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Cited by 230Epilepsy research and treatmentNeural dynamics and brain functionNeuroscience and Neuropharmacology Research

Topological determinants of epileptogenesis in large-scale structural and functional models of the dentate gyrus derived from experimental data

Dyhrfjeld-Johnsen, Jonas, Santhakumar, Vijayalakshmi, Morgan, Robert J., Huerta, Ramon, Tsimring, Lev, Soltesz, Ivan·2007·Journal of Neurophysiology
DOI 10.1152/jn.00950.2006
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Abstract

In temporal lobe epilepsy, changes in synaptic and intrinsic properties occur on a background of altered network architecture resulting from cell loss and axonal sprouting. Although modeling studies using idealized networks indicated the general importance of network topology in epilepsy, it is unknown whether structural changes that actually take place during epileptogenesis result in hyperexcitability. To answer this question, we built a 1:1 scale structural model of the rat dentate gyrus from published in vivo and in vitro cell type-specific connectivity data. This virtual dentate gyrus in control condition displayed globally and locally well connected ("small world") architecture. The average number of synapses between any two neurons in this network of over one million cells was less than three, similar to that measured for the orders of magnitude smaller C. elegans nervous system. To study how network architecture changes during epileptogenesis, long-distance projecting hilar cells were gradually removed in the structural model, causing massive reductions in the number of total connections. However, as long as even a few hilar cells survived, global connectivity in the network was effectively maintained and, as a result of the spatially restricted sprouting of granule cell axons, local connectivity increased. Simulations of activity in a functional dentate network model, consisting of over 50,000 multicompartmental single-cell models of major glutamatergic and GABAergic cell types, revealed that the survival of even a small fraction of hilar cells was enough to sustain networkwide hyperexcitability. These data indicate new roles for fractionally surviving long-distance projecting hilar cells observed in specimens from epilepsy patients.

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  • Reduced-scale models of large networks with realistic single cell electrophysiological properties remain silent unless synaptic strengths or numbers are arbitrarily increased beyond biologically relevant levels.

    “smaller models of large networks with realistic single cell electrophysiological properties (e.g., input resistance and resting membrane potential) remain silent unless synaptic strengths or numbers are arbitrarily increased beyond the biologically relevant levels to compensate for fewer inputs to their model cells”

    From Interneuronal mechanisms of hippocampal theta oscillations in a full-scale model of the rodent CA1 circuit (2016) · cites this paper as Dyhrfjeld-Johnsen et al., 2007

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Authors
Dyhrfjeld-Johnsen, J., Santhakumar, V., Morgan, R. J., Huerta, R., Tsimring, L., & Soltesz, I.
Affiliations
  • University of California, Irvine (US)
  • University of California San Diego (US)
ORCID
Venue
Journal of Neurophysiology
Publisher
American Physiological Society
Published
2007-02
Volume
97
Issue
2
Pages
1566-1587
ISSN
  • 0022-3077 (ISSN-L)
  • 1522-1598
DOI
10.1152/jn.00950.2006
OpenAlex
W2107566823
Cited by
230
References
108
Citations by year
2026: 1 · 2025: 4 · 2024: 4 · 2023: 10 · 2022: 5 · 2021: 11 · 2020: 4 · 2019: 7 · 2018: 13 · 2017: 9 · 2016: 14 · 2015: 16 · 2014: 16 · 2013: 22 · 2012: 21
FWCI
9.35
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Neurophysiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Neurological Disorders and Stroke (NS-35915)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
epileptogenesis, temporal lobe epilepsy, dentate gyrus, network topology, small-world networks, axonal sprouting, granule cells, hyperexcitability, cell-type specific connectivity, multicompartmental neuron models
MeSH terms
Animals, Axons, Cytoplasmic Granules, Electric Stimulation, Epilepsy, Models, Neurological, Nerve Net, Neural Conduction, Neurons, Sclerosis, Models, Statistical, Databases, Factual, Dentate Gyrus, Mossy Fibers, Hippocampal, Rats

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