Altered responses of MeCP2-deficient mouse brain stem to severe hypoxia

Abstract

Rett syndrome (RTT) patients suffer from respiratory arrhythmias with frequent apneas causing intermittent hypoxia. In a RTT mouse model (methyl-CpG-binding protein 2-deficient mice; Mecp2(-/y)) we recently discovered an enhanced hippocampal susceptibility to hypoxia and hypoxia-induced spreading depression (HSD). In the present study we investigated whether this also applies to infant Mecp2(-/y) brain stem, which could become life-threatening due to failure of cardiorespiratory control. HSD most reliably occurred in the nucleus of the solitary tract (NTS) and the spinal trigeminal nucleus (Sp5). HSD susceptibility of the Mecp2(-/y) NTS and Sp5 was increased on 8 mM K(+)-mediated conditioning. 5-HT(1A) receptor stimulation with 8-hydroxy-2-(di-propylamino)tetralin (8-OH-DPAT) postponed HSD by up to 40%, mediating genotype-independent protection. The deleterious impact of HSD on in vitro respiration became obvious in rhythmically active slices, where HSD propagation into the pre-Bötzinger complex (pre-BötC) immediately arrested the respiratory rhythm. Compared with wild-type, the Mecp2(-/y) pre-BötC was invaded less frequently by HSD, but if so, HSD occurred earlier. On reoxygenation, in vitro rhythms reappeared with increased frequency, which was less pronounced in Mecp2(-/y) slices. 8-OH-DPAT increased respiratory frequency but failed to postpone HSD in the pre-BötC. Repetitive hypoxia facilitated posthypoxic recovery only if HSD occurred. In 57% of Mecp2(-/y) slices, however, HSD spared the pre-BötC. Although this occasionally promoted residual hypoxic respiratory activity ("gasping"), it also prolonged the posthypoxic recovery, and thus the absence of central inspiratory drive, which in vivo would lengthen respiratory arrest. In view of the breathing disorders in RTTs, the increased hypoxia susceptibility of MeCP2-deficient brain stem potentially contributes to life-threatening disturbances of cardiorespiratory control.

Increased Mitochondrial Mass and Cytosolic Redox Imbalance in Hippocampal Astrocytes of a Mouse Model of Rett Syndrome: Subcellular Changes Revealed by Ratiometric Imaging of JC‐1 and roGFP1 Fluorescence

“…As structural changes, or even mitochondrial fragmentation, are quite commonly induced by FCCP [70, 82]; this explains the decreased mitochondrial length and increased number of individual mitochondria detected in some of the WT and Mecp2 −/y astrocytes upon mitochondrial uncoupling. The inhibition of respiratory complex IV by CN − also markedly depolarized mitochondria; the trend towards a more intense depolarization of Mecp2 −/y astrocytes may reflect the increased hypoxia susceptibility we found earlier in the hippocampal and brainstem slices of Mecp2 −/y mice [69, 83–85]. Furthermore, mitochondria of Mecp2 −/y astrocytes became slightly smaller upon CN − treatment.…”

“…Therefore, as pronounced genotype-related changes were not detected for mitochondrial size, mitochondrial content, and ΔΨm, it has to be assumed that mitochondria in WT and Mecp2 −/y astrocytes do not noticeably differ in their vulnerabilities to uncoupling and chemical hypoxia. In view of the earlier detected increased hypoxia susceptibility of hippocampal and brainstem networks of MeCP2-deficient mice [69, 85], this is an important finding. Yet, it also has to be considered that the pharmacological challenges applied in the present study were quite intense.…”

Brain Activity Mapping inMecp2Mutant Mice Reveals Functional Deficits in Forebrain Circuits, Including Key Nodes in the Default Mode Network, that are Reversed with Ketamine Treatment

“…Studies of RTT mice suggest there may be regional differences in how loss of MeCP2 affects neural circuits (Shepherd and Katz, 2011). For example, hyperexcitability is a widespread feature of brainstem nuclei in the respiratory pattern-generating network, including the medial nucleus tractus solitarius (Kline et al, 2010; Kron et al, 2011), the preBoetzinger complex (Medrihan et al, 2008), the nucleus Kölliker Fuse (Stettner et al, 2007) and the locus ceruleus (Taneja et al, 2009), as well as hippocampus (Moretti et al, 2006; Zhang et al, 2008; Fischer et al, 2009; Calfa et al, 2011; Nelson et al, 2011). On the other hand, excitatory synaptic transmission is reduced in microcircuits within sensory and motor-frontal cortices (Dani et al, 2005; Dani and Nelson, 2009; Wood et al, 2009; Wood and Shepherd, 2010).…”

Temporo-Spectral Imaging of Intrinsic Optical Signals during Hypoxia-Induced Spreading Depression-Like Depolarization

“…Hence there is an increasing use of the optical approach, often in combination with electrophysiological recordings from defined locations to benefit from the mutual complementation of the specific advantages of both techniques. To list just a few examples, we have used IOS analyses in the past in isolated rodent brain tissue to confirm that SD also occurs in brainstem [21], to analyze its propagation pattern in neurodevelopmental disorders [22], [23], and to define the impact of drugs on SD onset and propagation [24], [25], [26]. An IOS with very similar properties to that in rodent preparations has also been recorded in human brain slices [27], [28]).…”