DIPHTHERIA TOXIN TREATMENT OF PET-1-CRE FLOXED DIPHTHERIA TOXIN RECEPTOR MICE DISRUPTS THERMOREGULATION WITHOUT AFFECTING RESPIRATORY CHEMORECEPTION

In genetically-modified Lmx1b(f/f/p) mice, selective deletion of LMX1B in Pet-1 expressing cells leads to failure of embryonic development of serotonin (5-HT) neurons. As adults, these mice have a decreased hypercapnic ventilatory response and abnormal thermoregulation. This mouse model has been valuable in defining the normal role of 5-HT neurons, but it is possible that developmental compensation reduces the severity of observed deficits. Here we studied mice genetically modified to express diphtheria toxin receptors (DTR) on Pet-1 expressing neurons (Pet-I-Creffioxed DTR or Pet1/DTR mice). These mice developed with a normal complement of 5-HT neurons. As adults, systemic treatment with 2-35 itg of diphtheria toxin (DT) reduced the number of tryptophan hydroxylaseimmunoreactive (TpOH-ir) neurons in the raphe nuclei and ventrolateral medulla by 80%. There were no effects of DT on minute ventilation (V-E) or the ventilatory response to hypercapnia or hypoxia. At an ambient temperature (T-A) of 24 degrees C, all Pet1/DTR mice dropped their body temperature (TB) below 35 degrees C after DT treatment, but the latency was shorter in males than females (3.0 +/- 0.37 vs. 4.57 +/- 0.29 days, respectively; p < 0.001). One week after DT treatment, mice were challenged by dropping T-A from 37 degrees C to 24 degrees C, which caused TB to decrease more in males than in females (29.7 +/- 0.31 C vs. 33.0 +/- 1.3 degrees C, p <0.01). We conclude that the 20% of 5-HT neurons that remain after DT treatment in Pet1/DTR mice are sufficient to maintain normal baseline breathing and a normal response to CO2, while those affected include some essential for thermoregulation, in males more than females. In comparison to models with deficient embryonic development of 5-HT neurons, acute deletion of 5-HT neurons in adults leads to a greater defect in thermoregulation, suggesting that significant developmental compensation can occur. (c) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.