Accumulation of Polyribosomes in Dendritic Spine Heads, But Not Bases and Necks, during Memory Consolidation Depends on Cap-Dependent Translation Initiation

Abstract

Translation in dendrites is believed to support synaptic changes during memory consolidation. Although translational control mechanisms are fundamental mediators of memory, little is known about their role in local translation. We previously found that polyribosomes accumulate in dendritic spines of the adult rat lateral amygdala (LA) during consolidation of aversive pavlovian conditioning and that this memory requires cap-dependent initiation, a primary point of translational control in eukaryotic cells. Here we used serial electron microscopy reconstructions to quantify polyribosomes in LA dendrites when consolidation was blocked by the cap-dependent initiation inhibitor 4EGI-1. We found that 4EGI-1 depleted polyribosomes in dendritic shafts and selectively prevented their upregulation in spine heads, but not bases and necks, during consolidation. Cap-independent upregulation was specific to spines with small, astrocyteassociated synapses. Our results reveal that cap-dependent initiation is involved in local translation during learning and that local translational control varies with synapse type.

Translational Control in the Brain in Health and Disease

“…This may indicate that ribosomes are a limiting resource in neurons, which would be consistent with stalled polysomes, sequestering many of the ribosomes in dendrites and thus making the number of ribosomes rate-limiting for basal translation. A study examining changes in polysomes after learning (Ostroff et al 2017) identified polysomes that are both sensitive and resistant to the initiation inhibitor 4EGI-1, which blocks the association of eIF4E and eIF4G, which is required for cap-dependent translation (Moerke et al 2007). In this study, the sensitive and resistant polysomes were differentially distributed at distinct types of synapses (Ostroff et al 2017).…”

“…A study examining changes in polysomes after learning (Ostroff et al 2017) identified polysomes that are both sensitive and resistant to the initiation inhibitor 4EGI-1, which blocks the association of eIF4E and eIF4G, which is required for cap-dependent translation (Moerke et al 2007). In this study, the sensitive and resistant polysomes were differentially distributed at distinct types of synapses (Ostroff et al 2017). It was unclear in this study, however, whether the 4EGI-1-resistant polysomes were stalled or initiated in a cap-independent (and thus 4EGI-1-independent) manner.…”

Role of a VGF/BDNF/TrkB Autoregulatory Feedback Loop in Rapid-Acting Antidepressant Efficacy

“…Growing evidence supports the existence of polyribosomes in dendritic spines with dynamic changes during associative fear learning (Jasinska et al 2013; Ostroff et al 2017). Rough endoplasmic reticulum (RER) and trans-Golgi-like compartments have also been identified in dendrites (Pierce et al 2001), providing evidence for a satellite secretory pathway in spines.…”

Synaptically driven phosphorylation of ribosomal protein S6 is differentially regulated at active synapses versus dendrites and cell bodies by MAPK and PI3K/mTOR signaling pathways

“…Alternatively, rpS6 may have some role independent of translation initiation (for review, see Meyuhas 2015). Compelling evidence shows that the positioning of ribosomes in spines is regulated by synaptic activity (Ostroff et al 2002) and following learning experiences (Ostroff et al 2017). For example, a recent study reveals that there are increases in polyribosomes within spines in neurons in the amygdala following aversive conditioning.…”

“…For example, a recent study reveals that there are increases in polyribosomes within spines in neurons in the amygdala following aversive conditioning. Also, infusion of the cap-dependent initiation inhibitor, 4EGI-1, disrupts training-induced polyribosome positioning and leads to decreases in polyribosomes in dendritic shafts and prevented accumulation of polyribosomes in spine heads whereas polyribosomes at spine bases were preserved (Ostroff et al 2017). A provocative idea is that phosphorylation of rpS6 via different signaling pathways may play a role in regulating ribosome trafficking in response to synaptic activity.…”