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dc.contributor.authorTait, L
dc.contributor.authorWedgwood, K
dc.contributor.authorTsaneva-Atanasova, K
dc.contributor.authorBrown, JT
dc.contributor.authorGoodfellow, M
dc.date.accessioned2018-04-23T08:07:35Z
dc.date.issued2018-04-11
dc.description.abstractThe entorhinal cortex is a crucial component of our memory and spatial navigation systems and is one of the first areas to be affected in dementias featuring tau pathology, such as Alzheimer's disease and frontotemporal dementia. Electrophysiological recordings from principle cells of medial entorhinal cortex (layer II stellate cells, mEC-SCs) demonstrate a number of key identifying properties including subthreshold oscillations in the theta (4-12 Hz) range and clustered action potential firing. These single cell properties are correlated with network activity such as grid firing and coupling between theta and gamma rhythms, suggesting they are important for spatial memory. As such, experimental models of dementia have revealed disruption of organised dorsoventral gradients in clustered action potential firing. To better understand the mechanisms underpinning these different dynamics, we study a conductance based model of mEC-SCs. We demonstrate that the model, driven by extrinsic noise, can capture quantitative differences in clustered action potential firing patterns recorded from experimental models of tau pathology and healthy animals. The differential equation formulation of our model allows us to perform numerical bifurcation analyses in order to uncover the dynamic mechanisms underlying these patterns. We show that clustered dynamics can be understood as subcritical Hopf/homoclinic bursting in a fast-slow system where the slow sub-system is governed by activation of the persistent sodium current and inactivation of the slow A-type potassium current. In the full system, we demonstrate that clustered firing arises via flip bifurcations as conductance parameters are varied. Our model analyses confirm the experimentally suggested hypothesis that the breakdown of clustered dynamics in disease occurs via increases in AHP conductance.en_GB
dc.description.sponsorshipThe contribution of MG, KTR and JB was generously supported by a Wellcome Trust Institutional Strategic Support Award (WT105618MA). MG and KT gratefully acknowledge the financial support of the EPSRC via grant EP/N014391/1. LT’s doctoral studentship is supported by the Alzheimer’s Society in partnership with the Garfield Weston Foundation (grant reference 231). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en_GB
dc.identifier.citationVol. 449, pp. 23-34en_GB
dc.identifier.doi10.1016/j.jtbi.2018.04.013
dc.identifier.otherS0022-5193(18)30173-5
dc.identifier.urihttp://hdl.handle.net/10871/32562
dc.language.isoenen_GB
dc.publisherElsevieren_GB
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pubmed/29654854en_GB
dc.rights© 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license. (http://creativecommons.org/licenses/by/4.0/ )en_GB
dc.subjectDementiaen_GB
dc.subjectbifurcation analysisen_GB
dc.subjectburstingen_GB
dc.subjectneuron modelen_GB
dc.subjectsubthreshold oscillationsen_GB
dc.titleControl of clustered action potential firing in a mathematical model of entorhinal cortex stellate cells.en_GB
dc.typeArticleen_GB
dc.date.available2018-04-23T08:07:35Z
dc.identifier.issn0022-5193
exeter.place-of-publicationEnglanden_GB
dc.descriptionThis is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.en_GB
dc.identifier.journalJournal of Theoretical Biologyen_GB


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