title: Calcium regulation of HCN channels supports persistent activity in a multiscale model of neocortex.
abstract: Neuronal persistent activity has been primarily assessed in terms of electrical mechanisms, without attention to the complex array of molecular events that also control cell excitability. We developed a multiscale neocortical model proceeding from the molecular to the network level to assess the contributions of calcium (Ca(2+)) regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in providing additional and complementary support of continuing activation in the network. The network contained 776 compartmental neurons arranged in the cortical layers, connected using synapses containing AMPA/NMDA/GABAA/GABAB receptors. Metabotropic glutamate receptors (mGluR) produced inositol triphosphate (IP3) which caused the release of Ca(2+) from endoplasmic reticulum (ER) stores, with reuptake by sarco/ER Ca(2+)-ATP-ase pumps (SERCA), and influence on HCN channels. Stimulus-induced depolarization led to Ca(2+) influx via NMDA and voltage-gated Ca(2+) channels (VGCCs). After a delay, mGluR activation led to ER Ca(2+) release via IP3 receptors. These factors increased HCN channel conductance and produced firing lasting for ∼1min. The model displayed inter-scale synergies among synaptic weights, excitation/inhibition balance, firing rates, membrane depolarization, Ca(2+) levels, regulation of HCN channels, and induction of persistent activity. The interaction between inhibition and Ca(2+) at the HCN channel nexus determined a limited range of inhibition strengths for which intracellular Ca(2+) could prepare population-specific persistent activity. Interactions between metabotropic and ionotropic inputs to the neuron demonstrated how multiple pathways could contribute in a complementary manner to persistent activity. Such redundancy and complementarity via multiple pathways is a critical feature of biological systems. Mediation of activation at different time scales, and through different pathways, would be expected to protect against disruption, in this case providing stability for persistent activity.
authors.affiliation: Department of Physiology & Pharmacology, SUNY Downstate, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; Department of Neuroscience, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA. Electronic address: samn@neurosim.downstate.edu.
authors.forename: S A
authors.initials: SA
authors.lastname: Neymotin
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA. Electronic address: robert.mcdougal@yale.edu.
authors.forename: R A
authors.initials: RA
authors.lastname: McDougal
authors.affiliation: Department of Physiology & Pharmacology, SUNY Downstate, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; Department of Neuroscience, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA. Electronic address: anna.bulanova@downstate.edu.
authors.forename: A S
authors.initials: AS
authors.lastname: Bulanova
authors.affiliation: Department of Mathematics, Zirve University, 27260 Gaziantep, Turkey. Electronic address: zeki.mustafa@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Zeki
authors.affiliation: Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. Electronic address: PLakatos@nki.rfmh.org.
authors.forename: P
authors.initials: P
authors.lastname: Lakatos
authors.affiliation: Department of Mathematics, The Ohio State University, 231 W 18th Avenue, Columbus, OH 43210, USA. Electronic address: terman@math.osu.edu.
authors.forename: D
authors.initials: D
authors.lastname: Terman
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA. Electronic address: michael.hines@yale.edu.
authors.forename: M L
authors.initials: ML
authors.lastname: Hines
authors.affiliation: Department of Physiology & Pharmacology, SUNY Downstate, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; Department of Neurology, SUNY Downstate, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; Department Neurology, Kings County Hospital Center, 451 Clarkson Avenue, Brooklyn, NY 11203, USA. Electronic address: billl@neurosim.downstate.edu.
authors.forename: W W
authors.initials: WW
authors.lastname: Lytton
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000378:metabolism*; D008959:Models, Neurological; D019579:Neocortex / Q000166:cytology*; D009474:Neurons / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium
keywords: I(h); computer simulation; hyperpolarization-activated cyclic nucleotide-gated (HCN) channel; multiscale modeling; neocortex; persistent activity