EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice

Abstract

Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Deletion of Mecp2 in mice results in an imbalance of synaptic excitation and inhibition in hippocampal pyramidal neurons, which affects "Hebbian" long-term synaptic plasticity. Since the excitatory/inhibitory (E/I) balance is maintained by homeostatic mechanisms, we examined the role of MeCP2 in homeostatic synaptic plasticity (HSP) at excitatory synapses. Negative feedback HSP, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. Hippocampal neurons from Mecp2 knockout (KO) mice do not show the characteristic homeostatic scaling-up of the amplitude of miniature excitatory postsynaptic currents (mEPSC) and of synaptic levels of GluA1 after 48-hour silencing with the Na⁺ channel blocker tetrodotoxin (TTX). This deficit in HSP is bidirectional because Mecp2 KO neurons also failed to scale-down mEPSC amplitudes and GluA1 synaptic levels after 48 h blockade of GABA_AR-mediated inhibition with bicuculline. Consistent with the role of synaptic trafficking of AMPA-type of glutamate receptors (AMPAR) in HSP, Mecp2 KO neurons have lower levels of early-endosome-antigen-1 (EEA1), a protein involved in AMPAR endocytosis. In addition, expression EEA1 in Mecp2 KO neurons reduced mEPSC amplitudes to WT levels, and restored synaptic scaling-down of mEPSC amplitudes after 48 h blockade of GABA_AR-mediated inhibition with bicuculline. The identification of a molecular deficit in HSP in Mecp2 KO neurons provides potentially novel targets of intervention for improving hippocampal function in RTT individuals.

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