Skip to main content
SpringerLink
Log in

Computational modeling of GABAA receptor-mediated paired-pulse inhibition in the dentate gyrus

  • Published:
Journal of Computational Neuroscience Aims and scope Submit manuscript

Abstract

Paired-pulse inhibition (PPI) of the population spike observed in extracellular field recordings is widely used as a read-out of hippocampal network inhibition. PPI reflects GABAA receptor-mediated inhibition of principal neurons through local interneurons. However, because of its polysynaptic nature, it is difficult to assign PPI changes to precise synaptic mechanisms. Here we used a detailed network model of the dentate gyrus to simulate PPI of granule cell action potentials and analyze its network properties. Our computational analysis indicates that PPI results mainly from a combination of perisomatic feed-forward and feedback inhibition of granule cells by basket cells. Feed-forward inhibition mediated by basket cells appeared to be the most significant source of PPI. Our simulations suggest that PPI depends more on somatic than on dendritic inhibition of granule cells. Furthermore, PPI was modulated by changes in GABAA reversal potential (EGABA) and by alterations in intrinsic excitability of granule cells. In summary, computer modeling provides a useful tool for determining the role of synaptic and intrinsic cellular mechanisms in paired-pulse field potential responses.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Amaral, D. G., Scharfman, H. E., & Lavenex, P. (2007). The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). Progress in Brain Research, 163, 3–22.

    Article  PubMed  Google Scholar 

  • Andersen, P., Bliss, T. V., & Skrede, K. K. (1971). Unit analysis of hippocampal polulation spikes. Experimental Brain Research, 13(2), 208–221.

    CAS  Google Scholar 

  • Aponte, Y., Bischofberger, J., & Jonas, P. (2008). Efficient Ca2+ buffering in fast-spiking basket cells of rat hippocampus. Journal of Physiology, 586(8), 2061–2075.

    Article  CAS  PubMed  Google Scholar 

  • Aradi, I., & Holmes, W. R. (1999). Role of multiple calcium and calcium-dependent conductances in regulation of hippocampal dentate granule cell excitability. Journal of Computational Neuroscience, 6(3), 215–235.

    Article  CAS  PubMed  Google Scholar 

  • Atallah, B. V., & Scanziani, M. (2009). Instantaneous modulation of gamma oscillation frequency by balancing excitation with inhibition. Neuron, 62(4), 566–577.

    Article  CAS  PubMed  Google Scholar 

  • Benuskova, L., & Abraham, W. C. (2007). STDP rule endowed with the BCM sliding threshold accounts for hippocampal heterosynaptic plasticity. Journal of Computational Neuroscience, 22(2), 129–133.

    Article  PubMed  Google Scholar 

  • Blaesse, P., Airaksinen, M. S., Rivera, C., & Kaila, K. (2009). Cation-chloride cotransporters and neuronal function. Neuron, 61(6), 820–838.

    Article  CAS  PubMed  Google Scholar 

  • Bliss, T. V., Collinridge, G., & Morris, R. G. (2007). Synaptic plasticity in the hippocampus. In P. Andersen, R. G. Morris, D. G. Amaral, T. V. Bliss, & J. O’Keefe (Eds.), The hippocampus book (pp. 343–474). Oxford: Oxford University Press.

    Google Scholar 

  • Brill, J., & Huguenard, J. R. (2009). Robust short-latency perisomatic inhibition onto neocortical pyramidal cells detected by laser-scanning photostimulation. Journal of Neuroscience, 29(23), 7413–7423.

    Article  CAS  PubMed  Google Scholar 

  • Bronzino, J. D., Blaise, J. H., & Morgane, P. J. (1997). The paired-pulse index: a measure of hippocampal dentate granule cell modulation. Annals of Biomedical Engineering, 25(5), 870–873.

    Article  CAS  PubMed  Google Scholar 

  • Bucurenciu, I., Kulik, A., Schwaller, B., Frotscher, M., & Jonas, P. (2008). Nanodomain coupling between Ca2+ channels and Ca2+ sensors promotes fast and efficient transmitter release at a cortical GABAergic synapse. Neuron, 57(4), 536–545.

    Article  CAS  PubMed  Google Scholar 

  • Coulter, D. A., & Carlson, G. C. (2007). Functional regulation of the dentate gyrus by GABA-mediated inhibition. Progress in Brain Research, 163, 235–243.

    Article  CAS  PubMed  Google Scholar 

  • Davies, C. H., Starkey, S. J., Pozza, M. F., & Collingridge, G. L. (1991). GABA autoreceptors regulate the induction of LTP. Nature, 349(6310), 609–611.

    Article  CAS  PubMed  Google Scholar 

  • Davison, A. P., Morse, T. M., Migliore, M., Shepherd, G. M., & Hines, M. L. (2004). Semi-automated population of an online database of neuronal models (ModelDB) with citation information, using PubMed for validation. Neuroinformatics, 2(3), 327–332.

    Article  PubMed  Google Scholar 

  • Doischer, D., Hosp, J. A., Yanagawa, Y., Obata, K., Jonas, P., Vida, I., et al. (2008). Postnatal differentiation of basket cells from slow to fast signaling devices. Journal of Neuroscience, 28(48), 12956–12968.

    Article  CAS  PubMed  Google Scholar 

  • Dyhrfjeld-Johnsen, J., Santhakumar, V., Morgan, R. J., Huerta, R., Tsimring, L., & Soltesz, I. (2007). Topological determinants of epileptogenesis in large-scale structural and functional models of the dentate gyrus derived from experimental data. Journal of Neurophysiology, 97(2), 1566–1587.

    Article  PubMed  Google Scholar 

  • Farrant, M., & Kaila, K. (2007). The cellular, molecular and ionic basis of GABA(A) receptor signalling. Progress in Brain Research, 160, 59–87.

    Article  CAS  PubMed  Google Scholar 

  • Ferrante, M., Migliore, M., & Ascoli, G. A. (2009). Feed-forward inhibition as a buffer of the neuronal input-output relation. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 18004–18009.

    Article  CAS  PubMed  Google Scholar 

  • Freund, T. F., & Buzsáki, G. (1996). Interneurons of the hippocampus. Hippocampus, 6(4), 347–470.

    Article  CAS  PubMed  Google Scholar 

  • Freund, T. F., & Katona, I. (2007). Perisomatic inhibition. Neuron, 56(1), 33–42.

    Article  CAS  PubMed  Google Scholar 

  • Fritschy, J. M. (2008). Epilepsy, E/I Balance and GABA(A) Receptor Plasticity. Frontiers in Molecular Neuroscience, 1, 5.

    Article  PubMed  Google Scholar 

  • Fuchs, E. C., Zivkovic, A. R., Cunningham, M. O., Middleton, S., LeBeau, F. E., Bannerman, D. M., et al. (2007). Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior. Neuron, 53(4), 591–604.

    Article  CAS  PubMed  Google Scholar 

  • Glickfeld, L. L., & Scanziani, M. (2006). Distinct timing in the activity of cannabinoid-sensitive and cannabinoid-insensitive basket cells. Nature Neuroscience, 9(6), 807–815.

    Article  CAS  PubMed  Google Scholar 

  • Gold, C., Henze, D. A., Koch, C., & Buzsaki, G. (2006). On the origin of the extracellular action potential waveform: a modeling study. Journal of Neurophysiology, 95(5), 3113–3128.

    Article  CAS  PubMed  Google Scholar 

  • Hines, M. L., & Carnevale, N. T. (1997). The NEURON simulation environment. Neural Computation, 9(6), 1179–1209.

    Article  CAS  PubMed  Google Scholar 

  • Hines, M. L., Morse, T., Migliore, M., Carnevale, N. T., & Shepherd, G. M. (2004). ModelDB: a database to support computational neuroscience. Journal of Computational Neuroscience, 17(1), 7–11.

    Article  PubMed  Google Scholar 

  • Howard, A., Tamas, G., & Soltesz, I. (2005). Lighting the chandelier: new vistas for axo-axonic cells. Trends in Neurosciences, 28(6), 310–316.

    Article  CAS  PubMed  Google Scholar 

  • Houser, C. R. (2007). Interneurons of the dentate gyrus: an overview of cell types, terminal fields and neurochemical identity. Progress in Brain Research, 163, 217–232.

    Article  CAS  PubMed  Google Scholar 

  • Hu, H., Martina, M., & Jonas, P. (2009). Dendritic mechanisms underlying rapid synaptic activation of fast-spiking hippocampal interneurons. Science. doi:10.1126/science.1177876.

    Google Scholar 

  • Jalil, S., Grigull, J., & Skinner, F. K. (2004). Novel bursting patterns emerging from model inhibitory networks with synaptic depression. Journal of Computational Neuroscience, 17(1), 31–45.

    Article  CAS  PubMed  Google Scholar 

  • Jedlicka, P., & Backus, K. H. (2006). Inhibitory transmission, activity-dependent ionic changes and neuronal network oscillations. Physiological Research, 55(2), 139–149.

    CAS  PubMed  Google Scholar 

  • Jedlicka, P., Schwarzacher, S. W., Winkels, R., Kienzler, F., Frotscher, M., Bramham, C. R., et al. (2009a). Impairment of in vivo theta-burst long-term potentiation and network excitability in the dentate gyrus of synaptopodin-deficient mice lacking the spine apparatus and the cisternal organelle. Hippocampus, 19(2), 130–140.

    Article  CAS  Google Scholar 

  • Jedlicka, P., Papadopoulos, T., Deller, T., Betz, H., & Schwarzacher, S. W. (2009b). Increased network excitability and impaired induction of long-term potentiation in the dentate gyrus of collybistin-deficient mice in vivo. Molecular and Cellular Neuroscience, 41(1), 94–100.

    Article  CAS  Google Scholar 

  • Jonas, P., Bischofberger, J., Fricker, D., & Miles, R. (2004). Interneuron diversity series: fast in, fast out-temporal and spatial signal processing in hippocampal interneurons. Trends in Neurosciences, 27(1), 30–40.

    Article  CAS  PubMed  Google Scholar 

  • Jones, M. W., Errington, M. L., French, P. J., Fine, A., Bliss, T. V. P., Garel, S., et al. (2001). A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nature Neuroscience, 4(3), 289–296.

    Article  CAS  PubMed  Google Scholar 

  • Kang, T. C., Kim, D. S., Kim, J. E., Kwak, S. E., Yoo, K. Y., Hwang, I. K., et al. (2006). Altered expression of K + -Cl- cotransporters affects fast paired-pulse inhibition during GABA receptor activation in the gerbil hippocampus. Brain Research, 1072(1), 8–14.

    Article  CAS  PubMed  Google Scholar 

  • Klausberger, T., & Somogyi, P. (2008). Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science, 321(5885), 53–57.

    Article  CAS  PubMed  Google Scholar 

  • Kleschevnikov, A. M., Belichenko, P. V., Villar, A. J., Epstein, C. J., Malenka, R. C., & Mobley, W. C. (2004). Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. Journal of Neuroscience, 24(37), 8153–8160.

    Article  CAS  PubMed  Google Scholar 

  • Kraushaar, U., & Jonas, P. (2000). Efficacy and stability of quantal GABA release at a hippocampal interneuron-principal neuron synapse. Journal of Neuroscience, 20(15), 5594–5607.

    CAS  PubMed  Google Scholar 

  • Kullmann, D. M., & Lamsa, K. P. (2007). Long-term synaptic plasticity in hippocampal interneurons. Nature Reviews. Neuroscience, 8(9), 687–699.

    Article  CAS  PubMed  Google Scholar 

  • Kwak, S. E., Kim, J. E., Kim, D. S., Won, M. H., Lee, H. J., Choi, S. Y., et al. (2006). Differential paired-pulse responses between the CA1 region and the dentate gyrus are related to altered CLC-2 immunoreactivity in the pilocarpine-induced rat epilepsy model. Brain Research, 1115(1), 162–168.

    Article  CAS  PubMed  Google Scholar 

  • Lamsa, K., Heeroma, J. H., & Kullmann, D. M. (2005). Hebbian LTP in feed-forward inhibitory interneurons and the temporal fidelity of input discrimination. Nature Neuroscience, 8(7), 916–924.

    CAS  PubMed  Google Scholar 

  • Lamsa, K., Irvine, E. E., Giese, K. P., & Kullmann, D. M. (2007a). NMDA receptor-dependent long-term potentiation in mouse hippocampal interneurons shows a unique dependence on Ca(2+)/calmodulin-dependent kinases. Journal of Neurophysiology, 584(Pt 3), 885–894.

    CAS  Google Scholar 

  • Lamsa, K. P., Heeroma, J. H., Somogyi, P., Rusakov, D. A., & Kullmann, D. M. (2007b). Anti-Hebbian long-term potentiation in the hippocampal feedback inhibitory circuit. Science, 315(5816), 1262–1266.

    Article  CAS  Google Scholar 

  • Lomo, T. (2009). Excitability changes within transverse lamellae of dentate granule cells and their longitudinal spread following orthodromic or antidromic activation. Hippocampus, 19(7), 633–48.

    Article  PubMed  Google Scholar 

  • Lytton, W. W., Hellman, K. M., & Sutula, T. P. (1998). Computer models of hippocampal circuit changes of the kindling model of epilepsy. Artificial Intelligence in Medicine, 13(1–2), 81–97.

    Article  CAS  PubMed  Google Scholar 

  • Lytton, W. W. (2008). Computer modelling of epilepsy. Nature Reviews. Neuroscience, 9(8), 626–637.

    Article  CAS  PubMed  Google Scholar 

  • Magloczky, Z., & Freund, T. F. (2005). Impaired and repaired inhibitory circuits in the epileptic human hippocampus. Trends in Neurosciences, 28(6), 334–340.

    Article  CAS  PubMed  Google Scholar 

  • Miles, R., Toth, K., Gulyas, A. I., Hajos, N., & Freund, T. F. (1996). Differences between somatic and dendritic inhibition in the hippocampus. Neuron, 16(4), 815–823.

    Article  CAS  PubMed  Google Scholar 

  • Morgan, R. J., Santhakumar, V., & Soltesz, I. (2007). Modeling the dentate gyrus. Progress in Brain Research, 163, 639–658.

    Article  PubMed  Google Scholar 

  • Morgan, R. J., & Soltesz, I. (2008). Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures. Proceedings of the National Academy of Sciences of the United States of America, 105(16), 6179–6184.

    Article  CAS  PubMed  Google Scholar 

  • Moser, E. I. (1996). Altered inhibition of dentate granule cells during spatial learning in an exploration task. Journal of Neuroscience, 16(3), 1247–1259.

    CAS  PubMed  Google Scholar 

  • Naylor, D. E., & Wasterlain, C. G. (2005). GABA synapses and the rapid loss of inhibition to dentate gyrus granule cells after brief perforant-path stimulation. Epilepsia, 46(Suppl 5), 142–147.

    Article  CAS  PubMed  Google Scholar 

  • Naylor, D. E., Liu, H., & Wasterlain, C. G. (2005). Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. Journal of Neuroscience, 25(34), 7724–7733.

    Article  CAS  PubMed  Google Scholar 

  • Oliver, M. W., & Miller, J. J. (1985). Alterations of inhibitory processes in the dentate gyrus following kindling-induced epilepsy. Experimental Brain Research, 57(3), 443–447.

    Article  CAS  Google Scholar 

  • Pouille, F., & Scanziani, M. (2001). Enforcement of temporal fidelity in pyramidal cells by somatic feed- forward inhibition. Science, 293(5532), 1159–1163.

    Article  CAS  PubMed  Google Scholar 

  • Pouille, F., & Scanziani, M. (2004). Routing of spike series by dynamic circuits in the hippocampus. Nature, 429(6993), 717–723.

    Article  CAS  PubMed  Google Scholar 

  • Pouille, F., Marin-Burgin, A., Adesnik, H., Atallah, B. V., & Scanziani, M. (2009). Input normalization by global feedforward inhibition expands cortical dynamic range. Nature Neuroscience, 12(12), 1577–1585.

    Article  CAS  PubMed  Google Scholar 

  • Prescott, S. A., Sejnowski, T. J., & De, K. Y. (2006). Reduction of anion reversal potential subverts the inhibitory control of firing rate in spinal lamina I neurons: towards a biophysical basis for neuropathic pain. Molecular Pain, 2, 32.

    Article  PubMed  Google Scholar 

  • Prinz, A. A. (2008). Understanding epilepsy through network modeling. Proceedings of the National Academy of Sciences of the United States of America, 105(16), 5953–5954.

    Article  CAS  PubMed  Google Scholar 

  • Racz, A., Ponomarenko, A. A., Fuchs, E. C., & Monyer, H. (2009). Augmented hippocampal ripple oscillations in mice with reduced fast excitation onto parvalbumin-positive cells. Journal of Neuroscience, 29(8), 2563–2568.

    Article  CAS  PubMed  Google Scholar 

  • Ribak, C. E., & Shapiro, L. A. (2007). Ultrastructure and synaptic connectivity of cell types in the adult rat dentate gyrus. Progress in Brain Research, 163, 155–166.

    Article  PubMed  Google Scholar 

  • Rich-Bennett, E., Dahl, D., & Lecompte, B. B., III. (1993). Modulation of paired-pulse activation in the hippocampal dentate gyrus by cholecystokinin, baclofen and bicuculline. Neuropeptides, 24(5), 263–270.

    Article  CAS  PubMed  Google Scholar 

  • Santhakumar, V., Aradi, I., & Soltesz, I. (2005). Role of mossy fiber sprouting and mossy cell loss in hyperexcitability: a network model of the dentate gyrus incorporating cell types and axonal topography. Journal of Neurophysiology, 93(1), 437–453.

    Article  PubMed  Google Scholar 

  • Sayin, U., Osting, S., Hagen, J., Rutecki, P., & Sutula, T. (2003). Spontaneous seizures and loss of axo-axonic and axo-somatic inhibition induced by repeated brief seizures in kindled rats. Journal of Neuroscience, 23(7), 2759–2768.

    CAS  PubMed  Google Scholar 

  • Sloviter, R. S. (1991). Feedforward and feedback inhibition of hippocampal principal cell activity evoked by perforant path stimulation: GABA-mediated mechanisms that regulate excitability in vivo. Hippocampus, 1(1), 31–40.

    Article  CAS  PubMed  Google Scholar 

  • Steffensen, S. C., & Henriksen, S. J. (1991). Effects of baclofen and bicuculline on inhibition in the fascia dentata and hippocampus regio superior. Brain Research, 538(1), 46–53.

    Article  CAS  PubMed  Google Scholar 

  • Stoenica, L., Senkov, O., Gerardy-Schahn, R., Weinhold, B., Schachner, M., & Dityatev, A. (2006). In vivo synaptic plasticity in the dentate gyrus of mice deficient in the neural cell adhesion molecule NCAM or its polysialic acid. European Journal of Neuroscience, 23(9), 2255–2264.

    Article  PubMed  Google Scholar 

  • Thomas, M. J., Mameli, M., Carta, M., Valenzuela, C. F., Li, P. K., & Partridge, L. D. (2005). Neurosteroid paradoxical enhancement of paired-pulse inhibition through paired-pulse facilitation of inhibitory circuits in dentate granule cells. Neuropharmacology, 48(4), 584–596.

    Article  CAS  PubMed  Google Scholar 

  • Tuff, L. P., Racine, R. J., & Adamec, R. (1983). The effects of kindling on GABA-mediated inhibition in the dentate gyrus of the rat. I. Paired-pulse depression. Brain Research, 277(1), 79–90.

    Article  CAS  PubMed  Google Scholar 

  • Varona, P., Ibarz, J. M., Lopez-Aguado, L., & Herreras, O. (2000). Macroscopic and subcellular factors shaping population spikes. Journal of Neurophysiology, 83(4), 2192–2208.

    CAS  PubMed  Google Scholar 

  • Winkels, R., Jedlicka, P., Weise, F. K., Schultz, C., Deller, T., & Schwarzacher, S. W. (2009). Reduced excitability in the dentate gyrus network of betaIV-spectrin mutant mice in vivo. Hippocampus, 19(7), 677–686.

    Article  CAS  PubMed  Google Scholar 

  • Zappone, C. A., & Sloviter, R. S. (2004). Translamellar disinhibition in the rat hippocampal dentate gyrus after seizure-induced degeneration of vulnerable hilar neurons. Journal of Neuroscience, 24(4), 853–864.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft (JE 528/1-1 to P.J. and DE 551/8-1 to T.D.). We thank two anonymous reviewers for their helpful comments and suggestions.

Author information

Authors and Affiliations

  1. Institute of Clinical Neuroanatomy, Goethe-University, NeuroScience Center, 60590, Frankfurt am Main, Germany

    Peter Jedlicka, Thomas Deller & Stephan W. Schwarzacher

Authors
  1. Peter Jedlicka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Deller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephan W. Schwarzacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Jedlicka.

Additional information

Action Editor: Frances K. Skinner

Thomas Deller and Stephan W. Schwarzacher joint last authors

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 206 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jedlicka, P., Deller, T. & Schwarzacher, S.W. Computational modeling of GABAA receptor-mediated paired-pulse inhibition in the dentate gyrus. J Comput Neurosci 29, 509–519 (2010). https://doi.org/10.1007/s10827-010-0214-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10827-010-0214-y

Keywords

Search

Navigation