Functional Respiratory Rhythm Generating Networks in Neonatal Mice Lacking NMDAR1 Gene

Funk, Gregory D.; Johnson, Stephen E.; Smith, Jeffrey C.; Dong, Xiaowei; Lai, J.; Feldman, Jack L.

doi:10.1152/jn.1997.78.3.1414

Cited by 74 publications

(48 citation statements)

References 39 publications

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“…Activation of NMDAR increases Ca 2ϩ influx and enhances neuronal excitation. Although gene knockout studies imply that NMDAR may not be necessary for the prenatal development of circuits producing respiratory rhythm, these receptors may be important for proper postnatal development of the respiratory network in regulating respiratory rhythm (13) or in processing afferent inputs from chemosensors (29). Critical periods for NMDAR-mediated activity-dependent development occur postnatally in many systems (e.g., sensory system and spinal motoneuron circuits).…”

Section: Discussionmentioning

confidence: 99%

Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex

Liu

Wong‐Riley

2002

Journal of Applied Physiology

120

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Liu, Qiuli, and Margaret T. T. Wong-Riley. Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex. J Appl Physiol 92: 923-934, 2002; 10.1152/japplphysiol.00977.2001.-The preBötzinger complex (PBC) is postulated as the center of respiratory rhythmogenesis. Previously, we found a reduction or plateau of cytochrome oxidase (CO) activity in the PBC and other respiratory nuclei at postnatal days 3-4, despite a general increase of CO with age, suggesting a period of synaptic readjustment. The present study examined the expression of CO and a number of neurochemicals in the PBC at closer time intervals. At postnatal days 3-4 and, more prominently, at postnatal day 12, expression of CO, glutamate, and N-methyl-D-aspartate receptor subunit 1 was reduced, whereas expression of GABA, GABAB receptor, glycine receptor, and ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit 2 was increased. These findings are consistent with our hypothesis that decreased CO activity is associated with an increase in inhibitory drive (mediated by GABA and glycine, their receptors, and possibly blockage of Ca 2ϩ entry by glutamate receptor subunit 2) and a decrease in excitatory drive (mediated by glutamate and its receptors). Our findings point to two critical periods during postnatal development of the rat when their respiratory system may be more vulnerable to respiratory insults.N-methyl-D-aspartate receptor subunit 1; glutamate receptor subunit 2; GABAB receptor; neurokinin-1 receptor; glutamate THE MECHANISM OF RESPIRATORY rhythmogenesis is not fully understood, but cumulative evidence suggests that the pre-Bötzinger complex (PBC) may be the center or kernel of respiratory rhythm generation (12,37,38,42). The PBC is located at the rostroventrolateral medulla, ventral to the nucleus ambiguus (NA), and can be anatomically defined by the distribution of immunoreactive neurokinin-1 receptors (NK1R) (15). Removal of only the PBC in the brain stem eliminated respiratory rhythm generation in neonatal rats (42). All six basic types of respiratory neurons were identified in the PBC (9, 42), and neurons with voltagedependent pacemaker-like properties were also found there (6,7,17,22,47). It has been implied that the PBC functions as a central hypoxia chemosensor for respiration (44,45). The application of agonists and antagonists of some neurotransmitters and neuromodulators to the PBC can induce apparent changes in respiratory rhythm and pattern (8,21,34,41,43). However, very little is known about postnatal development of neurochemicals in the PBC when the system may be more vulnerable to respiratory distress.Cytochrome oxidase (CO) is the terminal enzyme of the mitochondrial respiratory chain and is considered to be a reliable marker of neurons' metabolic capacity and levels of functional activity (51). Previously, we found that the PBC and other respiratory nuclei in the rat exhibited a general increase in CO activity with postnatal development. However, there was a distin...

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Section: Discussionmentioning

confidence: 99%

Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex

Liu

Wong‐Riley

2002

Journal of Applied Physiology

120

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“…A simple explanation would be that pharmacology in vivo is unable to entirely disrupt glutamatergic transmission, whereas the present genetic inactivation does. The disruption of genes encoding glutamate NMDA receptor subunits (Forrest et al, 1994;Li et al, 1994;Sakimura et al, 1995;Ebralidze et al, 1996;Kadotani et al, 1996;Kutsuwada et al, 1996;Funk et al, 1997;Poon et al, 2000;Miyamoto et al, 2002), non-NMDA receptors (Jia et al, 1996(Jia et al, , 2001Pekhletski et al, 1996;Huettner, 2001;Gerlai et al, 2002;Morishima et al, 2005), glutamate-synthesizing enzyme (Masson et al, 2006), or of glutamate fate-determining selector genes (Cheng et al, 2004) failed to result in a complete collapse of the respiratory activity. Hence, genetically impacting the glutamate neuron itself provides a powerful tool to interfere with the activity of neural circuits.…”

Section: Impairedmentioning

confidence: 99%

“…It is located in the rostroventrolateral medulla and relies on excitatory glutamatergic connections (Funk et al, 1993;Rekling and Feldman, 1998). PBC interneurons discharge through activation of NMDA and non-NMDA glutamate receptors (Funk et al, 1993(Funk et al, , 1997 and are immunopositive for glutamate receptor subunits (Robinson and Ellenberger, 1997;Paarmann et al, 2005). Neurokinin-1-receptor (NK1R)-expressing PBC neurons, essential for maintenance of normal breathing in vivo (Gray et al, 2001;McKay et al, 2005), have been shown to contain Vglut2 mRNA and to receive VGLUT2-positive terminals (Gray et al, 1999;Guyenet et al, 2002;Stornetta et al, 2003a,b) but also have GABAergic and glycinergic terminals (Liu et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Vesicular Glutamate Transporter 2 Is Required for Central Respiratory Rhythm Generation But Not for Locomotor Central Pattern Generation

Gezelius²,

et al. 2006

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Glutamatergic excitatory neurotransmission is dependent on glutamate release from presynaptic vesicles loaded by three members of the solute carrier family, Slc17a6 -8, which function as vesicular glutamate transporters (VGLUTs). Here, we show that VGLUT2 (Slc17a6) is required for life ex utero. Vglut2 null mutant mice die immediately after birth because of the absence of respiratory behavior. Investigations at embryonic stages revealed that neural circuits in the location of the pre-Bötzinger (PBC) inspiratory rhythm generator failed to become active. However, neurons with bursting pacemaker properties and anatomical integrity of the PBC area were preserved. Vesicles at asymmetric synapses were fewer and malformed in the Vglut2 null mutant hindbrain, probably causing the complete disruption of AMPA/kainate receptor-mediated synaptic activity in mutant PBC cells. The functional deficit results from an inability of PBC neurons to achieve synchronous activation. In contrast to respiratory rhythm generation, the locomotor central pattern generator of Vglut2 null mutant mice displayed normal rhythmic and coordinated activity, suggesting differences in their operating principles. Hence, the present study identifies VGLUT2-mediated signaling as an obligatory component of the developing respiratory rhythm generator.

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“…Using the same methodology in the same anesthetized and freely behaving animals, we show that both non-NMDA and NMDA receptor mechanisms at the HMN contribute significantly to respiratory-related genioglossus activity in anesthetized adult rats. This result obtained under anesthesia is significant because it shows that, in addition to the fundamental role of non-NMDA receptor activation in the expression of respiratory-related hypoglossal motor activity, originally identified as the principal mechanism operating in vitro (Greer et al, 1991;Funk et al, 1993Funk et al, , 1997Rekling et al, 2000), NMDA receptor activation is also involved in vivo. The lesser involvement of NMDA receptors in respiratory drive transmission at the HMN in neonatal preparations may be influenced by deafferentation and removal of tonic excitatory inputs that are normally present in vivo and/or a function of an immature respiratory network (Rekling et al, 2000).…”

Section: Respiratory-related Activitymentioning

confidence: 88%

Endogenous Glutamatergic Control of Rhythmically Active Mammalian Respiratory Motoneurons In Vivo

Steenland¹,

Liu²,

Horner³

2008

Journal of Neuroscience

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The transmission of rhythmic drive to respiratory motoneurons in vitro is critically dependent on glutamate acting primarily on non-NMDA receptors. We determined whether both non-NMDA and NMDA receptors contribute to respiratory drive transmission at respiratory motoneurons in the intact organism, both in the state of anesthesia and in the same animals during natural behaviors. Twentyseven rats were implanted with electroencephalogram and neck electrodes to record sleep-wake states and genioglossus and diaphragm electrodes for respiratory muscle recordings. Microdialysis probes were inserted into the hypoglossal motor nucleus (HMN). Under anesthesia, non-NMDA or NMDA receptor antagonism significantly decreased respiratory-related genioglossus activity, indicating a contribution of each receptor to respiratory drive transmission at the HMN. However, despite the presence of respiratory-related genioglossus activity in the same rats across sleep-wake states, neither non-NMDA receptor antagonism at the HMN nor glutamate uptake inhibition had any effect on respiratory-related genioglossus activity. These results showed that, compared with anesthesia, respiratory drive transmission through the non-NMDA receptor is low in the behaving organism. In contrast, glutamate uptake inhibition increased tonic genioglossus activity in wakefulness and non-rapid-eye-movement sleep, indicating a functional endogenous glutamatergic modulation of tonic, but not respiratory, motor tone. Such an effect on tonic drive may contribute to the suppression of both tonic and respiratory-related genioglossus activity in wakefulness and sleep with NMDA receptor antagonism at the HMN. These data do not refute previous identification of a glutamatergic (mostly non-NMDA receptor activating) respiratory drive to hypoglossal motoneurons, but this mechanism is more prominent in anesthetized or in vitro preparations.

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Functional Respiratory Rhythm Generating Networks in Neonatal Mice Lacking NMDAR1 Gene

Cited by 74 publications

References 39 publications

Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex

Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex

Vesicular Glutamate Transporter 2 Is Required for Central Respiratory Rhythm Generation But Not for Locomotor Central Pattern Generation

Endogenous Glutamatergic Control of Rhythmically Active Mammalian Respiratory Motoneurons In Vivo

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