Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders

Abstract

Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-function mutations in MECP2, display impaired excitatory neurotransmission, the RTT phenotype can be largely reproduced in mice simply by removing MeCP2 from inhibitory GABAergic neurons. To determine what role excitatory signaling impairment might play in RTT pathogenesis, we generated conditional mouse models with Mecp2 either removed from or expressed solely in glutamatergic neurons. MeCP2 deficiency in glutamatergic neurons leads to early lethality, obesity, tremor, altered anxiety-like behaviors, and impaired acoustic startle response, which is distinct from the phenotype of mice lacking MeCP2 only in inhibitory neurons. These findings reveal a role for excitatory signaling impairment in specific neurobehavioral abnormalities shared by RTT and other postnatal neurological disorders.DOI: http://dx.doi.org/10.7554/eLife.14199.001

Are microRNAs true sensors of ageing and cellular senescence?

“…Consistent with rapid aging and neurodegeneration, increased expression of KSRP also resulted in a decrease in axonal outgrowth via downregulation of the growth factor GAP-43’s mRNA (Bird et al, 2013). Decreasing expression of MeCP2 in glutamatergic neurons of mice led to a shorter lifespan and various neurological abnormalities (Meng et al, 2016). All in all, regulation at the level of miRNA synthesis could have dire consequences on the lifespan of cells.…”

Paradoxical physiological responses to propranolol in a Rett syndrome patient: a case report

“…Recent evidence has shown that MeCP2 R306C mutation prevents it from interacting with the NCoR/histone deacetylase 3 (HDAC3) complex, which causes impairments in social and cognitive functioning [18]. In the developing brain stem, this impairment will more than likely have downstream effects such as perturbations in excitatory [19] and inhibitory [20] pathways, which in turn will have knock-on effects on vital brain regions implicated in sympathetic and parasympathetic elements of the autonomic nervous system (ANS). Any imbalance will result in dysautonomia; however whilst, autonomic manifestations in RTT include anxiety, pupillary dilation [21], raised serotonin receptor binding in brain stem nuclei [22], low vagal tone with poor vagal response to hyperventilation [23], lower heart rate variability with prolonged QTcF [15] and uncontrolled albeit normal sympathetic tone due to minimal negative feedback of the parasympathetic system [24], due to the inherent heterogeneous plasticity of RTT particularly in terms of maturity-related brainstem functioning [25], these manifestations are more than likely to differ between individuals and so the precise trajectory in terms of the developmental progression of dysautonomia in RTT is at the moment unclear.…”

Clinical and biological progress over 50 years in Rett syndrome

“…32 In contrast, deletion from glutamatergic cells causes anxiety and tremor. 40 Interestingly, postnatal deletion of Mecp2, even within a mature nervous system, results in RTT-like phenotypes. 41,42 In contrast, activation of a previously silenced Mecp2 allele globally, or within GABAergic neurons, reverses many established RTT-like phenotypes including locomotor, behavioural and aberrant functional and structural synaptic plasticity (see Fig 1).…”