title: Reduced excitability in the dentate gyrus network of betaIV-spectrin mutant mice in vivo.
abstract: 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 (qv(3j)) 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 qv(3j) 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 qv(3j) mice after electrical stimulation of the perforant path in vivo. This revealed an impaired input-output relationship between stimulus intensity and granule cell population spikes and an enhanced paired-pulse inhibition of population spikes, indicating a reduced ability of granule cells to generate action potentials and decreased network excitability. In contrast, the input-output 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 qv(3j) mutants. To corroborate our findings, we analyzed the influence of VGSC density reduction on dentate network activity using an established computational model of the dentate gyrus network. This in silico approach confirmed that the loss of VGSCs is sufficient to explain the electrophysiological changes observed in qv(3j) mice. Taken together, our findings demonstrate that betaIV-spectrin is required for normal granule cell firing and for physiological levels of network excitability in the mouse dentate gyrus in vivo.
authors.affiliation: Institute of Clinical Neuroanatomy, Goethe-University, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Winkels
authors.forename: Peter
authors.initials: P
authors.lastname: Jedlicka
authors.forename: Felix K
authors.initials: FK
authors.lastname: Weise
authors.forename: Christian
authors.initials: C
authors.lastname: Schultz
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Schwarzacher
mesh_terms: D000200:Action Potentials; D000818:Animals; D018891:Dentate Gyrus / Q000502:physiology*; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D019706:Excitatory Postsynaptic Potentials; D051379:Mice; D008817:Mice, Mutant Strains; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology*; D019580:Perforant Pathway / Q000502:physiology*; D017354:Point Mutation; D015222:Sodium Channels / Q000378:metabolism; D013049:Spectrin / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D013997:Time Factors
chemical_list: D015222:Sodium Channels; C504042:betaIV spectrin, mouse; D013049:Spectrin