Abstract
Non-associative learning is a basic neuroadaptive behavior exhibited in almost all animal species and sensory modalities but its functions and mechanisms in the mammalian brain are poorly understood. Previous studies have identified two distinct forms of non-associative learning in the classic Hering–Breuer inflation reflex (HBIR) induced apnea in rats: NMDA receptor (NMDAR)-independent habituation in a primary vagal pathway and NMDAR-dependent desensitization in a secondary pontine pathway. Here, we show that abnormal non-associative learning of the HBIR may underlie the endophenotypic tachypnea in an animal model of Rett syndrome (RTT), an autism-spectrum disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Mecp2+/− symptomatic mice on a mixed-strain background demonstrated significantly increased resting respiratory frequency with shortened expiration and normal inspiratory duration compared with asymptomatic mutants and wild-type controls, a phenotype that is characteristic of girls with RTT. Low-intensity electrical stimulation of the vagus nerve elicited fictive HBIR with time-dependent habituation in both Mecp2+/− and wild-type mice. However, time-dependent desensitization of the HBIR was evidenced only in wild-type controls and asymptomatic mutant mice but was absent or suppressed in Mecp2+/− symptomatic mice or in wild-type mice after blockade of NMDAR with dizocilpine. Remarkably, ∼50% of the Mecp2+/− mice developed these X-linked phenotypes despite somatic mosaicism. Such RTT-like respiratory endophenotypes in mixed-strain Mecp2+/− mice differed from those previously reported in Mecp2-/y mice on pure C57BL/6J background. These findings provide the first evidence indicating that impaired NMDAR-dependent desensitization of the HBIR may contribute to the endophenotypic tachypnea in RTT.
Highlights
Rett syndrome (RTT) is a neurological disorder most frequently caused by sporadic mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2; Amir et al, 1999), a transcriptional activator/repressor that regulates the expression of many genes (Chahrour et al, 2008)
Pronounced habituation and desensitization of fictive Hering–Breuer inflation reflex (HBIR) in wild-type mice To test whether the reported sensitization of HBIR prolongation of TE in the Mecp2tm1.1Bird wild-type mice (Poon and Song, 2007; Stettner et al, 2007) was specific to the C57BL/6J strain, we examined the use-dependent learning and memory of the HBIR in the mixed-strain Mecp2tm1.1Jae wild-type mice using an established protocol that has been shown to reproduce the habituation and desensitization of the HBIR induced by sustained lung inflation www.frontiersin.org mice of the Mecp2tm1.1Jae strain, respiratory frequency was significantly decreased and TI was significantly increased (Figure 2), as previously reported in vagotomized rats and mice (Cassus-Soulanis et al, 1995)
A salient respiratory symptom of the Mecp2tm1.1Jae heterozygous mutant mice was a shortening of TE and resultant increase in respiratory frequency, which is diametrically opposite to the repetitive spontaneous central apnea or prolongation of TE in the Mecp2tm1.1Bird null mice (Viemari et al, 2005; Stettner et al, 2007; Abdala et al, 2010)
Summary
Rett syndrome (RTT) is a neurological disorder most frequently caused by sporadic mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2; Amir et al, 1999), a transcriptional activator/repressor that regulates the expression of many genes (Chahrour et al, 2008). Among the cardinal symptoms of RTT is a highly irregular respiratory rhythm during daytime (Kerr et al, 2001; Hagberg et al, 2002; Julu et al, 2008). Recent studies in these patients reveal a predominantly hyperventilatory pattern with decreased expiratory duration (TE) and increased respiratory frequency; during wakefulness this is punctuated by frequent episodes of breath-holding/obstructive apnea or Valsalva breathing against closed airways (Julu et al, 2001; Weese-Mayer et al, 2006, 2008). In Mecp2tm1.1Jae null (hemizygous) mice on a mixed-strain background (Chen et al, 2001) the principal phenotype is tachypnea along with hyperventilation similar to human RTT patients (Ogier et al, 2007), whereas in Mecp2tm1.1Bird null or heterozygous mice on a pure C57BL/6J background (Guy et al, 2001) the principal phenotype is repetitive spontaneous central apnea (Viemari et al, 2005; Stettner et al, 2007; Abdala et al, 2010)
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