Upregulation of eIF4E, but not other translation initiation factors, in dendritic spines during memory formation

Abstract

Local translation can provide a rapid, spatially targeted supply of new proteins in distal dendrites to support synaptic changes that underlie learning. Learning and memory are especially sensitive to manipulations of translational control mechanisms, particularly those that target the initiation step, and translation initiation at synapses could be a means of maintaining synapse specificity during plasticity. Initiation predominantly occurs via recruitment of ribosomes to the 5 0 mRNA cap by complexes of eukaryotic initiation factors (eIFs), and the interaction between eIF4E and eIF4G1 is a particularly important target of translational control pathways. Pharmacological inhibition of eIF4E-eIF4G1 binding impairs formation of memory for aversive Pavlovian conditioning as well as the accompanying increase in polyribosomes in the heads of dendritic spines in the lateral amygdala (LA). This is consistent with a role for initiation at synapses in memory formation, but whether eIFs are even present near synapses is unknown. To determine whether dendritic spines contain eIFs and whether eIF distribution is affected by learning, we combined immunolabeling with serial section transmission electron microscopy (ssTEM) volume reconstructions of LA dendrites after Pavlovian conditioning. Labeling for eIF4E, eIF4G1, and eIF2α-another key target of regulation-occurred in roughly half of dendritic spines, but learning effects were only found for eIF4E, which was upregulated in the heads of dendritic spines. Our results support the possibility of regulated translation initiation as a means of synapse-specific protein targeting during learning and are consistent with the model of eIF4E availability as a central point of control.

Persistent up-regulation of polyribosomes at synapses during long-term memory, reconsolidation, and extinction of associative memory

“…3 D). In the LA, the spine apparatus is always present in the largest spines (PSD area >0.1 µm 2 ) but appears in some small spines as well ( Gindina et al 2021 ). Thus, we wondered whether the spine apparatus would account for the extra spines with polyribosomes, regardless of size.…”

“…2 E), but whether these represent separate processes or a single pool that is regulated collectively is an open question. The presence of translation initiation factors in dendritic spine heads ( Gindina et al 2021 ) suggests that some translational control is compartmentalized at the level of individual synapses. On the other hand, synapses in the same compartment can share new proteins during plasticity ( Sajikumar et al 2007 ), which could reflect a common pool of polyribosomes.…”

“…Since large synapses are stronger and thus could represent learning-related potentiation ( Nusser 2000 ; Matsuzaki et al 2004 ; Bourne and Harris 2007 ; Nicholson and Geinisman 2009 ), we hypothesized that if polyribosomes remained up-regulated in the long-term memory phase they would be associated with the largest spines. Likewise, because the spine apparatus is associated with learning and memory ( Deller et al 2007 ) and is present in all large spines ( Gindina et al 2021 ), we hypothesized that excess polyribosomes would be associated with the spine apparatus. Contrary to these expectations, polyribosomes remained up-regulated in spines of all sizes and in spines with and without a spine apparatus.…”

“…Synaptic activity during learning triggers a transient up-regulation of new synaptic proteins in dendrites ( Redondo and Morris 2011 ; Moncada et al 2015 ), and the spatiotemporal constraints on these new proteins strongly suggest that they are translated locally ( Sajikumar et al 2007 ; Doyle and Kiebler 2011 ). We have previously found by serial section transmission electron microscopy (ssTEM) volume reconstruction that polyribosomes and translation factors are up-regulated in dendritic spines in the rat lateral amygdala (LA) 1 h after cued aversive Pavlovian conditioning ( Ostroff et al 2010 , 2017 ; Gindina et al 2021 ). These polyribosomes presumably represent translation supporting consolidation, but no studies have addressed whether dendritic translation remains elevated or returns to baseline in the long-term memory phase.…”

Spine morphogenesis and synapse formation in tubular sclerosis complex models

“…A recent study revealed that synapse input induced an accumulation of eIF4E in the spine head. After the tone-shock fear conditioning test, accumulation of eIF4E protein was observed in the spine heads of the rat brain ( Gindina et al, 2021 ). There were more eIF4E-accumulated spines in the brains of trained rats at both the smaller (0.05–0.1 μm 2 ) and larger (> 0.2 μm 2 ) spine head areas of the range ( Gindina et al, 2021 ).…”