Remodelling of the respiratory network in a mouse model of Rett syndrome depends on brain-derived neurotrophic factor regulated slow calcium buffering

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Abstract

Rett syndrome caused by MeCP2 mutations is a devastating neurodevelopmental disorder accompanied by severe breathing irregularities. Using transduction of organotypic slices from model MeCP2-/y mice with neuron-specific calcium sensor protein D3cpv, we examined the slow calcium buffering in neurons in pre-Bötzinger complex (preBötC), a component of the complex respiratory network. Examination of wild-type (WT) and MeCP2 null mice showed clear differences in the spatial organisations of neurons in preBötC and also in the disturbances in calcium homeostasis in mutant mice during early postnatal development. Deregulated calcium buffering in MeCP2-/y neurons was indicated by increased amplitude and kinetics of depolarisation-induced calcium transients. Both effects were related to an insufficient calcium uptake into the endoplasmic reticulum that was restored after pretreatment with brain-derived neurotrophic factor (BNDF). Conversely, the inhibition of BDNF signalling in WT neurons produced disturbances similar to those observed in MeCP2-/y mice. Brief hypoxia and calcium release from internal stores induced global calcium increases, after which the processes of many MeCP2-/y neurons were retracted, an effect that was also corrected by pretreatment with BDNF. The data obtained point to a tight connection between calcium homeostasis and long-term changes in neuronal connectivity. We therefore propose that calcium-dependent retraction of neurites in preBötC neurons can cause remodelling of the neuronal network during development and set up the conditions for appearance of breathing irregularities in Rett model mice.

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