Adult Mice with 5‐HT Neuron‐specific Knockout of Lmx1b Exhibit an Attenuated Hypercapnic Ventilatory Response

Abstract

Conditional knockout (CKO) mice have recently been generated in which the transcription factor Lmx1b is specifically deleted in serotonin neurons, using cre recombinase under the control of the Pet1 enhancer region, which leads to a near-complete (>99%) loss of serotonergic neurons. Here we used flow through plethysmography to determine if there is a breathing defect in female CKO mice. During room air breathing, minute ventilation (VE; normalized to weight) was lower (P<0.05), but metabolic rate (VO2; normalized to weight) was not different between wild type (WT) (n=5) and CKO (n=5) mice. VE was less in 50% O2 relative to room air, but there were no differences in VE, VT or frequency between WT (n=5) and CKO (n=7) mice. However, there was a significant attenuation of the response to hypercapnia in 50% O2, to 35–40% of control at CO2 = 5% (p<0.001) & 7% (p<0.01), particularly due to an attenuated frequency response. The slope of the CO2 response curve (ΔVE/ΔCO2) in CKO mice was linear over the range from 0–7% CO2, and reduced to 38% of that in WT mice. Interestingly, the CO2 response was only attenuated to 72% of control at 10% CO2, suggesting that other chemoreceptors play a greater role at very high CO2 levels. Additionally, CKO mice exhibit a small deficit in the hypoxic ventilatory response (VE/VO2) to 80% of control (P<0.01). Thus, a >99% loss of serotonergic neurons greatly blunts the hypercapnic ventilatory response and to a lesser extent the hypoxic ventilatory response without an effect on metabolic rate. Supported by the NIH and VAMC.