Towards a better diagnosis and treatment of Rett syndrome: a model synaptic disorder

Abstract

With the recent 50th anniversary of the first publication on Rett syndrome, and the almost 20 years since the first report on the link between Rett syndrome and MECP2 mutations, it is important to reflect on the tremendous advances in our understanding and their implications for the diagnosis and treatment of this neurodevelopmental disorder. Rett syndrome features an interesting challenge for biologists and clinicians, as the disorder lies at the intersection of molecular mechanisms of epigenetic regulation and neurophysiological alterations in synapses and circuits that together contribute to severe pathophysiological endophenotypes. Genetic, clinical, and neurobiological evidences support the notion that Rett syndrome is primarily a synaptic disorder, and a disease model for both intellectual disability and autism spectrum disorder. This review examines major developments in both recent neurobiological and preclinical findings of Rett syndrome, and to what extent they are beginning to impact our understanding and management of the disorder. It also discusses potential applications of knowledge on synaptic plasticity abnormalities in Rett syndrome to its diagnosis and treatment.

Figure 1

Altered synapse-specific computation in Rett syndrome. While different synapses in distinct parts of the brain are differentially modulated upon loss of MECP2, three essential ideas capture synaptic-specific changes that alter excitatory and inhibitory (E/I) balance and increase E/I ratio in animal models of Rett syndrome. (A) A significant reduction of thalamocortical feedforward excitatory drive to supragranular excitatory pyramidal neurons (PYR) and inhibitory parvalbumin (PV+) interneurons in the cortex has been found (Banerjee et al., 2016). (B) Weakening of excitatory drive could be resulted from a long-term depression (LTD) like mechanism at glutamatergic synapses (thalamocortical as well as intracortical), upon a downregulation of AMPA-type glutamate receptors (AMPA-R). A third mechanism (C) is a reduction of inhibitory currents can be due to altered GABAA receptor (GABAAR) mediated reversal potential in excitatory neurons. This is caused by a developmental delay in the maturation of GABAergic inhibition and a reduction in chloride exporter KCC2 expression (Banerjee et al., 2016). SST = somatostatin; VIP = vasoactive intestinal polypeptide.