CO2-sensitivity of GABAergic Neurons in the Ventral Medullary Surface of GAD67-GFP Knock-in Neonatal Mice

Kuribayashi, Junya; Shibata, Shigeki; Hosokawa, Yuki; Hatori, Eiki; Tsujita, Miki; Takeda, Junzo; Yanagawa, Yuchio; Obata, Kunihiko; Kuwana, Shun-ichi

doi:10.1007/978-0-387-73693-8_59

Cited by 7 publications

(6 citation statements)

References 11 publications

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“…These abnormalities are of interest because the arcuate nucleus is the putative human homologue of the respiratory chemosensitive fields in the ventral medulla of experimental animals (64). We previously reported GABAergic neurons, receptors, and KCC2 within the arcuate nucleus of the normal human (25), consistent with known role of GABA in the enhancement of chemosensitivity at the ventral surface in animal models (15–17). The basis of the sparing of the arcuate nucleus in the GABA A receptor-binding deficit in SIDS cases is unknown.…”

Section: Discussionsupporting

confidence: 82%

“…We tested the hypothesis that markers of GABA A receptors are decreased in the medullary 5-HT system in SIDS cases vs. controls. We focused on GABA A receptors because they are critical markers of GABAergic function and are strongly implicated in medullary homeostatic functions (17, 18, 21–23, 26, 27). GABA A receptors are composed of at least 15 subunits (α1–6, β1–3, γ1–3, δ, and ρ1–2) encoded by distinct genes (28, 29).…”

Section: Introductionmentioning

confidence: 99%

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Decreased GABA_AReceptor Binding in the Medullary Serotonergic System in the Sudden Infant Death Syndrome

Broadbelt

Paterson

Belliveau

et al. 2011

J Neuropathol Exp Neurol

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γ-Aminobutyric acid (GABA) neurons in the medulla oblongata help regulate homeostasis, in part through interactions with the medullary serotonergic (5-HT) system. Previously, we reported abnormalities in multiple 5-HT markers in the medullary 5-HT system of infants dying from sudden infant death syndrome (SIDS), suggesting that 5-HT dysfunction is involved in its pathogenesis. Here, we tested the hypothesis that markers of GABAA receptors are decreased in the medullary 5-HT system in SIDS cases compared to controls. Using tissue receptor autoradiography with the radioligand 3H-GABA, we found 25–52% reductions in GABAA receptor binding density in 7 of 10 key nuclei sampled of the medullary 5-HT system in the SIDS cases (postconceptional age [PCA] = 51.7 ± 8.3, n = 28) vs. age-adjusted controls (PCA = 55.3 ± 13.5, n = 8) (p ≤ 0.04). By Western blotting there was 46.2% reduction in GABAAα3 subunit levels in the gigantocellularis (component of the medullary 5-HT system) of SIDS cases (PCA = 53.9 ± 8.4, n = 24) vs. controls (PCA = 55.3 ± 8.3, n = 8) (56.8% standard in SIDS cases vs. 99.35% in controls; p = 0.026). These data suggest that medullary GABAA receptors are abnormal in SIDS infants and that SIDS is a complex disorder of a homeostatic network in the medulla that involves deficits of the GABAergic and 5-HT systems.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Decreased GABA_AReceptor Binding in the Medullary Serotonergic System in the Sudden Infant Death Syndrome

Broadbelt

Paterson

Belliveau

et al. 2011

J Neuropathol Exp Neurol

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“…These functions include respiration (Pierrefiche et al, 1998; Shao et al, 1997), chemosensitivity to carbon dioxide (Curran et al, 2000; Curran et al, 2001; Curran et al, 2002; Kanazawa et al, 1998; Kuribayashi et al, 2008), blood pressure regulation (Dampney, 1994; Heesch et al, 2006; Menezes et al, 2007) and the laryngeal chemoreflex (Bohm et al, 2007; Van der Velde et al, 2003). While many biogenic amines and neuropeptides modulate the effects of GABA and vice-versa, GABA’s interactions with serotonin (5-HT) are particularly important and are the focus of this report.…”

Section: Introductionmentioning

confidence: 99%

Neuroanatomic relationships between the GABAergic and serotonergic systems in the developing human medulla

Broadbelt¹,

Paterson²,

Rivera³

et al. 2010

Autonomic Neuroscience

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Abstractγ-Amino butyric (GABA) critically influences serotonergic (5-HT) neurons in the raphé and extraraphé of the medulla oblongata. In this study we hypothesize there are marked changes in the developmental profile of markers of the human medullary GABAergic system relative to the 5-HT system in early life. We used single-and double-label immunocytochemistry and tissue receptor autoradiography in 15 human medullae from fetal and infant cases ranging from 15 gestational weeks to 10 postnatal months, and compared our findings with an extensive 5-HT-related database in our laboratory. In the raphé obscurus, we identified two subsets of GABAergic neurons using glutamic acid decarboxylase (GAD65/67) immunostaining: one comprised of small, round neurons; the other, medium, spindle-shaped neurons. In three term medullae cases, positive immunoflorescent neurons for both tryptophan hydroxylase and GAD65/67 were counted within the raphé obscurus. This revealed approximately 6% of the total neurons counted in this nucleus expressed both GAD65/67 and TPOH suggesting co-production of GABA by a subset of 5-HT neurons. The distribution of GABA A binding was ubiquitous across medullary nuclei, with highest binding in the raphé obscurus. GABA A receptor subtypes α1 and α3 were expressed by 5-HT neurons, indicating the site of interaction of GABA with 5-HT neurons. These receptor subtypes and KCC2, a major chloride transporter, were differentially expressed across early development, from mid-gestation (20wks) and thereafter. The developmental profile of GABAergic markers changed dramatically relative to the 5-HT markers. These data provide baseline information for medullary studies of human pediatric disorders, such as sudden infant death syndrome.

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“…Half of GABAergic neurons on the ventral medullary surface (overlapping regions traditionally considered to be chemosensitive) are hyperpolarized by hypercapnia, and GABA A receptors are expressed by CO 2 -sensitive neurons in those regions (Kanazawa et al, 1998; Kuribayashi et al, 2008). GABA A receptor activation also interferes with the hypoglossal reflex response to hypercapnia (Liu et al, 2003) and when GABA synthesis is prevented in the hypothalamus, the hypercapnic ventilatory response is enhanced (Peano et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…However, it is equally likely that neuronal inhibition/disinhibition may play a role in chemoreception (Nuding et al, 2009). For example, hypercapnia hyperpolarizes a subset of medullary neurons in organotypic cultures (Wellner-Kienitz and Shams, 1998) and CO 2 decreases discharge frequency of CO 2 -sensitive GABAergic neurons in medullary slices (Kuribayashi et al, 2008). About 15% of raphé neurons in acute slice are CO 2 -inhibited (Richerson, 1995; Wang and Richerson, 1999) and, in primary culture, up to 27% of raphé neurons are inhibited by CO 2 (Wang et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

CO2-inhibited neurons in the medullary raphé are GABAergic

Iceman

Corcoran

Taylor

et al. 2014

Respiratory Physiology & Neurobiology

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Previous studies have reported subsets of medullary raphé neurons that are either stimulated or inhibited by CO2/pH in vitro, in situ, and in vivo. We tested the hypothesis that medullary raphé CO2-inhibited neurons are GABAergic. Extracellular recordings in unanesthetized juvenile in situ rat preparations showed reversible hypercapnia-induced suppression of 19% (63/323) of medullary raphé neurons, and this suppression persisted after antagonism of NMDA, AMPA/kainate, and GABAA receptors. We stained a subset of CO2-inhibited cells and found that most (11/12) had glutamic acid decarboxylase 67 immunoreactivity (GAD67-ir). These data indicate that the majority of acidosis-inhibited medullary raphé neurons are GABAergic, and that their chemosensitivity is independent of major fast synaptic inputs. Thus, CO2-sensitive GABAergic neurons may play a role in central CO2/pH chemoreception.

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CO2-sensitivity of GABAergic Neurons in the Ventral Medullary Surface of GAD67-GFP Knock-in Neonatal Mice

Cited by 7 publications

References 11 publications

Decreased GABA_AReceptor Binding in the Medullary Serotonergic System in the Sudden Infant Death Syndrome

Decreased GABA_AReceptor Binding in the Medullary Serotonergic System in the Sudden Infant Death Syndrome

Neuroanatomic relationships between the GABAergic and serotonergic systems in the developing human medulla

CO2-inhibited neurons in the medullary raphé are GABAergic

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CO2-sensitivity of GABAergic Neurons in the Ventral Medullary Surface of GAD67-GFP Knock-in Neonatal Mice

Cited by 7 publications

References 11 publications

Decreased GABAAReceptor Binding in the Medullary Serotonergic System in the Sudden Infant Death Syndrome

Decreased GABAAReceptor Binding in the Medullary Serotonergic System in the Sudden Infant Death Syndrome

Neuroanatomic relationships between the GABAergic and serotonergic systems in the developing human medulla

CO2-inhibited neurons in the medullary raphé are GABAergic

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Resources

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Decreased GABA_AReceptor Binding in the Medullary Serotonergic System in the Sudden Infant Death Syndrome

Decreased GABA_AReceptor Binding in the Medullary Serotonergic System in the Sudden Infant Death Syndrome