Molecular mechanisms underlying NMDA Receptor regulation and implications in Alzheimer’s disease
Our lab looks at how neuronal communication is mediated by the activation of glutamate receptors (GluRs), which triggers mechanisms able to induce changes at synaptic level that are thought to underlie higher cognitive functions. In particular, activation of N-methyl-D-aspartate receptors (NMDARs), a subtype of GluRs, regulates synaptic plasticity and plays a central role in synaptic development and maturation. Accordingly, NMDARs are extremely well regulated in a cell- and synapse-specific manner. Several mechanisms including the control of expression/degradation level, intracellular trafficking or channel properties work coordinately to regulate NMDARs. We are interested in elucidating the detailed molecular mechanisms controlling NMDAR subunit composition and synaptic localization since these are highly dynamic parameters which deeply influence NMDAR function.
Because of their importance in controlling synaptic functions, NMDARs have emerged as promising pharmacological targets for the treatment of several neurological disorders. Specifically, compelling studies demonstrate a critical role for NMDARs in the pathogenesis of Alzheimer’s disease. We are investigating whether alterations in mechanisms controlling the balance between synaptic and extrasynaptic NMDARs contributes to the pathogenesis of this devastating dementia.
Synapse unsilencing and implications in Rett syndrome
Synapses are generated in excess during development but many of them are non-functional (or “silent”) Synaptic activity activates (“unsilences”) and stabilizes some of these silent synapses whereas others are eliminated. We are interested in determining the mechanisms underlying synaptic unsilencing with a focus on the role of the neuronal factor BDNF in the process by controlling glutamate receptor trafficking.
Many neurodevelopmental disorders share a common hallmark: an aberrant neuronal connectivity and immature spine and neuronal morphology. These defects are thought to be due to alterations in the processes of synaptic activation and/or maturation at early stages of development. Rett syndrome (RTT) is the leading cause of genetic intellectual disability in girls and patients and animal models of RTT show a reduction in BDNF levels and exhibit immature spine morphology and altered neurotransmission. We are investigating the impairment in the BDNF-dependent glutamate receptor plasticity as a possible contributor to RTT pathogenesis.