Molecular mechanisms of metabotropic glutamate receptor function

Abnormal maturation of brain circuitry during development is a critical determinant of pathological manifestations in many neuropsychiatric conditions including intellectual disability, Fragile X syndrome, and schizophrenia. 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 these conditions. Group I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, 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 mGluR activity is implicated in neurodevelopmental disorders including Fragile X syndrome and schizophrenia.

Research in the laboratory focuses on elucidating the molecular and cellular underpinnings of metabotropic glutamatergic functions in the brain, with the ultimate goal of developing a molecular rationale for targeted interventions in neuropsychiatric disorders. 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 transmission. Ongoing studies pursue interrelated lines of investigation by examining the role of receptor interacting proteins in orchestrating and fine-tuning mGluR activity under physiological conditions and in animal models of Fragile X syndrome and intellectual disability; and by investigating the mechanisms by which mGluR signaling contributes to synaptogenesis and neuronal maturation.

Research in our laboratory has been supported by NINDS, NIMH, Autism Speaks and Brain & Behavior Research Foundation Young Investigator Awards.

Donoso M*, Speranza L*, Kalinowska M, Castillo C, De Sanctis C, Francesconi A (2020) The G protein-coupled Metabotropic Glutamate Receptor I controls neuronal macroautophagy. bioRxiv doi: 10.1101/2020.11.02.365783 (*equal contribution). 

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. PMCID: PMC4912012

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. PMCID: PMC4983749

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.