Long-term Pannexin 1 Ablation Produces an Imbalance Between Small Rho-GTPases Activity and Actin Polymerization Leading to Structural and Functional Modifications in Hippocampal Neurons

Enhanced activity and overexpression of Pannexin 1 (PANX1) channels contribute to neuronal pathologies, such as epilepsy and Alzheimer’s disease (AD). In the hippocampus, the PANX1 channel ablation alters glutamatergic neurotransmission, synaptic plasticity, and memory flexibility. Nevertheless, PANX1-knockout (PANX1-KO) mice still preserve the ability to learn, suggesting that compensatory mechanisms work to stabilize neuronal activity. Here, we show that the absence of PANX1 in the adult brain promotes a series of structural and functional modifications in PANX1-KO CA1 hippocampal synapses, preserving spontaneous activity. Adult CA1 neurons of PANX1-KO mice exhibit enhanced excitability, a more complex dendritic branching, enhanced spine maturation, and multiple synaptic contacts compared to the WT condition. These modifications seem to rely on the actin-cytoskeleton dynamics as an increase in actin polymerization and an imbalance between Rac1 and RhoA GTPase activity is observed in the absence of PANX1. Our findings highlight a novel interaction between PANX1, actin, and small Rho GTPases, which appear to be relevant for synapse stability.

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.

3-year-old children’s memory flexibility allows adaptation to an altered context

Imitation provides a reliable method to investigate the developing memory functions in childhood. The present study explored whether 3-year-old children are able to revise their previous experiences after a 1 week delay in order to adapt to an altered context. We used a combined immediate (Session 1) and delayed (Session 2) imitation paradigm. The constraints (target object close/far) and relatedly the relevance of using a tool in a goal attainment task (irrelevant/relevant, respectively) changed between the sessions. We found that children in Session 1 used the tool only when it was needed (relevant/object far context). After the 1 week delay when the tool was previously irrelevant and then became relevant, children remembered the irrelevant act and applied it in the altered context. When the tool lost its relevance after 1 week, children used the tool less than before, but did not fully omit it, despite its reduced efficiency. We propose that the flexible restoration of a formerly irrelevant act and the maintenance of a formerly successful solution indicate flexibility of children’s memory when guiding imitation. This flexibility, however, interacts with children’s tendency to remain faithful to strategies that were previously ostensively demonstrated to them.

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.

Measures of bilingual cognition – from infancy to adolescence

An extensive literature exists regarding the effect of bilingualism on cognition in developing populations. However, the term ‘cognition’ is vague and applies to a large number of different abilities. We reviewed 57 publications examining cognition in simultaneous bilingual children to understand what aspects of cognition have been studied in this population and what tasks have been used, in addition to qualitatively assessing the results of bilingual/monolingual comparisons. Executive function was the most frequently assessed cognitive ability across all age groups, paralleling the adult bilingual literature, with memory flexibility and theory of mind also emerging as common targets within infant and preschool age groups. Results are discussed in light of developmental trajectories and assessment methodologies currently available for the cognitive abilities represented in this literature.

Proof of Concept for the Autobiographical Memory Flexibility (MemFlex) Intervention for Posttraumatic Stress Disorder

Autobiographical memory distortions are a key feature of posttraumatic stress disorder (PTSD). In this proof-of-concept randomized controlled trial ( N = 43), we evaluated an autobiographical memory flexibility intervention, MemFlex. We aimed to determine whether the mechanism-focused intervention, which aims to improve autobiographical memory processes, may also affect other cognitive predictors of PTSD and potentially reduce PTSD symptoms in Iranian trauma survivors diagnosed with PTSD. Results indicated significant, moderate to large between-groups effect sizes in favor of MemFlex, relative to wait-list control, for the targeted cognitive mechanism of autobiographical memory flexibility and PTSD symptoms. A large, significant effect was also observed on maladaptive posttraumatic cognitions—a strong predictor of PTSD prognosis, which is a key target of high-intensity cognitive therapies for PTSD. Findings support future completion of a scaled-up trial to evaluate treatment efficacy of MemFlex for PTSD to determine whether MemFlex may offer a culturally adaptive, low-cost, low-intensity intervention able to improve cognitive mechanisms of PTSD.

Impaired Autobiographical Memory Flexibility in Iranian Trauma Survivors With Posttraumatic Stress Disorder

Reduced ability to retrieve specific autobiographical memories is a well-defined feature of posttraumatic stress disorder (PTSD), and science-driven interventions have emerged to improve memory specificity and thereby symptoms. However, research in depressed samples indicates that the ability to flexibly move between retrieval of specific and general memory types (i.e., memory flexibility) may more accurately conceptualize autobiographical memory deficits in emotional disturbance. In this study, we evaluated memory specificity and memory flexibility in Iranian trauma survivors ( N = 63) with and without PTSD relative to community control participants. Trauma-exposed participants had experienced a serious road-traffic accident. Results indicated that individuals with PTSD experienced reduced memory specificity and memory flexibility relative to trauma-exposed participants and community control participants. A small sample size limits the strength of conclusions, although good statistical power was obtained. Findings suggest that reduced memory flexibility may be a transdiagnostic marker of emotional disturbance and support further development of memory flexibility interventions for PTSD.

EXECUTIVE FUNCTIONS IN HEALTHY AND MILD COGNITIVE IMPAIRMENT ELDERLY: THE ROLE OF READING AND WRITING HABITS

Background: Few studies have been made to investigate the role of cognitive stimulating habits such as frequency of reading and writing habits (FRWH) in executive functions (EF) of elderlies with mild cognitive impairment (MCI), who suffers from EF deficits. Objectives: investigate whether FRWH, a possible proxy of cognitive reserve, contributes to EF performance in healthy vs MCI elderlies. Methods: 135 elderlies with MCI (n = 88) and healthy controls (n = 47) were divided into groups of high FRWH (n = 78) and low FRWH (n = 57). Composite scores from EF tasks were extracted, including working memory, flexibility, inhibition, verbal fluency, and total EF scores. A two-way ANOVA was conducted with both clinical and FRWH groups, controlling the effects of education (years). Results: No interaction was found between the clinical group and FRWH. Significant differences between clinical groups were found in all five EF composite scores, with high and moderate effect size, showing worst scores in MCI group. Significant differences were found between FRWH groups in total EF composite score with low effect size, demonstrating worst performance from low FRWH group. Conclusions: These results indicate changes in EF in elderly people with MCI and low FRWH. Limitations regarding FRWH questionnaire measuring only frequency and not quality of reading and writing should be considered.