Project Portugal 2030

Summary

N-methyl-D-aspartate type receptors (NMDARs) mediate most excitatory transmission in the central nervous system. Because of their crucial role in synaptic plasticity mechanisms (i.e., the ability of the neurons to alter their strength), disrupting the activity of these receptors is often associated with learning and memory deficits. The PI has dedicated her career to the study of these receptors, specifically at the synapse level, mainly focused on the mechanisms of regulation of their trafficking, dynamics by extra- and intracellular partners, and, more recently, their nanoscale synaptic distribution and its impact on synaptic plasticity mechanisms. As proper neuronal communication depends on the precise post-synaptic receptor localization and their proximity to the presynaptic release of neurotransmitters, the fine regulation of this architecture is central to the efficacy of synaptic transmission. The recent advances in super-resolution microscopy revealed a precise nanoscale organization of several synaptic components that, together with a finely-modulated molecular dynamics, confer great adaptability to the brain. This proposal aims to answer two major questions: i) how the synapse architecture changes during the neuron’s lifetime and ii) how perturbations to this synapse architecture contribute to cognitive performance in aging. To address these challenges, we propose to study if aging-induced changes to the synapse nanostructure are a determinant mechanism for cognitive performance, by inducing a shift in the modulation of NMDAR-dependent plasticity (Fig. 1). To fulfill this goal, we will: 1) Define what distinguishes an age-resilient synapse, which can perform better for longer lifetimes, from an age-impaired synapse, which is associated with cognitive impairment, by studying the nanoscale organization of key synaptic organizing proteins; 2) Study the molecular processes underlying the age-related decline versus age-resilience in cognitive performance and memory at the synaptic level, by exploring non-canonical NMDAR-mediated plasticity mechanisms; 3) Develop molecular tools to fine-tune NMDAR nanoscale organization and analyze its impact on cognitive performance in animal behavior experiments; 4) Address highly debated questions of whether there are sex-specific alterations at the synapse level during aging; 5) Develop outreach activities to emphasize the importance of promoting cognitive engagement among the elderly. The scientific breakthroughs achieved with this project will add to the body of knowledge on the importance of the synapse architecture for synaptic transmission and how its dysregulation may contribute to symptoms of cognitive impairment in aging and in neurodegenerative diseases characterized by dementia. According to a World Health Organization (WHO) report, one in four people in the world will be affected by mental or neurological disorders at some point in their lives, age being a major risk factor. Our research is therefore essential for the future development of novel and effective therapies to promote healthy cognitive aging, and approaches to decrease the economic and social burden, especially on caregivers. Cognitive decline associated with aging strongly compromises the ability to perform activities of daily living, quickly leading to loss of independence. Moreover, our groundbreaking work will highlight the importance of incorporating dedicated cognitive health activities into healthy aging actions.