Habituation without NMDA Receptor-Dependent Desensitization of Hering–Breuer Apnea Reflex in a Mecp2+/− Mutant Mouse Model of Rett Syndrome

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.

Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X

“…Two other studies have found an asymptomatic as well as a symptomatic population of Mecp2 deficient female mice (Song et al, 2011) (Schmid et al, 2012). As noted above both studies used Mecp2 Jae/+ females.…”

“…However, the normal respiratory frequency we observed in Mecp2 T158A/+ mice and the decrease in respiratory frequency in Mecp2 R168X/+ mice differ from the human findings. In contrast, an increase in frequency was found in Mecp2 Jae/+ heterozygous female mice (Song et al, 2011) (Schmid et al, 2012). The frequency in Mecp2 Bird/+ heterozygous female mice, on two different background strains, however, was the same as their respective wild type littermates (Samaco et al, 2013).…”

“…PHFD requires intact signaling from neurons in the ventrolateral pons and depends on NMDA receptor function (Dick and Coles, 2000). While impaired NMDA receptor signaling has been demonstrated in symptomatic, but not asymptomatic, Mecp2 Jae/+ female mice (Song et al, 2011), the extent to which alterations in NMDA function and EPSCs in the NTS contribute to hypoxic ventilatory response in Mecp2 T158A/+ and Mecp2 R168X/+ mice has yet to be studied.…”

Learning to breathe: Habituation of Hering–Breuer inflation reflex emerges with postnatal brainstem maturation

“…Both human patients and Mecp2 mice develop a severe respiratory disorder after they emerge from the neonatal period (see Katz et al, 2009). Investigators suggest that a lack of HBR habituation (Stettner et al, 2007; Song et al, 2011) may contribute to instability of the breathing pattern due to competing sensory and central mechanisms impinging on the IOS.…”

The competitive NMDA receptor antagonist CPP disrupts cocaine-induced conditioned place preference, but spares behavioral sensitization

“…Indeed, some forms of non-associative learning do not require the mechanisms typically implicated in associative learning. For example, habituation of the Hering-Breuer apnea reflex in the primary vagal pathway, a classic model of non-associative memory, recruits NMDAR-independent plasticity [88]. Likewise, mossy fiber longterm potentiation is NMDAR-independent and often non-Hebbian [89]; it can be induced without any post-synaptic activity or calcium influx at all [90].…”