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The interoceptive homeostatic mechanism that controls breathing, blood gases and acid‐base balance in response to changes in CO2/H+ is exquisitely sensitive, with convergent roles proposed for chemosensory brainstem neurons in the retrotrapezoid nucleus (RTN) and their supporting glial cells. For astrocytes, a central role for NBCe1, a Na+‐HCO3− cotransporter encoded by Slc4a4, has been envisaged in multiple mechanistic models (i.e. underlying enhanced CO2‐induced local extracellular acidification or purinergic signalling). We tested these NBCe1‐centric models by using conditional knockout mice in which Slc4a4 was deleted from astrocytes. In GFAP‐Cre;Slc4a4fl/fl mice we found diminished expression of Slc4a4 in RTN astrocytes by comparison to control littermates, and a concomitant reduction in NBCe1‐mediated current. Despite disrupted NBCe1 function in RTN‐adjacent astrocytes from these conditional knockout mice, CO2‐induced activation of RTN neurons or astrocytes in vitro and in vivo, and CO2‐stimulated breathing, were indistinguishable from NBCe1‐intact littermates; hypoxia‐stimulated breathing and sighs were likewise unaffected. We obtained a more widespread deletion of NBCe1 in brainstem astrocytes by using tamoxifen‐treated Aldh1l1‐Cre/ERT2;Slc4a4fl/fl mice. Again, there was no difference in effects of CO2 or hypoxia on breathing or on neuron/astrocyte activation in NBCe1‐deleted mice. These data indicate that astrocytic NBCe1 is not required for the respiratory responses to these chemoreceptor stimuli in mice, and that any physiologically relevant astrocytic contributions must involve NBCe1‐independent mechanisms. Key points: The electrogenic NBCe1 transporter is proposed to mediate local astrocytic CO2/H+ sensing that enables excitatory modulation of nearby retrotrapezoid nucleus (RTN) neurons to support chemosensory control of breathing.We used two different Cre mouse lines for cell‐specific and/or temporally regulated deletion of the NBCe1 gene (Slc4a4) in astrocytes to test this hypothesis.In both mouse lines, Slc4a4 was depleted from RTN‐associated astrocytes but CO2‐induced Fos expression (i.e. cell activation) in RTN neurons and local astrocytes was intact.Likewise, respiratory chemoreflexes evoked by changes in CO2 or O2 were unaffected by loss of astrocytic Slc4a4.These data do not support the previously proposed role for NBCe1 in respiratory chemosensitivity mediated by astrocytes. [ABSTRACT FROM AUTHOR]

Intraparenchymal injection of the saporin conjugate [[Sar.sup.9], Met [([O.sub.2]).sup.11]] substance P-saporin (SSP-SAP) into the ventrolateral medulla (VLM) destroys neurokinin-1 receptor-immunoreactivity (NK1R-ir) neurons selectively. This treatment attenuates the hypotension caused by injection of DL-homocysteic acid (DLH) into the caudal VLM (CVLM). Here we ask whether SSP-SAP creates this deficit by destroying the CVLM GABAergic interneurons that mediate the sympathetic baroreflex (baroactivated depressor neurons) or by destroying other VLM neurons. Two weeks after unilateral SSP-SAP treatment (97% loss of VLM NK1R-ir neurons) DLH-induced hypotension and sympathetic tone inhibition were blunted on the lesioned side. Unlesioned or unilaterally lesioned rats received phenylephrine (PE) while awake to identify CVLM baroactivated depressor neurons by the presence of Fos-ir nuclei. Although CVLM Fos-ir cells were not NK1R-ir, their number was reduced ~60-70% on the SSP-SAP-injected side. SSP-SAP spared VLM neurons devoid of NK1R-ir, such as the catecholaminergic cells and the precerebellar glutamatergic neurons. In the pre-Botzinger region of the VLM the toxin killed glutamatergic neurons while sparing glycinergic and GABAergic inhibitory neurons. In the CVLM region ~26% of the inhibitory cells were destroyed. In conclusion, the baroactivated depressor neurons of the CVLM do not appear to express NK1Rs but their activity is probably modulated by a population of excitatory NK1R-ir cells located in the VLM. The results also suggest that a region located below the CVLM (subCVLM) may contain an unrelated population of GABAergic depressor neurons that are NK1R-ir but are either not barosensitive or do not express Fos during baroreceptor stimulation. sympathetic tone; blood pressure; respiration; pre-Botzinger complex; respiratory rhythm generation; substance P; saporin