N-methyl-D-aspartate type receptors (NMDARs) mediate most of the excitatory transmission in the central nervous system. Because of their crucial role in synaptic plasticity mechanisms (i.e. the neurons' ability to alter their strength), disrupting these receptors' activity is often associated with learning and memory deficits. In this project, we propose to study if the nanoscale synapse architecture in aging is a key mechanism for cognitive performance. We will:

1) Study the molecular processes underlying the age-related decline versus age-resilience in cognitive performance and memory at the synaptic level;

2) Address highly debated questions of whether there are sex-specific alterations at the synapse level during aging;

3)    Define what distinguishes an age-resilient synapse that can best perform for longer lifetimes from an age-impaired synapse that is associated with cognitive impairment.

Proper neuronal communication at synapses depends on precise receptor localization at the postsynaptic side and their proximity to the presynaptic release site of neurotransmitters. To achieve this architecture, cell-adhesion molecules play a major role in the establishment of transsynaptic connections. Compelling research revealed that cell-adhesion molecules impact the function of postsynaptic receptors, yet little is known about the molecular mechanisms involved in this process as well as its possible involvement in the genesis of schizophrenia (SCZ). The project aims to study the interaction between two major synaptic players, the GluN2B subunit of N-methyl-D-aspartate type receptors (NMDARs) and the presynaptic molecule Neurexin2 (Nrxn2). 

NMDA receptors (NMDARs) and AMPA receptors (AMPARs) are ionotropic glutamate receptors, composed of multiple subunits, NMDARs include two GluN1 subunits, plus two GluN2 (GluN2A-D), and/or GluN3 (GluN3A-B) subunits, AMPARs are comprised of different combinations of GluA1–GluA4. Regulation of AMPARs to NMDARs ratio in synapses contributes to modulating the efficacy of synaptic transmission and synaptic plasticity that underlie learning and memory in long-term potentiation and depression. Dysfunction of these processes has been implicated in several neurological disorders such as dementia and depression. EphA4 is a protein that belongs to the family of Ephrin receptors, known to play important roles in the development and function of the nervous system. Recent research has unveiled EphA4’s emerging role in several neurological disorders, including Alzheimer’s disease. However, the exact mechanisms by which it contributes to their pathogenesis are still not fully understood. Previous data indicated decreased EphA4 levels at PSDs of GluN2B-/- neuronal cultures, while AMPARs levels were increased. This led us to hypothesize that GluN2B-containing NMDARs negatively regulate AMPARs levels through the action of EphA4 and that potentially any disruption of EphA4-NMDAR interplay may be responsible for neuronal dysregulation.