U.O. name

Pharmacology and Toxicology

Scientific Coordinator

Prof. Giambattista Bonanno

Description

Neuron to neuron signalling is based on the release of transmitters from presynaptic boutons into the synaptic cleft, their binding to specific postsynaptic receptors and termination of the effects of the released transmitters. Neurotransmitter exocytosis is a complex process involving intraterminal calcium increase that, in turn, activates a myriad of intracellular proteins, which act in concert to induce the fusion of synaptic vesicles with the plasmamembrane. At the presynaptic level, this process is tightly regulated by auto- and heteroreceptors that can tune the exact amount of released transmitter needed for the exact information to pass to postsynaptic cells. Released transmitters then activate specific postsynaptic receptors that trigger functional changes of target neurons, thus permitting the flow of information between neuronal circuits. Finally, intercellular communication is terminated by re-uptake of the released transmitters into nerve terminals and/or by their enzymatic inactivation. Besides the importance of neuron-neuron communication, in the last decade a large body of evidence has demonstrated that bi-directional signalling also occur between neurons and glial cells, which is necessary for a correct functioning of cerebral circuits.
The components of the Pharmacology and Toxicology Unit have been involved for more than 30 years in functional studies concerning the mechanisms of neuro- and gliotransmission in the Central Nervous System and their pharmacological manipulation, using a variety of experimental models, from in vitro synaptic preparations (synaptosomes and gliosomes) isolated from native brain tissues, to cultured astrocytes and neurons, to in vivo neuronal networks.

List of publications

1. Milanese M, Bonifacino T, Fedele E, Rebosio C, Cattaneo L, Benfenati F, Usai C, Bonanno G. Exocytosis regulates trafficking of GABA and glycine heterotransporters in spinal cord glutamatergic synapses: A mechanism for the excessive heterotransporter-induced release of glutamate in experimental amyotrophic lateral sclerosis. Neurobiol Dis. 2015; 74:314-324. PMID: 25497732
2. Ricciarelli R, Fedele E. Phosphodiesterase-4D: an enzyme to remember. Br J Pharmacol. 2015; 172:4785-89. PMID: 26211680
3. Marchi M, Grilli M, Pittaluga AM. Nicotinic modulation of glutamate receptor function at nerve terminal level: a fine-tuning of synaptic signals. Front Pharmacol. 2015; 6:89. PMID:25972809
4. Cervetto C, Frattaroli D, Venturini A, Passalacqua M, Nobile M, Alloisio S, Tacchetti C, Maura G, Agnati LF, Marcoli M. Calcium-permeable AMPA receptors trigger vesicular glutamate release from Bergmann gliosomes. Neuropharmacology. 2015; 99:396-407. PMID: 26260232
5. Romei C, Sabolla C, Raiteri L. High-affinity GABA uptake by neuronal GAT1 transporters provokes release of [3H]GABA by homoexchange and through GAT1-independent Ca2+-mediated mechanisms. Neuropharmacology 2015; 88:164-170. PMID: 25150942
6. Milanese M, Giribaldi F, Melone M, Bonifacino T, Musante I, Carminati E, Rossi P.I.A., Vergani L, Voci A, Conti F, Puliti A, Bonanno G. Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2014; 64:48-59. PMID: 24361555
7. Treccani G, Musazzi L, Perego C, Milanese M, Nava N, Bonifacino T, Lamanna J, Malgaroli A, Drago F, Racagni G, Nyengaard JR, Wegener G, Bonanno G, Popoli M. Stress and corticosterone increase the readily releasable pool of glutamate vesicles in synaptic terminals of prefrontal and frontal cortex. Mol Psych. 2014; 19:433-443. PMID: 24535456
8. Ricciarelli R, Puzzo D, Bruno O, Canepa E, Gardella E, Rivera D, Privitera L, Domenicotti C, Marengo B, Marinari UM, Palmeri A, Pronzato MA, Arancio O, Fedele E. A novel mechanism for cAMP-mediated memory formation: role of amyloid Ann Neurol 2014; 75:602-607. PMID: 24591104
9. Di Prisco S, Merega E, Lanfranco M, Casazza S, Uccelli A, Pittaluga A. Acute desipramine restores presynaptic cortical defects in murine experimental autoimmune encephalomyelitis by suppressing central CCL5 overproduction. Br J Pharmacol. 2014; 171:2457-2467. PMID:24528439  
10. Milanese M, Romei C, Usai C, Oliveri M, Raiteri L. A new function for glycine GlyT2 transporters: Stimulation of γ-aminobutyric acid release from cerebellar nerve terminals through GAT1 transporter reversal and Ca2+ -dependent anion channels. J Neurosci Res. 2014; 92:398-408. PMID: 24273061
11. Giribaldi F, Milanese M, Bonifacino T, Rossi PIA, Di Prisco S, Pittaluga A, Tacchetti C, Puliti A, Usai C, Bonanno G. Group I metabotropic glutamate autoreceptors induce abnormal glutamate exocytosis in a mouse model of amyotrophic lateral sclerosis. Neuropharmacology 2013; 56:253-263. PMID: 22634363
12. Di Prisco S, Merega E, Milanese M, Summa M, Casazza S, Raffaghello L, Pistoia V, Uccelli A, Pittaluga A. CCL5-Glutamate interaction in central nervous system: early and acute  presynaptic defects in EAE mice. Neuropharmacology 2013; 75:337-46. PMID:23958452
13. Nasca C, Xenos D, Barone Y, Caruso A, Scaccianoce S, Matrisciano F, Battaglia G, Mathé AA, Pittaluga A, Lionetto L, Simmaco M, Nicoletti F. L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc Natl Acad Sci USA. 2013; 110(12):4804-9. PMID:23382250  
14. Romei C, Raiteri M, Raiteri L Glycine release is regulated by metabotropic glutamate receptors sensitive to mGluR2/3 ligands and activated by N-acetylaspartylglutamate (NAAG). Neuropharmacology 2013; 66: 311-316. PMID: 22659408
15. Milanese M, Zappettini S. Onofri F, Musazzi L, Tardito D, Bonifacino T, Messa M, Racagni G, Usai C, Benfenati F, Popoli P, Bonanno G Abnormal exocytotic release of glutamate in a mouse model of amyotrophic lateral sclerosis. J Neurochem. 2011; 116:1028-1042. PMID: 21175617
16. Bari M, Bonifacino T, Milanese M, Spagnuolo P, Zappettini S, Battista N, Giribaldi F, Usai C, Bonanno G, Maccarrone M. The endocannabinoid system in rat gliosomes and its role in the modulation of glutamate. Release Cell Mol Life Sci. 2011; 68:833-845. PMID: 20711816
17. Bruno O*, Fedele E*, Prickaerts J*, Parker LA, Canepa E, Brullo C, Cavallero A, Gardella E, Balbi A, Domenicotti C, Bollen E, Gijselaers HJM, Vanmierlo T, Erb K, Limebeer CL, Argellati F, Marinari UM, Pronzato MA, Ricciarelli R. GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses. *equally contributed. Br J Pharmacol. 2011; 164:2054-2063. PMID: 21649644
18. Marte A, Cavallero A, Morando S, Uccelli A, Raiteri M, Fedele E. Alterations of glutamate release in the spinal cord of mice with experimental autoimmune encephalomyelitis. J Neurochem. 2010; 115:343-352. PMID: 20649849
19. Marcoli M, Cervetto C, Paluzzi P, Guarnieri S, Alloisio S, Thellung S, Nobile M, Maura G. P2X7 pre-synaptic receptors in adult rat cerebrocortical nerve terminals: a role in ATP-induced glutamate release. J. Neurochem 2008; 105(6):2330-42. PMID: 18315565
20. Chiappalone M, Vato A, Tedesco MB, Marcoli M, Davide F, Martinoia S. Networks of neurons coupled to microelectrode arrays: a neuronal sensory system for pharmacological applications. Biosens Bioelectron. 2003; 18(5-6):627-34. PMID: 12706572

Main research lines

• Cellular and molecular mechanisms of neurotransmitter release under physiological and pathological conditions, and regulation through presynaptic receptors.
• Mechanisms of glutamate and GABA release under stress conditions and following antidepressant treatment.
• Metabotropic glutamate receptors for neurochemistry and functions of motoneuron, astrocytes and microglia in amyotrophic lateral sclerosis.
• Effects of cyto/chemokines on central neurotransmission in physiological conditions and in multiple sclerosis
• Functional cross-talk between presynaptic receptors co-localized on the same nerve terminal.
• Modulation of β-amyloid production and its physiological and pathological effects on neurotransmission in the central nervous system.
• Pharmacological manipulation of cAMP and cGMP production and metabolism.
• Modulation of glutamate, GABA and glycine release through activation of hetero-transporters, under physiolgical and pathological conditions.
• Purinergic P2X7 receptors and glutamate release in physiological and pathological conditions in CNS.
• Network activity and transmitter release in neuron networks coupled to Multi Electrode Arrays (MEA): effects of neuroactive substances.

Research group ERC sector

LS5_3 Neurochemistry and neuropharmacology
LS5_11 Neurological disorders

Internal personnel

Other personnele

• Silvio Palmero, Associate Professor, DIFAR.
• Massimo Grilli, Assistant Professor, DIFAR.
• Chiara Cervetto, Assistant Professor, DIFAR.
• Marco Milanese, Assistant Professor, DIFAR.
• Tiziana Bonifacino, Assistant Professor, DIFAR.
• Giuseppe Marazzotta, Tecnico stabularista, DIFAR.
• Guendalina Olivero, post DOC, DIFAR.
• Claudia Rebosio, PhD student, DIFAR.
• Cristina Padolecchia, PhD student, DIFAR.
• Luca Cattaneo, PhD student, DIFAR.
• Arianna Venturini, PhD student, DIFAR.
• Tommaso Bonfiglio, PhD student, DIFAR.

Collaborations

• Prof. Luigi Francesco Agnati, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze, Università degli Studi di Modena and Reggio Emilia, Modena, Italia.
• Prof. Ottavio Arancio, Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, USA.
• Dr. Joachim Berger, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Australia.
• Dott.ssa Manuela Cervelli, Dipartimento di Scienze, Università degli Studi di Roma “Roma Tre”, Roma, Italia.
• Prof. Rodrigo A. Cunha, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portogallo.
• Prof. Kjell Fuxe, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
• Prof.ssa Susanna Genedani, Dipartimento di Medicina Diagnostica, Clinica e Sanità Pubblica, Università degli Studi di Modena and Reggio Emilia, Modena, Italia.
• Prof.ssa Carla Ghelardini, Dipartimento di Neuroscienze, Area del Farmaco e Salute del Bambino, Università degli Studi di Firenze, Firenze, Italia.
• Dott. Diego Guidolin, Dipartimento di Medicina Molecolare, Università degli Studi di Padova, Padova, Italia.
• Dr. Alice Guyon, Laboratoire de Catherine Heurteaux, Institut de Pharmacologie Moleculaire et Cellulaire CNRS - UMR 7275, ZA Sophia Antipolis, Valbonne , France.
• Dr. Salamon Z. Langer, Synaptic Pharma Ltd., Tel Aviv, Israel.
• Dr. Stefania Maccari, Glycobiology of stress-related diseases team L.I.A. (lnternational Associated Laboratory), Prenatal Stress and Neurodegenerative Diseases UMR 8576 CNRS, University of Lille, France.
• Prof. Lamberto Maffei, Istituto di Neuroscienze CNR, Pisa, Italia
• Prof. Paolo Mariottini, Dipartimento di Scienze, Università degli Studi di Roma “Roma Tre”, Roma, Italia.
• Dr. James A. Monn, Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, USA.
• Prof. Jos Prickaerts, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
• Prof. Maurizio Popoli, Dipartimento di Scienze Farmacologiche e Biomolecolari and CEND, Laboratorio di Neuropsicofarmacologia e Neurogenomica Funzionale, Università degli Studi di Milano, Milano Italia.
• Dott.ssa Daniela Puzzo, Dipartimento di Scienze Bio-Mediche, Sezione di Fisiologia, Università degli Studi di Catania, Catania, Italia.
• Dr. Paul A. Smith, Novartis Institutes for BioMedical Research, Autoimmunity, Transplantation & Inflammation Disease Area, Basel, Switzerland.
• Prof. Paolo Stanzione, Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Roma, Italia.
• Prof. Alessandro Stefani, Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Roma, Italia.
• Dr. Mark HG Verheijen, Department of Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, The Netherlands.
• Dr. Amina S. Woods, NIH National Institute of Drug Abuse, Intramural Research Program, Structural Biology Unit, Baltimore, USA.