Deficiency of GABAergic synaptic inhibition in the Kölliker–Fuse area underlies respiratory dysrhythmia in a mouse model of Rett syndrome

Abstract

Key pointsr Life threatening breathing irregularity and central apnoeas are highly prevalent in children suffering from Rett syndrome.r Abnormalities in inhibitory synaptic transmission have been associated with the physiopathology of this syndrome, and may underlie the respiratory disorder.r In a mouse model of Rett syndrome, GABAergic terminal projections are markedly reduced in the Kölliker-Fuse nucleus (KF) in the dorsolateral pons, an important centre for control of respiratory rhythm regularity.r Administration of a drug that augments endogenous GABA localized to this region of the pons reduced the incidence of apnoea and the respiratory irregularity of Rett female mice. Conversely, the respiratory disorder was recapitulated by blocking GABAergic transmission in the KF area of healthy rats.r This study helps us understand the mechanism for generation of respiratory abnormality in Rett syndrome, pinpoints a brain site responsible and provides a clear anatomical target for the development of a translatable drug treatment.Abstract Central apnoeas and respiratory irregularity are a common feature in Rett syndrome (RTT), a neurodevelopmental disorder most often caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2). We used a MECP2 deficient mouse model of RTT as a strategy to obtain insights into the neurobiology of the disease and into mechanisms essential for respiratory rhythmicity during normal breathing. Previously, we showed that, systemic administration of a GABA reuptake blocker in MECP2 deficient mice markedly reduced the occurrence of central apnoeas. Further, we found that, during central apnoeas, post-inspiratory drive (adductor motor) to the upper airways was enhanced in amplitude and duration in Mecp2 heterozygous female mice. Since the pontine Kölliker-Fuse area (KF) drives post-inspiration, suppresses inspiration, and can reset the respiratory oscillator phase, we hypothesized that synaptic inhibition in this area is essential for respiratory rhythm regularity. In this study, we found that: (i) Mecp2 heterozygous mice showed deficiency of GABA perisomatic bouton-like puncta and processes in the KF nucleus; (ii) blockade of GABA reuptake in the KF of RTT mice reduced breathing irregularity; (iii) conversely, blockade of GABA A receptors in the KF of healthy rats mimicked the RTT respiratory phenotype of recurrent central apnoeas and prolonged post-inspiratory activity. Our results show that reductions in synaptic inhibition within the KF induce rhythm irregularity whereas boosting GABA transmission reduces respiratory arrhythmia in a murine model of RTT. Our data suggest that manipulation of synaptic inhibition in KF may be a clinically important strategy for alleviating the life threatening respiratory disorders in RTT.

Neurobiologically-based treatments in Rett syndrome: opportunities and challenges

“…In the next subsection, we provide more details about glutamatergic dysfunction, probably the best characterized neurotransmitter abnormality in RTT, and its potential role in the developmental regression that characterizes RTT [65]. More recently, MeCP2-related deficits in GABAergic neurons have been linked to a variety of clinical features in RTT [66–68]. MeCP2 deficiency in GABAergic neurons and abnormalities in GABA receptors may also lead to impairments in other GABA-dependent regulatory processes [69], excitatory-inhibitory imbalance [70], and epileptogenesis [71].…”

“…In addition to the relatively global neurotransmitter changes summarized above, there are complex patterns of interrelated abnormalities involving specific brain regions. The best examples are the changes in noradrenergic, serotoninergic, glutamatergic, and GABAergic components involving brainstem nuclei that regulate breathing [68,72,73]. The multiple disruptions in neurotransmitter systems suggest that, unless targeting the period in which the specific neurotransmitter abnormality plays the greatest role, the effects of treatment may be limited in range and duration.…”

C57BL/6J mouse apolipoprotein A2 gene is deterministic for apnea

“…The pause trait, as recapitulated by a prolonged time between two cycles, is seen in the in situ preparation. The network property could represent an active inhibition, like that seen in RETT syndrome mice (Abdala et al, 2016), or a failure of breath generation (Del Negro et al, 2005), or a combination of interactions (Abdala et al, 2009) influenced by the B6 apoa2 polymorphism.…”

Breathing abnormalities in animal models of Rett syndrome a female neurogenetic disorder

“…Reduced breathing irregularity in these female mice with RTT is achieved by directly microinjecting the GABA reuptake blocker NO-711 into the KF nucleus. Also blockade of GABA A Rs in the KF nucleus with microinjection of bicuculline induces typical respiratory irregularity in wild type Wistar rats (Abdala et al, 2016). These findings are consistent with the imbalanced inhibition/excitation affecting KF nucleus function in breathing regulation.…”