Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly

De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement.

Improving second language vocabulary learning and retention by leveraging memory enhancement techniques: A multidomain pedagogical approach

We investigated whether learning and retaining vocabulary in a second language (L2) can be improved by leveraging a combination of memory enhancement techniques. Specifically, we tested whether combining retrieval practice, spacing, and related manipulations in a ‘multidomain’ pedagogical approach enhances vocabulary acquisition as compared to a typical learning approach. In a classroom-laboratory design, 48 Turkish university students studying L2 English were trained on 64 English words over 17 days. They were assigned to either a ‘typical’ study regimen of (re)studying the words on the first day (initial study) and last day (cramming) of training, or an ‘optimized’ regimen of retrieval practice (retrieving the words), moreover with feedback, spaced throughout the period, moreover with expanding gaps. The target words were tested before training (pre-test) and one and 11 days afterwards (post-tests). Mixed-effects modeling revealed a training-group by test-session interaction, due to greater improvements from optimized training (a striking 18 percentage-point accuracy increase from pre-test to both post-tests) than typical training (an 8 percentage-point increase). Further analyses showed that the optimized training advantages were mainly driven by high (rather than low) frequency words. Overall, the results suggest that a multidomain approach of combining different memory enhancement techniques can lead to substantial gains in both the learning and retention of L2 words, as compared to a typical study pattern. The findings have implications for L2 learning and pedagogy.

Mnemonic prediction errors promote detailed memories

When our experience violates our predictions, it is adaptive to update our knowledge to promote a more accurate representation of the world and facilitate future predictions. Theoretical models propose that these mnemonic prediction errors should be encoded into a distinct memory trace to prevent interference with previous, conflicting memories. We investigated this proposal by repeatedly exposing participants to pairs of sequentially presented objects (A → B), thus evoking expectations. Then, we violated participants’ expectations by replacing the second object in the pairs with a novel object (A → C). The following item memory test required participants to discriminate between identical old items and similar lures, thus testing detailed and distinctive item memory representations. In two experiments, mnemonic prediction errors enhanced item memory: Participants correctly identified more old items as old when those items violated expectations during learning, compared with items that did not violate expectations. This memory enhancement for C items was only observed when participants later showed intact memory for the related A → B pairs, suggesting that strong predictions are required to facilitate memory for violations. Following up on this, a third experiment reduced prediction strength prior to violation and subsequently eliminated the memory advantage of violations. Interestingly, mnemonic prediction errors did not increase gist-based mistakes of identifying old items as similar lures or identifying similar lures as old. Enhanced item memory in the absence of gist-based mistakes suggests that violations enhanced memory for items’ details, which could be mediated via distinct memory traces. Together, these results advance our knowledge of how mnemonic prediction errors promote memory formation.

EXPRESS: Automatically binding relevant and irrelevant features in visual working memory

It is generally assumed that, in order to save storage space, features are stored as integrated objects in visual working memory (VWM). Although such an object-based account does not always hold because features can be processed in parallel, a previous study has shown that different features can be automatically bound with their locations (task-irrelevant feature) into an integrated unit, resulting in improved memory performance (Wang, Cao, Theeuwes, Olivers, & Wang, 2016). The present study was designed to further explore this phenomenon by investigating whether other features, that are not spatial in origin, can act as the binding cue to form such automatical binding. To test this, we used three different features as binding cues (i.e., color, spatial frequency, and shape) over multiple separate experiments. The results consistently showed that when two features shared the same binding cue, memory performance was better relative to when each of those features had their own binding cue. We conclude, that any task-irrelevant feature can act as a binding cue to automatically bind with task-relevant features even across different objects, resulting in memory enhancement.

Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly

De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mTOR kinase and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement.