4E-BP2-dependent translational control in GABAergic interneurons is required for long-term memory

Abstract mRNA translational repression by eukaryotic initiation factor 4E-binding proteins (4E-BPs), plays a critical role in synaptic plasticity and the formation of long-term memory (LTM). Among the three 4E-BP paralogs, 4E-BP2 is the predominant form expressed in neurons, and its full-body deletion in mice causes memory deficits. Mice lacking 4E-BP2 in GABAergic inhibitory interneurons, but not excitatory neurons, display autistic-like behaviors and deficits in object location and recognition. The specific mRNAs translationally regulated by 4E-BP2 in GABAergic interneurons, and how they contribute to spatial and associative memory, are unknown. Here, we show that conditional knockout (cKO) mice lacking 4E-BP2 selectively in GABAergic interneurons exhibit impairments in long-term spatial and contextual fear memory formation. We further demonstrate that 4E-BP2 deletion controls the translation of selective mRNAs in interneurons without increasing general protein synthesis. One of the mRNAs is Gal , which encodes a neuropeptide that modulates memory. Our findings provide evidence that 4E-BP2 selectively controls the translation of a subset of mRNAs in inhibitory neurons that are required for LTM formation.