page_title: Pre-Bötzinger complex
section_title: Homeostatic changes
hierarchical_section_title: Pre-Bötzinger complex / Function / Homeostatic changes
caption_attribution_description: English: The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB 3KG2.
context_page_description: The pre-Bötzinger complex is a cluster of interneurons in the ventral respiratory group of the medulla of the brainstem. This complex has been proven to be essential for the generation of the respiratory rhythm in mammals. The exact mechanism of the rhythm generation and transmission to motor nuclei remains controversial and the topic of much research.
  Several synthetic compounds have been shown to act on neurons specific to the preBötC, most being selective agonists or antagonists to receptor subtypes on neurons in the vicinity. Since many of these neurons express GABA, glutamate, serotonin and adenosine receptors, chemicals custom tailored to bind at these sites are most effective at altering respiratory rhythm.
  Adenosine modulates the preBötC output via activation of the A₁ and A2A receptor subtypes. An adenosine A₁ receptor agonist has been shown to depress preBötC rhythmogenesis independent of the neurotransmitters GABA and glycine in in vitro preparations from 0-7 day old mice. Another synthetic drug specific to the adenosine A2A receptor subtype is CGS-21680 that has been shown to cause apneas in 14- to 21-day-old rat pups in vivo.
context_section_description: Investigation of the respiratory response to Acute intermittent hypoxia (AIH), repeated episodes of hypoxia, reveals connection to various breathing disorders, such as Rett syndrome and obstructive sleep apnea. AIH leads to persistent increases in respiratory frequency and amplitude of integrated motor neuronal bursts in vivo. These changes lasting for 90 minutes or longer are termed long-term facilitation (LTF). AIH causes homeostatic changes in multiple sites of the respiratory system; the pre-BötC is likely the site for the LTF, since intermittent hypoxia causes an increase in persistent frequency after ongoing hypoxia.The respiratory system is regulated by multiple forms of long-term synaptic plasticity.The role of synaptic inhibition has been proved widespread and critical within the expiratory Botzinger complex respiratory network, through cross-correlation and antidromic mapping techniques. The inhibitory connections discovered indicate their ability to connect different classes of neurons, their importance in regulating the interval of inspiration, and their ability to control driving potential of respiratory neurons. These characteristics show the interaction between the parafacial respiratory group and the pre-Bötzinger complex, which allows for active expiration to be produced by synaptic inhibition within the respiratory network. Synaptic inhibition is critical for allowing the pre-Bötzinger complex to communicate with other respiratory centers in order to generate respiratory activity.
  Glycinergic and GABAergic inhibitory neurons make up half of all inspiratory neurons. Exposure of the pre-Bötzinger complex to these inhibitory neurotransmitters results in the rhythmic nature associated with respiration. Blocking this inhibition from Glycine or GABA causes its neurons to be incapable of switching from the active phase to the inspiration phase, demonstrated by shorter inspiratory activity (as seen in vivo). However, the absence of inhibitory synapses still resulted in rhythmic respiratory activity in vitro and in situ. This is largely due to the fact that respiratory rhythm results from numerous aspects, with synaptic inhibition playing only a single part.
  In addition to the inhibitory synaptic regulation of respiratory rhythm within the pre-Bötzinger complex, there is also an excitatory component utilizing mostly AMPA receptors. The generation of inspirations is due to a signaling cascade involving transient Ca2+ influx as a result of glutamate activating a postsynaptic receptor. In addition to glutamates role in activating the synaptic drive of inspiration, it is also understood that pacemaker neurons, with autonomous voltage-dependent properties, are also responsible for the generation of respiratory rhythm. Evidence of this is seen when isolating neurons within the pre-Bötzinger complex, which results in rhythmic bursts due to synaptically coupled micronetworks.
  However, the generation of respiratory rhythm requires other excitatory components, such as glutamate, in order to produce a wide range of behavioral functions including eupneic and sigh activity. The pre-Bötzinger complex is responsible for generating the wide variety of components that make up the respiratory rhythm. The accomplishment of these precise activities requires distinct neuron populations that overlap to allow the generation of different respiratory actions. Eupneic activity is generated using the excitatory mechanism through the NMDA glutamate receptor. Sighs have a differential generation originating from pacemaker neurons. The pre-Bötzinger complex is capable of generating differential rhythmic activities due the intricate integration of modulatory, synaptic, and intrinsic properties of the neurons involved.
caption: AMPA receptor
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