Effect of Positive Allosteric Modulation of Dopamine D2 Receptors on Respiration in Mouse Models of Rett Syndrome

Abstract

Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the methyl-CPG-binding protein 2 (Mecp2) gene. Frequent apneas and respiratory disturbances are prevalent in Rett syndrome, and also occur in rodent models of the disorder, including Mecp2Bird and Mecp2R168X mice. Prior research has demonstrated that sarizotan, a serotonin 5-HT1a and dopamine D2-like receptor agonist, reduces the incidence of apneas and irregular breathing in mouse models of RTT. However, the contribution of D2 receptors in correcting these respiratory disturbances remains untested. Given that D2 receptors inhibit expiratory neurons in the parabrachial complex and the caudal ventral respiratory group, we hypothesized that compounds targeting the D2 receptor would correct apnea and irregular breathing in mouse models of RTT by enhancing dopamine responses in expiratory neurons. PAOPA, the dopamine D2 receptor positive allosteric modulator, and quinpirole, a dopamine D2 receptor agonist, were used in conjunction with whole-body plethysmography to evaluate whether activation of D2 receptors is sufficient to restore a normal respiratory phenotype in Mecp2Bird and Mecp2R168X mice. There were no significant differences in apnea incidence or irregularity score between saline and PAOPA treated RTT mice. PAOPA also had no effect on the ventilatory response to hypercapnia (7 % CO2). These results suggest that dopamine D2 receptor activity may not be an ideal candidate in the correction of respiratory abnormalities in Rett syndrome.