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Lorenzo Cingolani graduated in Molecular Biology at the University of Pisa. For his Ph.D., he joined the department of Prof. Walter Stühmer at the Max-Planck Institute for Experimental Medicine, Göttingen, where he investigated the developmental regulation of calcium-activated potassium channels in the rodent brain. For these studies, he received a Ph.D. in Neurobiology from the Humboldt University of Berlin in 2002. As postdoctoral fellow, he joined the laboratory of Dr. Yukiko Goda at the MRC Laboratory for Molecular Cell Biology (University College London), where he studied the relationship between synaptic structure and function, uncovering the role of cell adhesion molecules in homeostatic synaptic plasticity. Since 2012, he is an independent investigator at the Italian Institute of Technology (IIT).
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Molecular mechanisms of synapse specificity and function in the central nervous system
Our goal is to identify the key molecular mechanisms controlling assembly and remodeling of synaptic connections in the mammalian brain. Knowledge of the general principles governing development and function of neuronal connections is fundamental for understanding neurological and psychiatric disorders.
Quite possibly the most complex organ in our body, the brain determines how we behave and think, and who we are. Activity-dependent changes in the structure and function of the brain make it possible to form new memories and learn new skills. Alterations in its connectivity and excitability can lead to diseases such as epilepsy and autism, which are amongst the most common and disabling mental disorders.
Brain function: focus on cell adhesion molecules and calcium channels
Brain function critically depends on how neurons interact and communicate with each others at specialized contact sites, the synapses. Our aim is to identify the key molecular mechanisms governing formation, specialization and remodeling of synaptic connections in the central nervous system. Synapses can be viewed as learning and memory storage devices. They are highly ‘plastic’, changing the way they transmit information between neurons in response to specific patterns of neuronal activity. At the same time, they are also highly ‘tenacious’, with many synapses retaining their structural and functional properties over many years. Our overarching interest is in the questions of how synapses find the right balance between plasticity and stability, and how alterations in this delicate equilibrium contribute to neurological disorders.
We address these questions at a cellular and molecular level.
First, we investigate how a class of synaptic cell adhesion molecules (CAMs), the integrins, contribute to synaptic specificity and to coordinating pre- and postsynaptic activity under physiological and pathological conditions. During synapse formation, CAMs are critically involved in determining synapse specificity by mediating the initial target recognition between pre- and post-synaptic neurons. In mature synapses, they regulate structural and functional synaptic plasticity by signaling between the two sides of the synapse.
Second, we investigate how alternative splicing of synaptic genes contributes to synapse diversity. Alternative splicing of pre-mRNAs is prominent in the mammalian brain, where it is thought to expand proteome diversity. For example, alternative splicing of calcium channels can potentially generate thousands of different versions of these synaptic proteins. However, the impact of this molecular diversity on brain function, especially on synaptic transmission, starts only now to be understood.
Synaptic functions of integrin-mediated cell adhesion in physiological conditions and autism-related abnormalities in mice, project supported by the European Research Council (SynAMPAdhesion, FP7-PEOPLE-2012-CIG) and the Italian Institute of Technology.
Autism has a complex genetic architecture, with up to hundreds of genes involved in its etiology. A major question in the neurobiology of autism is how alterations in these many genes translate into similar behavioral phenotypes. The goal of this project is to provide mechanistic insights on how the interplay between cell adhesion molecules (integrins) and glutamate receptors alters key neuronal circuits in autism. To this end, we employ bioinformatics, brain slice electrophysiology coupled with optogenetics and behavioral analysis in mice.
Elucidation of causality between αV integrin deficiency and epilepsy, project part of the European Training Network on Extracellular Matrix in Epileptogenesis (ECMED, H2020-MSCA-ITN-2014).
Extracellular matrix proteins and their receptors are readily accessible to pharmacological and molecular interventions, and they play a fundamental role in neural development and network excitability, crucial events in the pathogenesis of epilepsy. This project aims at understanding the molecular mechanisms of epileptogenesis mediated by activity-dependent remodeling of extracellular matrix receptors, and to develop treatments for 'opening a window' of persistent structural normalization of neural circuitries in epileptogenesis, as well as in established epilepsy. To this end, we employ electrophysiological recordings from brain slices and primary neuronal cultures, Ca2+ imaging and viral-mediated rescue strategies.
Activity-dependent alternative splicing of presynaptic calcium channels, project supported by the Italian Institute of Technology
The majority of neuronal genes are subject to alternative splicing, which is thought to increase proteome complexity and optimize protein function to specific cellular tasks. In support of a dedicated function of individual splice variants, some mutations that cause brain diseases impair only one of the splice isoforms of a neuronal gene. By combining optogenetic stimulation with isoform-specific knock-down, along with imaging of presynaptic calcium and vesicle turnover, we have recently demonstrated that alternative splicing of P/Q-type calcium channels is regulated in an activity-dependent manner to control vesicle release and presynaptic plasticity at hippocampal synapses. .
Genome-editing approaches for personalized medicine in inherited diseases, project supported by the Compagnia San Paolo and the Italian Institute of Technology.
This project aims at developing novel strategies for personalized medicine in inherited brain diseases with a complex and multifactorial genetic architecture. To this end, we employ CRISPR/Cas9-based genome editing technology to correct the genetic defects at the base of inherited forms of autism and ataxia.
Dr. Agnes Thalhammer, Senior postdoctoral fellow; email@example.com
Dr. Fanny Jaudon, Postdoctoral fellow; firstname.lastname@example.org
Eduardo Morais, Ph.D. student; email@example.com
Carmela Vitale, Ph.D. student; firstname.lastname@example.org
Jessica Muià, undergraduate student
Davide Franzone, undergraduate student
Eleonora Garré, undergraduate student
Thalhammer, A., Jaudon, F., and Cingolani, L.A. (2018). Combining Optogenetics with Artificial microRNAs to Characterize the Effects of Gene Knockdown on Presynaptic Function within Intact Neuronal Circuits. JoVE 133, e57223. Video
Thalhammer, A., Contestabile, A., Ermolyuk, Y.S., Ng, T., Volynski, K.E., Soong, T.W., Goda, Y., and Cingolani, L.A. (2017). Alternative Splicing of P/Q-Type Ca2+ Channels Shapes Presynaptic Plasticity. Cell Rep 20, 333-343.
Kerrisk, M.E., Cingolani, L.A., and Koleske, A.J. (2014). ECM receptors in neuronal structure, synaptic plasticity, and behavior. Prog Brain Res 214, 101-131.
Korotchenko, S., Cingolani, L.A., Kuznetsova, T., Bologna, L.L., Chiappalone, M., and Dityatev, A. (2014). Modulation of network activity and induction of homeostatic synaptic plasticity by enzymatic removal of heparan sulfates. Philos Trans R Soc Lond B Biol Sci 369. Full text
Ronzitti, G., Bucci, G., Emanuele, M., Leo, D., Sotnikova, T.D., Mus, L.V., Soubrane, C.H., Dallas, M.L., Thalhammer, A., Cingolani, L.A., Mochida, S., Gainetdinov, R. R., Stephens, G. J., and Chieregatti, E. (2014). Exogenous alpha-Synuclein Decreases Raft Partitioning of Cav2.2 Channels Inducing Dopamine Release. J Neurosci 34, 10603-10615. Abstract
Gymnopoulos, M., Cingolani, L.A., Pedarzani, P., and Stocker, M. (2014). Developmental mapping of small-conductance calcium-activated potassium channel expression in the rat nervous system. J Comp Neurol 522, 1072-1101. Abstract
Thalhammer, A., and Cingolani, L.A. (2014). Cell adhesion and homeostatic synaptic plasticity. Neuropharmacology 78, 23-30. Abstract
McGeachie, A. B., Skrzypiec, A. E., Cingolani, L.A., Letellier, M., Pawlak, R. and Goda, Y. (2012) β3 integrin is dispensable for conditioned fear and Hebbian forms of plasticity in the hippocampus. Eur J Neurosci 36, 2461-2469. Abstract
Bassani, S. and Cingolani, L.A. (2012) Tetraspanins: interactions and interplay with integrins. Int J Biochem Cell Biol 44, 703-708. Abstract
Bassani, S., Cingolani, L.A., Valnegri, P., Folci A., Zapata, J., Gianfelice, A., Sala, C., Goda, Y., and Passafaro., M. (2012) TSPAN7, a protein involved in X-linked intellectual disability, promotes development of excitatory synapses and regulates AMPAR trafficking through interaction with PICK1. Neuron 73, 1143-1158. Full text
Pozo, K., Cingolani, L.A., Bassani, S., Laurent, F., Passafaro, M. and Goda, Y. (2012) β3 integrin interacts directly with GluA2 AMPA receptor subunit and regulates AMPA receptor expression in hippocampal neurons. Proc Natl Acad Sci USA 109, 1323-1328. Full text
McGeachie, A. B., Cingolani, L.A., and Goda, Y. (2011). A stabilizing influence: Integrins in regulation of synaptic plasticity. Neurosci Res 70, 24-29. Full text
Thalhammer, A., Edgington, R. J., Cingolani, L.A., Schoepfer, R., and Jackman, R. B. (2010). The use of nanodiamond monolayer coatings to promote the formation of functional neuronal networks. Biomaterials 31, 2097-2104. Abstract
Cingolani, L.A. and Goda, Y. (2009). Differential involvement of β3 integrin in pre- and postsynaptic forms of adaptation to chronic activity deprivation. Neuron Glia Biol 4, 179-187. Abstract
Cingolani, L.A.* (2008). In vivo glutamate receptor dynamics: lessons from the fly neuromuscular junction. Cell Science 5, 25-33.
Cingolani, L.A., Thalhammer, A., Yu, L. M., Catalano, M., Ramos, T., Colicos, M. A., and Goda, Y. (2008). Activity-Dependent Regulation of Synaptic AMPA Receptor Composition and Abundance by β3 Integrins. Neuron 58, 749-762. Full text
Previewed in Aizenman, C. D., and Pratt, K. G. (2008). There is more than one way to scale a synapse. Neuron 58, 651-653. Full text
Cingolani, L.A. and Goda, Y. (2008). Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nat Rev Neurosci 9, 344-356. Abstract
Okuda, T., Yu, L. M., Cingolani, L.A., Kemler, R., and Goda, Y. (2007). β-Catenin regulates excitatory postsynaptic strength at hippocampal synapses. Proc Natl Acad Sci USA 104, 13479-13484. Full text
Cingolani, L.A., Gymnopoulos, M., Boccaccio, A., Stocker, M., and Pedarzani, P. (2002). Developmental regulation of small-conductance Ca2+-activated K+ channel expression and function in rat Purkinje neurons. J Neurosci 22, 4456-4467. Full text
Pedarzani, P., Mosbacher, J., Rivard, A., Cingolani, L.A., Oliver, D., Stocker, M., Adelman, J. P., and Fakler, B. (2001). Control of electrical activity in central neurons by modulating the gating of small conductance Ca2+-activated K+ channels. J Biol Chem 276, 9762-9769. Full text