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Two distinct forms of long-term depression coexist at the mossy fiber-CA3 synapse in the hippocampus during development.

ABSTRACT: During a critical period of postnatal development, between postnatal days 6 and 14, a high-frequency stimulation train (100 Hz for 1 s) to the mossy fibers induces a long-term depression (LTD) of synaptic efficacy of 29 +/- 5.2%. This form of LTD is homosynaptic. It is independent of the activation of N-methyl-D-aspartate or metabotropic glutamate receptors but needs an increase in calcium into the postsynaptic cell for its induction. At the same synapse LTD also could be induced by low-frequency stimulation of the mossy fibers (1 Hz for 15 min). In this case the magnitude of the depression is 37 +/- 4.2%. This form of LTD is N-methyl-D-aspartate independent but requires the activation of metabotropic glutamate receptors because it is prevented by (S)-alpha-methyl-4-carboxyphenylglycine (1 mM). Moreover its induction appears to be presynaptic, because, in contrast with the high-frequency one, it is not blocked by loading the postsynaptic cell with the calcium chelator EGTA or bis-(-o-aminophenoxy)ethane-N, N,N',N'-tetraacetic acid (BAPTA). Saturation of one form of LTD does not occlude the other, suggesting that high and low frequency-induced LTD depend on distinct mechanisms of induction and expression. Quantal (noise deconvolution) analysis of minimal excitatory postsynaptic potentials shows, similarly to high-frequency LTD, a decrease in quantal content without any change in quantal size after low-frequency LTD, suggesting that in both forms of LTD the site where maintenance mechanisms are located is presynaptic.

SUBMITTER: Domenici MR

PROVIDER: S-EPMC20972 | biostudies-other | 1998 Jul

REPOSITORIES: biostudies-other

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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.

Project description:Epileptic seizures potently modulate hippocampal adult neurogenesis, and adult-born dentate granule cells contribute to the pathologic retrograde sprouting of mossy fiber axons, both hallmarks of temporal lobe epilepsy. The characteristics of these sprouted synapses, however, have been largely unexplored, and the specific contribution of adult-born granule cells to functional mossy fiber sprouting is unknown, primarily due to technical barriers in isolating sprouted mossy fiber synapses for analysis. Here, we used DcxCreERT2 transgenic mice to permanently pulse-label age-defined cohorts of granule cells born either before or after pilocarpine-induced status epilepticus (SE). Using optogenetics, we demonstrate that adult-born granule cells born before SE form functional recurrent monosynaptic excitatory connections with other granule cells. Surprisingly, however, although healthy mossy fiber synapses in CA3 are well characterized "detonator" synapses that potently drive postsynaptic cell firing through their profound frequency-dependent facilitation, sprouted mossy fiber synapses from adult-born cells exhibited profound frequency-dependent depression, despite possessing some of the morphological hallmarks of mossy fiber terminals. Mature granule cells also contributed to functional mossy fiber sprouting, but exhibited less synaptic depression. Interestingly, granule cells born shortly after SE did not form functional excitatory synapses, despite robust sprouting. Our results suggest that, although sprouted mossy fibers form recurrent excitatory circuits with some of the morphological characteristics of typical mossy fiber terminals, the functional characteristics of sprouted synapses would limit the contribution of adult-born granule cells to hippocampal hyperexcitability in the epileptic hippocampus.SIGNIFICANCE STATEMENT In the hippocampal dentate gyrus, seizures drive retrograde sprouting of granule cell mossy fiber axons. We directly activated sprouted mossy fiber synapses from adult-born granule cells to study their synaptic properties. We reveal that sprouted synapses from adult-born granule cells have a diminished ability to sustain recurrent excitation in the epileptic hippocampus, which raises questions about the role of sprouting and adult neurogenesis in sustaining seizure-like activity.

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Two distinct forms of long-term depression coexist at the mossy fiber-CA3 synapse in the hippocampus during development.

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