Dr. Anna Francesconi

We are interested in understanding the molecular mechanisms underlying trafficking of neurotransmitter receptors to and from synaptic sites. The precise targeting of neurotransmitter receptors and ion channels to pre- and post-synaptic sites is a fundamental process for the establishment and efficiency of neuronal circuitry. The morphological complexity of neurons and the existence of highly specialized membrane microdomains, such as dendritic spines and synaptic terminals, is likely to require multiple mechanisms to ensure correct spatial localization during synapse formation and in response to activity-dependent changes. These mechanisms may include signal-mediated sorting in the secretory and/or endosomal pathway, and selective protein removal or retention at specific sites. Research in the lab focuses on the molecular mechanisms underlying trafficking of metabotropic glutamate receptors (mGluRs). mGluRs - together with ionotropic glutamate receptors - mediate glutamate excitatory actions in the central nervous system. mGluRs are members of the large gene superfamily of 7-transmembrane, G protein-coupled receptors and are enriched at excitatory synapses, where they serve to modulate glutamatergic transmission. Signaling by mGluRs is implicated in cortical development, activity-dependent synaptic plasticity and neuropsychiatric disorders including schizophrenia, Parkinson’s disease, stroke, addiction and Fragile X syndrome.

Using a combination of molecular biology, biochemistry and imaging techniques we are pursuing two principal lines of investigation. First, we are elucidating the signals (i.e. protein motifs) and cellular machinery involved in trafficking of group I mGluRs (mGluR1/5). These studies entail the use of genetic and proteomic approaches to identify mGluR1 interacting proteins. We have already uncovered several novel mGluR1 interacting partners and are currently examining their role in receptor trafficking. Second, we are investigating the endocytic mechanisms regulating mGluR surface expression at synapses. We have recently found that mGluR1/5 constitutive (agonist independent) internalization is partly mediated by clathrin-independent, caveolar/lipid raft-dependent endocytosis. This finding suggests the enticing possibility that the caveolar/lipid raft pathway may play a critical role in the remodeling of the postsynaptic membrane and thereby impact on synaptic strength and neuronal function. We are currently examining the molecular mechanismsunderlying clathrin-independent endocytosis of mGluR1/5 in neurons. Moreover, we are examining how activity regulates mGluR1/5 synaptic trafficking under physiological and pathological conditions, including Fragile X syndrome and Huntington’s disease.

 

Selected Publications