Early detonation by sprouted mossy fibers enables aberrant dentate network activity

In temporal lobe epilepsy, sprouting of hippocampal mossy fiber axons onto dentate granule cell dendrites creates a recurrent excitatory network. However, unlike mossy fibers projecting to CA3, sprouted mossy fiber synapses depress upon repetitive activation. Thus, despite their proximal location, r...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-05, Vol.116 (22), p.10994-10999
Main Authors: Hendricks, William D., Westbrook, Gary L., Schnell, Eric
Format: Article
Language:English
Subjects:
Action potential
Activation
Adenosine
Adenosine - metabolism
Adenosine - pharmacology
Animals
Axon sprouting
Axons
Biological Sciences
CA3 Region, Hippocampal - physiopathology
Dendrites
Dentate Gyrus - physiopathology
Detonation
Disease Models, Animal
Epilepsy
Epilepsy - physiopathology
Fibers
Granular materials
Granule cells
Hippocampus
Male
Mice
Mice, Transgenic
Mossy fibers
Mossy Fibers, Hippocampal - drug effects
Mossy Fibers, Hippocampal - metabolism
Mossy Fibers, Hippocampal - physiopathology
Optogenetics
Short-term depression
Synapses
Synapses - metabolism
Temporal lobe
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Summary:In temporal lobe epilepsy, sprouting of hippocampal mossy fiber axons onto dentate granule cell dendrites creates a recurrent excitatory network. However, unlike mossy fibers projecting to CA3, sprouted mossy fiber synapses depress upon repetitive activation. Thus, despite their proximal location, relatively large presynaptic terminals, and ability to excite target neurons, the impact of sprouted mossy fiber synapses on hippocampal hyperexcitability is unclear. We find that despite their short-term depression, single episodes of sprouted mossy fiber activation in hippocampal slices initiated bursts of recurrent polysynaptic excitation. Consistent with a contribution to network hyperexcitability, optogenetic activation of sprouted mossy fibers reliably triggered action potential firing in postsynaptic dentate granule cells after single light pulses. This pattern resulted in a shift in network recruitment dynamics to an “early detonation” mode and an increased probability of release compared with mossy fiber synapses in CA3. A lack of tonic adenosine-mediated inhibition contributed to the higher probability of glutamate release, thus facilitating reverberant circuit activity.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1821227116