Chapter 2 - Effects of Glycinergic Inhibition Failure on Respiratory Rhythm and Pattern Generation

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Abstract

Inhibitory interactions between neurons of the respiratory network are involved in rhythm generation and pattern formation. Using a computational model of brainstem respiratory networks, we investigated the possible effects of suppressing glycinergic inhibition on the activity of different respiratory neuron types. Our study revealed that progressive suppression of glycinergic inhibition affected all neurons of the network and disturbed neural circuits involved in termination of inspiration. Causal was a dysfunction of postinspiratory inhibition targeting inspiratory neurons, which often led to irregular preterm reactivation of these neurons, producing double or multiple short-duration inspiratory bursts. An increasing blockade of glycinergic inhibition led to apneustic inspiratory activity. Similar disturbances of glycinergic inhibition also occur during hypoxia. A clear difference in prolonged hypoxia, however, is that the rhythm terminates in expiratory apnea. The critical function of glycinergic inhibition for normal respiratory rhythm generation and the consequences of its reduction, including in pathological conditions, are discussed.

Introduction

Inhibitory interactions between neurons of the brainstem respiratory network have been proposed to play a critical role in respiratory rhythm generation and the adjustment of normal breathing movements in vivo (Richter et al., 1986, Richter et al., 1992). Disturbances of these synaptic interactions may become dangerously life threatening as they can lead to an abnormally prolonged inspiration (apneusis) producing breath holdings or to complete cessation of breathing (apnea). There are reports of several diseases in which such disturbances of breathing originate from a failure of glycinergic inhibition that may even cause sudden death, for example, in Rett Syndrome (Stettner et al., 2007), hyperekplexia (Büsselberg et al., 2001a, Harvey et al., 2008, Markstahler et al., 2002), developmental disorders, such as olivo-ponto-cerebellar atrophy (OPCA) (Richter et al., 2003), and also brainstem infarction (El-Khatib et al., 2003).

The circuit mechanisms underlying inhibitory regulation of respiratory network activity and the associated emergent pathogenic processes contributing to network dysfunctions are difficult to analyze in a complex system such as the brainstem respiratory network. Specifically, there is incomplete understanding about the effects of such disturbances on the activity of different respiratory neuron types. In this study, we tried to fill this gap using computational modeling of the effects of progressive depression of glycinergic inhibition on the activity of various types of respiratory neurons. We believe that such an approach is promising as it not only predicts network behavior but allows theoretical and experimental testing of therapeutic strategies to recover breathing as was successfully performed for opioid-induced apnea by potentiating glycinergic synaptic transmission (Shevtsova et al., 2011).

As synaptic transmission of inhibitory neurons is also very sensitive to hypoxia and fades quickly during reduced levels of brain oxygen (Congar et al., 1995), we used our simulations to investigate the possible effects of progressive suppression of glycinergic inhibition to gain insights into basic mechanisms of respiratory rhythm generation and pattern formation and to explore potential inhibitory mechanisms involved in hypoxia-related disturbances of respiratory network activity. Based on our simulations and their comparisons to experimental data, we were able to identify and interpret some of the stages of hypoxic perturbations of neural activity at both the neuronal and the network levels. We suggest that identifying different states of these disturbances can be used to diagnose the degree of severity of disruptions of network inhibitory processes, which might be beneficial for protective medicine.

Section snippets

Modeling Methods

The computational model of the brainstem respiratory network used in this study had been developed and described in detail by Shevtsova et al. (2011). All neurons were modeled in the Hodgkin–Huxley style (single-compartment models) and incorporated known biophysical properties and available information on channel kinetics as previously characterized in respiratory neurons in vitro. In the model, each population contained 20–50 neurons. Heterogeneity of neurons within each population was set by

Model Description and Operation in Control Conditions

In this study, we used our computational model of the brainstem respiratory network (Shevtsova et al., 2011) that was specially developed to simulate and theoretically analyze the possible neural mechanisms involved in the recovery of breathing after opioid-induced apnea by potentiating glycinergic inhibition via the 5-HT1A receptor agonist 8-OH-DPAT as demonstrated in experimental studies (Manzke et al., 2010). This model was the first computational model of the brainstem respiratory network

Discussion

Under normal conditions, the three-phase pattern of rhythmic breathing depends on intact excitatory and inhibitory synaptic interactions between populations of respiratory neurons in the complex respiratory network (Richter, 1982, Smith et al., 2007). Inhibitory interactions include glycinergic inhibition involved in termination of respiratory phases and GABAergic inhibition that stabilizes antagonistic inspiratory and expiratory phases of oscillation (Schmid et al., 1996). The specific roles

Acknowledgments

This study was supported in the United States by National Institutes of Health, grants R33 HL087377, R01 NS057815, and R01 NS069220 to I. A. R., in part by the Intramural Research Program of the NIH, NINDS (J. C. S.), and in Germany by the Excellence Cluster “Nanoscale microscopy and molecular physiology of the brain” (CNMPB) funded by the DFG and BMBF (D. W. R.).

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