Anna Francesconi, Ph.D.
Associate Professor, Dominick P. Purpura Department of Neuroscience
(neuroscience category)
Functions of metabotropic glutamatergic signaling in neuronal plasticity and homeostasis; impact of mGluR-interacting proteins and lipids on synaptic functions in animal models of Fragile X syndrome, intellectual disability and schizophrenia
Molecular mechanisms of metabotropic glutamate receptor function.
Research in the laboratory focuses on elucidating the molecular and cellular underpinnings of metabotropic glutamate receptor function in the brain, with the ultimate goal of developing a molecular rationale for targeted interventions in neuropsychiatric disorders. A growing body of evidence from studies in human subjects and animal models has established a link between dysfunctions in glutamatergic neurotransmission and developmental brain abnormalities associated with intellectual disability, autism and schizophrenia. Group I metabotropic glutamate receptors, mGlu1 and mGlu5, are G protein-coupled receptors critical to the formation and maintenance of brain circuitry and activity-dependent synaptic plasticity, a cellular substrate of learning and memory. Dysregulation of group I mGlu receptor activity is implicated in neurodevelopmental disorders including Fragile X syndrome and schizophrenia.
We use a combination of molecular biology, biochemistry and imaging techniques to uncover the molecular mechanisms underlying temporo-spatial regulation of mGluR signaling and to examine mGluR functions in neuronal homeostasis and synaptic plasticity. Ongoing studies pursue interrelated lines of investigation by examining the role of adaptor proteins in orchestrating and fine-tuning mGluR activity under physiological conditions and in animal models of Fragile X syndrome; and by investigating the cellular mechanisms by which mGluR signaling contributes to synaptogenesis and neuronal maturation.
Group I mGluRs are enriched in spines endowed with Spine Apparatus. A subset of telencephalic mushroom-type spines is endowed with a spine apparatus, an organelle composed of sER stacks intercalated by electron-dense plates formed by synaptopodin and actin. Visualization of synaptopodin in dendritic spines of hippocampal neurons labeled with DiI: confocal images illustrate synaptopodin presence within the head of mature mushroom spines. Ultrastructure of the spines apparatus visualized by electron microscopy (from the SynapseWeb).
Selected Publications
Mende M, Fletcher EV, Belluardo JL, Pierce JP, Bommareddy PK, Weinrich JA, Kabir ZD, Schierberl KC, Pagiazitis JG, Mendelsohn AI, Francesconi A, Edwards RH, Milner TA, Rajadhyaksha AM, van Roessel PJ, Mentis GZ, Kaltschmidt JA. (2016) Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord. Neuron 90: 1189-1202. PMID: 27263971.
Kalinowska, M., and Francesconi A. (2016) Group I Metabotropic Glutamate Receptor Interacting Proteins: Fine-Tuning Receptor Functions in Health and Disease. Current Neuropharmacology 14(5): 494-503. PMID: 27296642.
Kalinowska, M., Chavez, A.E., Lutzu, S., Castillo, P.E., Bukauskas, F.F., and Francesconi. A. (2015) Actinin-4 Governs Dendritic Spine Dynamics and Promotes their Remodeling by Metabotropic Glutamate Receptors. J. Biol. Chem. 290: 15909-20. PMCID: PMC4481196.
Kalinowska, M., Castillo, C., and Francesconi A. (2015) Quantitative profiling of brain lipid raft proteome in a mouse model of fragile x syndrome. PLoS One. Apr 7;10(4):e0121464. PMCID: PMC4388542
Kumari, R., Castillo, C., and Francesconi, A. (2013) Agonist-dependent signaling by group I metabotropic glutamate receptors is regulated by association with lipid domains J. Biol. Chem. 288: 32004-32019. PMCID: PMC3814796
Kumari, R., and A. Francesconi. (2011). Identification of GPCR localization in Detergent-Resistant Membranes. Methods Mol. Biol. 746:411-423.
Takayasu, Y., Takeuchi, K., Kumari, R., Bennett, M.V., Zukin, R.S., and A. Francesconi. (2010) Caveolin-1 knockout mice exhibit impaired induction of mGluR-dependent long-term depression at CA3-CA1 synapses. Proc. Natl. Acad. Sci. U S A. 107:21778-83.
Francesconi, A., Kumari, R. and R.S. Zukin. (2009). Proteomic analysis reveals novel binding partners of metabotropic glutamatereceptor 1. J. Neurochem. 108:1515-1525.
Francesconi, A., Kumari, R. and R.S. Zukin. (2009). Regulation of group I mGluR trafficking and signaling by the caveolar/lipid raft pathway. J. Neurosci. 29:3590-3602.
Castillo PE, Francesconi A, Carroll RC. (2008) The ups and downs of translation-dependent plasticity. Neuron 59: 1-3. PMID: 18614022.