Elsevier

Neuroscience

Volume 225, 6 December 2012, Pages 76-87
Neuroscience

Patterns of the UP–Down state in normal and epileptic mice

https://doi.org/10.1016/j.neuroscience.2012.08.059Get rights and content

Abstract

Goal of this manuscript is to investigate whether changes that exist in epileptic brain generating spontaneous seizures are reflected in the pattern of the UP–Down state (UDS) recorded from the neocortex and dentate gyrus. Experiments were carried out on naive and epileptic mice under urethane anesthesia. Local field potentials were recorded with chronically implanted microelectrodes and single unit activity was recorded with glass microelectrodes. Recorded neurons were labeled by neurobiotin and identified later as granular cells or interneurons in histological sections. The following major features differentiate the pattern of UDS in epilepsy from normal. (1) The duration of UP and Down phases is significantly longer. (2) Recovery of network excitability after termination of the UP phase is longer. (3) UP-spikes occur during the UP phase, which transiently interrupt the development of the normal electrographic pattern of UP phase. Our data provide evidence that UP-spikes result from gigantic EPSPs generated in response to afferent activity. UP-spikes in the neocortex and dentate gyrus occur in close temporal relationship indicating the existence of direct or indirect pathological functional connections between these areas. Changes in the duration of UP and Down phases as well increased time of recovery of excitability of epileptic brain after termination of UP phase suggest alterations in the homeostatic properties of neuronal network in epileptic brain. We suggest that the existence of UP-spikes in epileptic brain may be an additional electrographic pattern indicating epileptogenicity. Unraveling the neuronal substrates of UP-spikes may further improve our understanding of the mechanisms of epilepsy.

Highlights

► UP–Down state pattern is different in normal and epileptic mice. ► There is a longer recovery of excitability of the network after termination of UP phase in epileptic animals. ► The UP phase of epileptic mice contains UP-spikes. ► UP-spikes are gigantic EPSPs and they reflect a weak balance between inhibitory and excitatory networks in epileptic brain.

Introduction

Electrographic interictal epileptiform events are signatures of epileptogenicity of the brain. They are used clinically for diagnosis and for localization of the epileptogenic region in surgical candidates. Interictal spikes and pathological high frequency oscillations (pHFOs) are among the few electrographic events that characterize epileptogenicity of brain areas (Dichter and Ayala, 1987, Gotman and Wang, 1991, Schwartzkroin, 1997, Bragin et al., 1999, Bragin et al., 2010, de Curtis and Avanzini, 2001, Staley and Dudek, 2006, Engel et al., 2009). Among electrographic patterns that have not been studied in epileptic brain is the UP–Down state (UDS). This pattern occurs in situations when the flow of afferent signals to the brain, or to certain brain areas, decreases (sleep or anesthesia). In these conditions the brain generates an electrographic pattern mostly determined by the properties of internal connections of these brain areas (Buzsaki, 2006). UDS during slow wave sleep (SWS) and anesthesia was originally described by Steriade and co-workers (Steriade et al., 1993a, Steriade et al., 1993b, Timofeev et al., 2001). UDS is characterized by the occurrence of slow <1.0 Hz waves with superimposed 20–80 Hz oscillations (beta–gamma activity, BGA). During awake conditions neurons are in an active state when their membrane potentials are slightly depolarized, while during SWS neuronal membrane potentials oscillate between depolarized and hyperpolarized states (Steriade et al., 1993b, Sanchez-Vives and McCormick, 2000, Timofeev et al., 2000, Timofeev et al., 2002). The depolarized state is called the UP phase and the hyperpolarized phase is called the Down phase. There is an increase in BGA amplitude and an increase in neuron discharges occur during the UP phase and low amplitude BGA when most neurons are silent during the Down phase (Steriade et al., 1993b, Sanchez-Vives and McCormick, 2000, Timofeev et al., 2000, Timofeev et al., 2002).

It is well accepted that one of the characteristics of the epileptic brain is imbalance between excitatory and inhibitory networks and altered metabolism (Schwartzkroin, 1983, Dichter and Ayala, 1987, Chang and Lowenstein, 2003). Some features of this imbalance should be reflected as changes in the UDS pattern, because GABAA receptor-mediated inhibition is necessary for balancing persistent activity during the UP phase and activation of GABAB receptors contributes to its termination (Mann et al., 2009, Sanchez-Vives et al., 2010).

Considering that UDS is a global electrographic phenomenon and that epilepsy is a multifactorial disorder involving wide spread changes in brain functions at the molecular, neuronal and systems levels (Spencer, 2002, Rakhade and Jensen, 2009, Loscher and Brandt, 2010, Pitkanen and Lukasiuk, 2011), analysis of changes in the UDS pattern related to epilepsy may yield new insights into our understanding of the mechanisms of epilepsy. The goal of these experiments was to compare characteristics of UDS in the neocortex and dentate gyrus of normal and epileptic mice using recordings from local field potentials and identified neurons.

Section snippets

Experimental procedures

All procedures described here were approved by the University of California, Los Angeles, Institutional Animal Care and Use Committee. Experiments were carried out on adult male C57B6/J mice (15–30 g; Harlan, Indianapolis, IN).

Spontaneous UDS

In accordance with previous publications in mice (Cossart et al., 2003, Hahn et al., 2007) and rats (Isomura et al., 2006, Wolansky et al., 2006), we found the UDS, which was characterized by slow <1.0 Hz waves with oscillations of 20–80 Hz (BGA) both in the neocortex and dentate gyrus (Fig. 1A, A1). The phase with increased BGA amplitude is termed the UP phase and the phase with decrease amplitude of BGA is termed the Down phase. The duration of UP phase during urethane anesthesia was 0.6 ± 0.5 s

Discussion

The main general finding of this study is that several parameters of UDS are different in epileptic animals. Although frequency of BGA is not significantly different, the duration of the UP phase and the Down phase is longer in epileptic animals. Also in these animals recovery of excitability after termination of the UP phase is longer. At present little is known about the mechanisms of occurrence of the UDS as well as mechanisms of termination of UP phase. Therefore, it is difficult to

Disclosure

None of the authors has any conflicts of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Acknowledgments

This study was supported NIH Grants NS065877, NS02808, NS33310.

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