Reduced excitability in the dentate gyrus network of βIV‐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.

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

“…Tuff et al 1983;Oliver and Miller 1985;Moser 1996;Jones et al 2001;Sayin et al 2003;Zappone and Sloviter 2004;Lomo 2009;Jedlicka et al 2009a, b;Winkels et al 2009). PPI of GC population spikes depends on GABAergic synaptic inhibition in the dentate network as it can be blocked or enhanced with GABA A R antagonists or agonists, respectively (Sloviter 1991;Steffensen and Henriksen 1991;Rich-Bennett et al 1993;Bronzino et al 1997;Kang et al 2006).…”

“…In vivo electrophysiological recordings in the dentate gyrus were carried out as described before (Winkels et al 2009;Jedlicka et al 2009a, b). Briefly, adult mice were anesthetized with an intraperitoneal injection of urethane.…”

“…An established computational model of the dentate gyrus network was used as described before (Santhakumar et al 2005;Winkels et al 2009). Briefly, the network model contained 4 major dentate cell types: 500 granule cells (GCs, cells 0-499), 15 mossy cells (MCs, cells 506-520), 6 basket cells (BCs, cells 500-505), and 6 hilar cells (HCs, cells 521-526) representing a 2000:1 scaled-down version of the dentate gyrus (Santhakumar et al 2005;).…”

“…Stoenica et al 2006;Jedlicka et al 2009b;Winkels et al 2009). In the dentate gyrus, electrical stimuli delivered to perforant path elicit field excitatory postsynaptic potentials (fEPSPs).…”

Functional consequences of the lack of amyloid precursor protein in the mouse dentate gyrus in vivo

“…Electrophysiological characterization of APP knockout and wildtype mice was carried out as described before (Jedlicka et al 2009a;Winkels et al 2009;Jedlicka et al 2011). Briefly, mice were anesthetized with an intraperitoneal injection of urethane (Sigma Aldrich, St. Louis, MO, USA; 1.2 g/kg body weight, supplemental doses of 0.3-1 g/kg s.c. g/kg as needed).…”