Proceedings of The Physiological Society
University College Dublin (2009) Proc Physiol Soc 15, C102
Reduced synaptic inhibition underlies respiratory apneas in a mouse model of Rett syndrome (RTT).
A. P. Abdala2, M. Dutschmann3, J. M. Bissonnette1, J. F. Paton2
1. Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon, USA. 2. Physiology & Pharmacology, University of Bristol, Bristol, United Kingdom. 3. Membrane & Systems Biology, University of Leeds, Leeds, United Kingdom.
RTT is a neurodevelopmental disorder caused by mutations in the X-linked gene that encodes the transcription factor methyl-CpG-binding protein 2 (Mecp2) (1). Included in the phenotype are respiratory disorders that include frequent apneas and periodic breathing that are most prevalent in young females (2). Heterozygous female mice (Mecp2+/-) with deletion of the 3rd and 4th exons of Mecp2 mimic these respiratory disturbances but the central neuronal mechanisms have not been fully determined. We have hypothesized that insufficient GABAA synaptic inhibition underlies these respiratory disorders and augmenting GABA in awake animals reduces their incidence. Studies were carried out in B6.129P2(C) tm1.1Bird (3) heterozygous females (Mecp2+/-) and wild type littermates (Mecp2+/+) using an in situ preparation to record phrenic, central vagal (cVN), hypoglossal (HN) and abdominal (ABD) nerve activity (4). Animals were anaesthetized deeply with 5% halothane and once they failed to respond to noxious pinching of a paw and the tail were decerebrated. Apneas (TE ≥ 1.0 s) were more frequent in Mecp2+/- (168.2±29.1/hr) (SEM) (n=9) than Mecp2+/+ mice (56.8±12.9/hr) (n=13) (p= 0.005, Student t test). Apneas were characterized by prolonged postinspiratory activity in cVN (as observed previously in male Mecp2-/y mice;(5)) that terminated before the end of phrenic apnea. In addition, during the apnea there was a hypoglossal nerve discharge that occurred at the time a phrenic burst was anticipated from the respiratory cycle length of preceding bursts. This continued throughout the duration of the apnea (Fig). In some apneas the abdominal nerve exhibited a sustained burst. 1-[2-[[(Diphenylmethylene)imino] oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NO-711), 5 - 10µM in the perfusate was used to block GABA reuptake. Apneas were reduced from 152.3±12.1 to 115.3±16.0/hr (p=0.009, n=5) in Mecp2+/- mice. The apneas that remained after NO-711 were characterized by a shorter duration, lower activity in HN and absence of activity in ABD, consistent with reduced excitability of the network or increased synaptic inhibition. The results suggest that apnea in this mouse model of RTT results from, in part, insufficient GABA mediated synaptic inhibition in the ponto-medullary respiratory network leading to a loss of rhythmic phrenic bursts.
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