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