Restoring EEAquilibrium: rebalancing excitation and inhibition in Rett mouse model neurons with early endosome antigen‐1

Rett syndrome is a neurological disorder resulting from loss of function of MECP2, an X-linked transcription factor, which controls the expression of hundreds of genes involved in synapse formation and development by binding primarily to methylated DNA. A body of evidence shows deficits in dendritic structure and the formation and maintenance of neural circuits throughout the CNS resulting in cognitive, motor and sensory dysfunction that appear several months after birth. Restoring Mecp2 gene function can reverse even advanced symptoms in knockout (KO) Rett model mice reinforcing the view that this disorder is primarily due to improper wiring of otherwise intact circuits (Leonard et al. 2017). Electrophysiological studies from several brain areas indicate that MeCP2 loss-of-function alters excitation/inhibition (E/I) balance. Mecp2-KO mouse hippocampus is hyperactive due to an E/I imbalance and perhaps not surprisingly long-term potentiation (LTP) is affected. One approach to restoring proper circuit function targets neurotrophic factors or their downstream targets, which are downregulated in MeCP2-deficient mice. Another strategy currently in early stage clinical trials targets inflammatory pathways and microglial function potentially involved in synaptic pruning. In this issue of The Journal of Physiology, Xu and Pozzo-Miller take a more direct approach to restoring balanced neuronal connectivity by manipulating AMPA receptor trafficking (Xu & Pozzo-Miller, 2012). During development and in adult brain, neurons adjust their excitability and strength of synaptic inputs in response to ongoing neural activity by processes broadly defined as homeostatic plasticity and homeostatic scaling. Chronic enhancement or blockade of spiking or fast neurotransmission reveals homeostatic processes that alter synaptic strength and intrinsic neuronal excitability to maintain balanced activity (Turrigiano, 2008). Using primary cell cultures the authors show that MeCP2-null hippocampal neurons are bi-directionally deficient in their homeostatic capacity. They neither scale up the amplitude of miniature excitatory postsynaptic currents (mEPSCs) after silencing with tetrodotoxin (TTX), nor do they scale down amplitudes after blockade of inhibitory GABAA receptors with bicuculline. Amplitude versus variance analyses indicate that MeCP2-null neurons have proportionately more high conductance glutamic acid receptor 1 subunit (GluA1)-containing receptors compared to wild-type, which accounts for their larger amplitude and is posited to be the reason they fail to scale up with TTX. AMPA receptor removal mediates scaling down mEPSCs so the authors examined levels of early endosome antigen-1 (EEA1), which is a key element in their endocytosis. EEA1 mRNA and protein are reduced in Mecp2-KO hippocampus and increasing expression of EEA1 reduces mEPSC amplitudes to wild-type levels, although frequency remains high. Since KO mIPSCs are similar to wild-type the result is a near rebalancing of E/I for spontaneous release. Importantly it also mostly restores scaling down by GABAA blockade, consistent with an increased capacity for receptor endocytosis. Synaptic homeostasis is essential to normal brain function so this demonstration of a role for EEA1 levels in synaptic down-scaling in MeCP2-deficient neurons probably has implications beyond the cellular pathology of Rett syndrome. As with all good studies this one stimulates many questions. Why are mEPSC frequencies enhanced in MeCP2-null neurons and what can normalize this? Does increasing EEA1 normalize the density and subunit composition of receptors to be the same as in wild-type? Is scaling down by bicuculline in MeCP2-null neurons + EEA1 due to reduction in the number of AMPA receptors without a change in conductance as in wild-type? Does knockdown of EEA1 in wild-type neurons to levels equivalent to MeCP2-null neurons block synaptic scaling down? It will also be interesting to see to what extent, if any, normalizing EEA1 can restore normal LTP. The failure of TTX to scale up amplitude in MeCP2-null neurons may reflect an already high insertion rate of high conductance receptors, which is unchanged by EEA1. While baseline amplitudes are restored by EEA1 is LTP still compromised? Bicuculline scales down mEPSC amplitudes in EEA1-enhanced MeCP2-null neurons, but are these scaled down synapses still LTP impaired? If the problem is mainly one of available postsynaptic space for receptors then there may be scope for LTP to develop after scaling down. Phosphorylated MeCP2 is required for scaling down (Zhong et al. 2012). Xu and Pozzo-Miller have moved discussion downstream from MeCP2 to EEA1. Is there a link between phosphorylated MeCP2 and levels of EEA1? Although the study was performed using cultured neurons during a period spanning 7–11 days in vitro, well before the appearance of symptoms in mice, the effects are clear and suggest an early role for EEA1 in development of the Rett phenotype. Given the ubiquitous role of EEA1 in endosome cycling the trails into the receptor trafficking forest will surely lead in many directions. Cell culture studies facilitate detailed investigation of biochemical pathways but in vivo manipulation of EEA1 levels in Mecp2-KO mouse hippocampus is desired for both acute slice as well as behavioural studies. None declared.

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