronson Stefanie L SL Hester Michael S MS Murphy Brian L BL Dahlquist-Topalá Renée R Richards David A DA Danzer Steve C SC

Hippocampus 20110101 1

Impaired gating by hippocampal dentate granule cells may promote the development of limbic epilepsy by facilitating seizure spread through the hippocampal trisynaptic circuit. The second synapse in this circuit, the dentate granule cell≫CA3 pyramidal cell connection, may be of particular importance because pathological changes occurring within the dentate likely exert their principal effect on downstream CA3 pyramids. Here, we utilized GFP-expressing mice and immunolabeling for the zinc transpor ...[more]

PMID: 20014385

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Project description:Structural changes that alter hippocampal functional circuitry are implicated in learning impairments, mood disorders and epilepsy. Reorganization of mossy fiber (MF) axons from dentate granule cells is one such form of plasticity. Increased neurotrophin signaling is proposed to underlie MF plasticity, and there is evidence to support a mechanistic role for brain-derived neurotrophic factor (BDNF) in this process. Transgenic mice overexpressing BDNF in the forebrain under the α-calcium/calmodulin-dependent protein kinase II promoter (TgBDNF mice) exhibit spatial learning deficits at 2-3months of age, followed by the emergence of spontaneous seizures at ∼6months. These behavioral changes suggest that chronic increases in BDNF progressively disrupt hippocampal functional organization. To determine if the dentate MF pathway is structurally altered in this strain, the present study employed Timm staining and design-based stereology to compare MF distribution and projection volumes in transgenic and wild-type mice at 2-3months, and at 6-7months. Mice in the latter age group were assessed for seizure vulnerability with a low dose of pilocarpine given 2h before euthanasia. At 2-3months, TgBDNF mice showed moderate expansion of CA3-projecting MFs (∼20%), with increased volumes measured in the suprapyramidal (SP-MF) and intra/infrapyramidal (IIP-MF) compartments. At 6-7months, a subset of transgenic mice exhibited increased seizure susceptibility, along with an increase in IIP-MF volume (∼30%). No evidence of MF sprouting was seen in the inner molecular layer. Additional stereological analyses demonstrated significant increases in molecular layer (ML) volume in TgBDNF mice at both ages, as well as an increase in granule cell number by 8months of age. Collectively, these results indicate that sustained increases in endogenous BDNF modify dentate structural organization over time, and may thereby contribute to the development of pro-epileptic circuitry.

Dataset Information

Altered patterning of dentate granule cell mossy fiber inputs onto CA3 pyramidal cells in limbic epilepsy.

Publications

Altered patterning of dentate granule cell mossy fiber inputs onto CA3 pyramidal cells in limbic epilepsy.

Similar Datasets

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