Removing 4E-BP Enables Synapses to Refine without Postsynaptic Activity

Abstract

Summary: Throughout the developing nervous system, considerable synaptic re-organization takes place as postsynaptic neurons extend dendrites and incoming axons refine their synapses, strengthening some and eliminating others. It is well accepted that these processes rely on synaptic activity; however, the mechanisms that lead to this developmental reorganization are not fully understood. Here, we explore the regulation of cap-dependent translation, a mechanism known to play a role in synaptic growth and plasticity. Using sympathetic ganglia in α3 nicotinic acetylcholine receptor (nAChR)-knockout (KO) mice, we establish that electrophysiologically silent synapses between preganglionic axons and postsynaptic sympathetic neurons do not refine, and the growth of dendrites and the targeting of synapses on postsynaptic neurons are impaired. Remarkably, genetically removing 4E-BP, a suppressor of cap-dependent translation, from these α3 nAChR-KO mice largely restores these features. We conclude that synaptic connections can re-organize and refine without postsynaptic activity during post-natal development when 4E-BP-regulated cap-dependent translation is enhanced. : Synaptic activity is required for synaptic refinement and reorganization during post-natal development. Chong et al. find that silent synapses in superior cervical ganglia (SCG) refine when 4E-BP is genetically removed, suggesting that enhanced cap-dependent translation promotes synaptic refinement in the absence of postsynaptic activity. Keywords: sympathetic neurons, cap-dependent translation, synaptic refinement, synaptic activity, nicotinic receptors, silent synapses