Computational modeling of reduced excitability in the dentate gyrus of betaIV-spectrin mutant mice

Abstract

Event Abstract Back to Event Computational modeling of reduced excitability in the dentate gyrus of betaIV-spectrin mutant mice Peter Jedlicka1*, Raphael Winkels1, Felix K. Weise1, Christian Schultz2, Thomas Deller1 and Stephan W. Schwarzacher1 1 Goethe University, NeuroScience Center, Clinical Neuroanatomy, Germany 2 Justus Liebig University, Institute of Anatomy and Cell Biology, Germany The submembrane cytoskeletal meshwork of the axon contains the scaffolding protein betaIV-spectrin. It provides mechanical support for the axon and anchors membrane proteins. Quivering (qv3j) mice lack functional betaIV-spectrin and have reduced voltage-gated sodium channel (VGSC) immunoreactivity at the axon initial segment and nodes of Ranvier. Because VGSCs are critically involved in action potential generation and conduction, we hypothesized that qv3j mice should also show functional deficits at the network level. To test this hypothesis, we investigated granule cell function in the dentate gyrus of anesthetized qv3j mice after electrical stimulation of the perforant path in vivo. This revealed an impaired input-output (IO) relationship between stimulus intensity and granule cell population spikes and an enhanced paired-pulse inhibition (PPI) of population spikes, indicating a reduced ability of granule cells to generate action potentials and decreased network excitability. In contrast, the IO curve for evoked field excitatory postsynaptic potentials (fEPSPs) and paired-pulse facilitation of fEPSPs were unchanged, suggesting normal excitatory synaptic transmission at perforant path-granule cell synapses in qv3j mutants.To better understand the influence of betaIVspectrin and VGSC density changes on the dentate gyrus network activity, we employed computational modeling approach. We used a recently developed and highly detailed computational model of the dentate gyrus network (Santhakumar et al., J Neurophysiol 93:437–453, 2005). The network model is based on realistic morphological and electrophysiological data and consists of perforant path inputs and connections of granule, mossy, basket and hilar cells. The role of VGSCs in network excitability was analyzed by systematically varying their densities in axosomatic compartments. This in silico approach confirmed that the loss of VGSCs is sufficient to explain the electrophysiological changes observed in qv3j mice. Computer simulations of the IO and PPI test indicated that in the dentate circuit with altered VGSCs, network excitability decreases owing to impaired spike-generator properties of granule cells and subsequent relative increase of GABAergic inhibitory control over granule cell firing.Taken together, our in vivo and in silico data demonstrate that the destabilization of VGSC clustering in qv3j mice leads to a reduced spike-generating ability of granule cells and considerably decreased network excitability in the dentate circuit. This provides the first evidence that betaIV-spectrin is required for normal granule cell firing and for physiological levels of network excitability in the mouse dentate gyrus in vivo. Conference: Bernstein Conference on Computational Neuroscience, Frankfurt am Main, Germany, 30 Sep - 2 Oct, 2009. Presentation Type: Poster Presentation Topic: Information processing in neurons and networks Citation: Jedlicka P, Winkels R, Weise FK, Schultz C, Deller T and Schwarzacher SW (2009). Computational modeling of reduced excitability in the dentate gyrus of betaIV-spectrin mutant mice. Front. Comput. Neurosci. Conference Abstract: Bernstein Conference on Computational Neuroscience. doi: 10.3389/conf.neuro.10.2009.14.054 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 26 Aug 2009; Published Online: 26 Aug 2009. * Correspondence: Peter Jedlicka, Goethe University, NeuroScience Center, Clinical Neuroanatomy, Frankfurt, Germany, jedlicka@em.uni-frankfurt.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Peter Jedlicka Raphael Winkels Felix K Weise Christian Schultz Thomas Deller Stephan W Schwarzacher Google Peter Jedlicka Raphael Winkels Felix K Weise Christian Schultz Thomas Deller Stephan W Schwarzacher Google Scholar Peter Jedlicka Raphael Winkels Felix K Weise Christian Schultz Thomas Deller Stephan W Schwarzacher PubMed Peter Jedlicka Raphael Winkels Felix K Weise Christian Schultz Thomas Deller Stephan W Schwarzacher Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.