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Lorenzo Cingolani

Affiliated Researcher

Research Line

Neuroscience and Smart Materials

Center

IIT Central Research Labs Genova

Contacts

Largo R. Benzi, 10, Genoa 16132
+39 010 5558 382
Contact Me

About

After graduating in Molecular Biology at the University of Pisa, Lorenzo Cingolani joined the department of Prof. Walter Stühmer at the Max-Planck Institute for Experimental Medicine, Göttingen, where he investigated the development of intrinsic excitability in the brain. For these studies, he received a Ph.D. in Neurobiology from the Humboldt University of Berlin in 2002. As postdoctoral fellow, he specialized in synaptic physiology in the laboratory of Dr. Yukiko Goda at the MRC Laboratory for Molecular Cell Biology (University College London), where he uncovered the role of cell adhesion in homeostatic plasticity. Since 2012, he is an independent investigator at the Italian Institute of Technology (IIT) and since 2018 associate professor at the University of Trieste.

 

Please take a minute to visit this exciting research topic:

https://www.frontiersin.org/research-topics/9320/homeostatic-synaptic-plasticity-from-synaptic-circuit-assembly-to-neurological-disorders

and feel free to contact me for further information.

Projects

 

Molecular mechanisms of synapse specificity and function in the central nervous system

 

Our goal is to identify the molecular mechanisms that control assembly and remodeling of synaptic connections in the mammalian brain. Knowledge of the general principles governing development and function of neuronal connections is fundamental to the understanding of 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 ataxia and autism, which are amongst the most common and disabling brain disorders.

 

Brain function: focus on cell adhesion molecules and calcium channels

FigWebSiteTextRedBrain 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 the cellular and molecular level.

First, we investigate how a class of synaptic cell adhesion molecules (CAMs), the integrins, contribute to synapse 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 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, we do not know how this richness influences brain function and synaptic plasticity.

 

 

Current projects

NeuronIntegrinIntegrins in glutamatergic circuits: molecular targets for brain disorders, project supported by the European Research Council (SynAMPAdhesion, FP7-PEOPLE-2012-CIG; ECMED, H2020-MSCA-ITN-2014), the Compagnia San paolo and the Cariplo foundation.

Extracellular matrix proteins and their receptors, the integrins, 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 brain disorders. The goal of this project is to provide mechanistic insights on how the interplay between integrins and glutamate receptors alters neuronal circuits in autism and depression, and to develop treatments for 'opening a window' of persistent structural normalization of neural circuitries in these pathologies. To this end, we employ proteomics, brain slice electrophysiology coupled with optogenetics and behavioral analyses in mice. Paper here.

 

 GenomeEditing Persmedicine LC

 

CRISPR/Cas9-dependent regulation of alternative splicing: new therapeutic opportunities for ataxia, project supported by Ataxia UK and the Telethon foundation (GGP19181).

Calcium channels are subject to extensive alternative splicing, which is thought to optimize their function to specific cellular tasks. In support of a dedicated function for splice variants, some mutations that cause brain diseases impair only one of the possible isoforms of calcium channels. By combining optogenetic stimulation with CRISPR/Cas9-dependent regulation of alternative splicing, along with imaging of presynaptic calcium and vesicle turnover, we investigate the relevance of alternative splicing of calcium channels for synapse plasticity and leverage on this to develop new therapeutic strategies for ataxia. Paper here.


GraphicalAbstract2

 

 

Lab members:

Dr. Agnes Thalhammer, Senior postdoctoral fellow; agnes.thalhammer@iit.it

Dr. Fanny Jaudon, Postdoctoral fellow; fanny.jaudon@iit.it

Carmela Vitale, Ph.D. student; carmela.vitale@iit.it

Lucia Celora, Ph.D student; lucia.celora@phd.units.it

Jessica Muià, undergraduate student

Sara Riccardi, undergraduate student

 

Picture1

 

 

Selected Publications

Jaudon, F., Thalhammer, A., and Cingolani, L.A. (2020). Integrin adhesion in brain assembly: From molecular structure to neuropsychiatric disorders. Eur J Neurosci, in press. Full text

Thalhammer, A., Jaudon, F., and Cingolani, L.A. (2020). Emerging roles of activity-dependent alternative splicing in homeostatic plasticity. Front Cell Neurosci 14, 104. Full text

Cingolani, L.A., Vitale, C., and Dityatev, A. (2019). Intra- and Extracellular Pillars of a Unifying Framework for Homeostatic Plasticity: A Crosstalk Between Metabotropic Receptors and Extracellular Matrix. Front Cell Neurosci 13, 513. Full text

Jaudon, F., Thalhammer, A. and Cingolani, L.A. (2019). Correction of beta3 integrin haplo-insufficiency by CRISPRa normalizes cortical network activity. BioRxiv doi.org/10.1101/664706

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.   Full text

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.  Full text

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.   Full Text

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.   Full text

Thalhammer, A., and Cingolani, L.A. (2014). Cell adhesion and homeostatic synaptic plasticity. Neuropharmacology 78, 23-30.   Full text

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.   Full text

Bassani, S. and Cingolani, L.A. (2012) Tetraspanins: interactions and interplay with integrins. Int J Biochem Cell Biol 44, 703-708.   Full text

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.   Full text

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

Awards

 

The lab is supported by Ataxia UK, the Telethon foudation (GGP19181), the Cariplo foundation, the Italian Institute of Technology and the University of Trieste.

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