Elsevier

Early Human Development

Volume 75, Supplement, December 2003, Pages 167-174
Early Human Development

Sleep apnea in mice: a useful animal model for study of SIDS?

https://doi.org/10.1016/j.earlhumdev.2003.08.019Get rights and content

Abstract

Although the incidence of sudden infant death syndrome (SIDS) has been decreased by education programs to avoid sleeping in prone position, the pathological mechanisms of SIDS have not fully been understood. Basic research on sleep apnea using experimental animals may help further understanding and prevention of SIDS because the syndrome is thought as inability to wake up from respiratory arrest (apnea) during sleep. Although several animal models of sleep apnea have been described previously, mice would be useful experimental animals in that these animals are frequently used in genetic engineering. Those considerations prompted us to establish a method for measuring ventilation of mice concomitantly with electroencephalography and electromyography for assessing sleep–wake states. Normal wild-type mice developed two types of central sleep apneas (CSA), that is, post-sigh and spontaneous apneas, as normal humans do. Moreover, post-sigh apneas in mice were observed exclusively during slow-wave sleep (SWS) while spontaneous apneas were seen in both SWS and rapid eye movement (REM) sleep. These characteristics are very similar to those of sleep apneas in healthy human infants and children. Therefore, mice seem to be a promising experimental animal model for studying the genetic and molecular basis of respiratory regulation and dysregulation during sleep in humans, especially infants and children. However, we should keep in mind limitations in studying mice as an animal model of SIDS, since they are nocturnal rodents and they sleep in the prone position.

Introduction

Sudden infant death syndrome (SIDS) is thought as inability to wake up from respiratory arrest (apnea) during sleep [1], [2]. Paradoxically, however, retrospective study showed low incidence of sleep apnea in SIDS victims before they died [3]. We do not know at present whether there is fundamental difference between physiologically returnable sleep apnea and irreversible one. We do not know even precise mechanisms how sleep apnea occurs. Therefore, basic research on sleep apnea using experimental animals may help further understanding and prevention of SIDS.

On the other hand, there is ample evidence suggesting a genetic link in etiology of SIDS [4], [5], although the gene(s) that is responsible for pathogenesis of SIDS has not been identified so far. Therefore, use of mice, especially genetically engineered mice, seems promising not only to understand the still unknown mechanisms of sleep apnea, but also to elucidate molecular basis of SIDS.

In this short review, we will briefly summarize classification and clinical aspects of sleep apneas and then address experimental methods and new findings in our recent study using mice on sleep-related regulation of breathing [6]. Future directions and limitations using genetically engineered mice will also be discussed.

Section snippets

Classification of sleep apneas

There are two major forms of sleep apneas: obstructive sleep apneas (OSA) and central sleep apneas (CSA). Sleep apneas are classified as obstructive in type if the presence of chest or abdominal wall motion associated with the absence of airflow at the mouth or nose. They are classified as central in type if the absence of chest or abdominal wall motion associated with the absence of airflow at the mouth or nose. Sleep apneas are observed not only in sleep apnea syndrome patients but also in

Detailed classification and frequency of central sleep apneas in human children and adolescents

Although detailed classification and terminology are not commonly approved to date, CSA may be further classified into either of three types in healthy children [3], [12], [14]. First type is associated with the preceding sigh and second type with preceding movement. They are termed as “post-sigh” and “post-movement” apneas, respectively. The third type of CSA, arising without the preceding sighs or movements, is termed as “isolated” apneas [12]. Among 433 children of 8–11 years old, 398 (92%)

Sleep apnea in mice

Although several animal models of sleep apnea have been described during the last two decades [21], [22], [23], no report had been available on mice until recently. Mice are particularly intriguing in that these animals are frequently used in genetic engineering. Actually, use of transgenic mice has already allowed us to investigate the possible effects of specific genes on certain respiratory functions (see Section 5). We introduce here our recently established method [6] for measuring

Future research for understanding of the genetic and molecular basis of sleep apneas using mice

Mouse may be a useful animal model for study of SIDS from the following two reasons. First, as mentioned above, there is resemblance between mice and human in that type of sleep apnea is associated with sleep stage. Namely, normal mice developed post-sigh apneas exclusively in SWS, as healthy human children and adolescents have post-sigh apneas predominantly in NREM sleep. Elucidating the mechanism of the post-sigh apneas in mice may shed light on the understanding pathophysiological basis of

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