Abstract
Differential trafficking of AMPA receptors (AMPARs) to and from the postsynaptic membrane is a key determinant of the strength of excitatory neurotransmission, and is thought to underlie learning and memory. The transcription factor MEF2 is a negative regulator of memory in vivo, in part by regulating trafficking of the AMPAR subunit GluA2, but the molecular mechanisms behind this have not been established. Here we show, via knockdown of endogenous MEF2A in primary neuronal culture, that MEF2A is specifically required for Group I metabotropic glutamate receptor (mGluR)-mediated GluA2 internalisation, but does not regulate AMPAR expression or trafficking under basal conditions. Furthermore, this process occurs independently of changes in expression of Arc/Arg3.1, a previously characterised MEF2 transcriptional target and mediator of mGluR-dependent long-term depression. These data demonstrate a novel MEF2A-dependent mechanism for the regulation of activity-dependent AMPAR trafficking.
Highlights
MEF2 proteins are best characterised as regulators of the structural changes that occur during synapse formation, differentiation and plasticity
It has been proposed that the effect of MEF2 on memory is, at least in part, mediated by the activity induced immediate early gene product Arc/Arg3.1 (Arc), which is a key regulator of AMPAR trafficking in certain forms of plasticity[18]
We show that ablating MEF2A expression does not alter total or surface levels of AMPAR subunits under basal conditions
Summary
Manipulation of MEF2A expression does not affect total AMPAR expression under basal conditions. There was no difference in mEPSC kinetics between shMEF2A and control cells (Supp Fig. 2), suggesting MEF2A knockdown does not affect basal synaptic AMPAR subunit composition or properties Together, these results demonstrate that MEF2A does not play a role in the total or surface expression of AMPARs under basal conditions, but is important for maintaining a normal number of functional AMPAR-containing synapses. MEF2A knockdown for four days in cortical neurons did not reduce Arc protein levels under basal conditions or compromise the induction of Arc following DHPG-mediated Group I mGluR activation (Fig. 4), even though mGluR-dependent AMPAR internalisation was completely blocked in the absence of MEF2A (Fig. 3A). How neuronal activity modulates MEF2A to regulate this function, and which MEF2A target genes mediate its effect, are intriguing future questions
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