CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Neural plasticity in health and disease

We used ocular dominance plasticity to probe into the mechanisms regulating cortical plasticity. Because of the developmental downregulation of this form of plasticity, this model can be used to unravel factors modulating plasticity levels by comparing juvenile and adult animals. From this knowledge, we try to develop strategies for functional recovery in models of neuropathlogy.

Extracellular matrix

 

Perineuronal nets are made of condensed extracellular matrix mainly composed of chondroitin sulphate proteoglycans (CSPGs). We found that their abundance in the cortex increases late during development while the sensitive period for visual cortical plasticity declines. Eliminating CSPGs from the cortical tissue in adult rats with chondroitinase ABC results in activation of ocular dominance plasticity in the adult (Pizzorusso et al., 2002). Further analysis showed that chABC promotes recovery form the effects of early monocular deprivation after eye reopening in adult animals (Pizzorusso et al., 2006). Thus, CSPG are inhibitory factors for adult cortical plasticity.

Future studies: can genetic targeting of key structural components of the net promote plasticity in the adult? Is extracellular matrix dynamically modified during plasticity? Can we use chronic 2-photon imaging to analyze structural plasticity of dendritic spines after treatments targeting extracellular matrix (in collaboration with Scuola Normale)?

Neuropathology model: To test whether removal of extracellular matrix could be effective also in neuropathology models not involving visual areas we are investigating the effect of chABC on behavioral recovery from stroke of the primary motor areas.

Experience-dependent regulation of gene transcription

 

Synaptic plasticity is thought to involve translational and transcriptional events. We have analyzed in vivo the signaling pathways leading from visual experience to activation of gene transcription in the visual cortex. We have found that visual experience triggers in the juvenile cortex a pathway involving ERK, MSK and CREB-mediated gene transcription. In addition, we found that vision is able to trigger mechanisms of epigenetic control of gene expression like histone acetylation and phosphorylation. Blocking ERK activation completely inhibited ocular dominance plasticity in juvenile animals. By analyzing the same pathway in adult animals we found that the nuclear experience-dependent events involving CREB and histon phosphoacetylation were strongly downregulated in the adult. Increasing histone acetylation by means of trichostatin was able to promote ocular dominance plasticity in the adult.

Future studies: Can we identify promoters undergoing experience-dependent histone acetylation using chromatin immunoprecipitation? Can we use histone deacetylase inhibitors to promote recovery form the effects of monocular deprivation in the adult?

Neuropathology model: Epigenetic regulation of gene transcritpion is important for many neurodevelopmental disorders involving defects in synaptic development and plasticity. Mutations of the methyl-DNA binding protein MeCP2 is responsible for most Rett syndrome cases. We are investigating the synaptic alterations of MeCP2 mutants in correlation with electrophysiological and behavioural studies.

Other collaborative projects

  • in vivo electrophysiological assessment of cortical spreading depression in collaboration.
  • Assessment of the efficacy of non viral gene and siRNA delivery using carbon nanotubes.

Publications

  • van den Maagdenberg AM, Pizzorusso T, Kaja S, Terpolilli N, Shapovalova M, Hoebeek FE, Barrett CF, Gherardini L, van de Ven RC, Todorov B, Broos LA, Tottene A, Gao Z, Fodor M, De Zeeuw CI, Frants RR, Plesnila N, Plomp JJ, Pietrobon D, Ferrari MD (2010) High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice. Ann. Neurol. 67:85-98.
  • Lonetti G, Angelucci A, Morando L, Boggio EM, Giustetto M, Pizzorusso T (2010) Early environmental enrichment moderates the behavioral and synaptic phenotype of MeCP2 null mice. Biol. Psychiatry 67:657-65.
  • Harauzov A, Spolidoro M, DiCristo G, De Pasquale R, Cancedda L, Pizzorusso T, Viegi A, Berardi N, Maffei L (2010) Reducing intracortical inhibition in the adult visual cortex promotes ocular dominance plasticity. J. Neurosci. 30:361-71.
  • Pizzorusso T (2009) Neuroscience. Erasing fear memories. Science 325:1214-5.
  • Fasano S, D'Antoni A, Orban PC, Valjent E, Putignano E, Vara H, Pizzorusso T, Giustetto M, Yoon B, Soloway P, Maldonado R, Caboche J, Brambilla R (2009) Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) controls activation of extracellular signal-regulated kinase (ERK) signaling in the striatum and long-term behavioral responses to cocaine. Biol. Psychiatry 66:758-68.
  • Mainardi M, Landi S, Berardi N, Maffei L, Pizzorusso T (2009) Reduced responsiveness to long-term monocular deprivation of parvalbumin neurons assessed by c-Fos staining in rat visual cortex. PLoS ONE 4:e4342.
  • Bardi G, Tognini P, Ciofani G, Raffa V, Costa M, Pizzorusso T (2009) Pluronic-coated carbon nanotubes do not induce degeneration of cortical neurons in vivo and in vitro. 5:96-104.
  • Viggiano MP, Giovannelli F, Borgheresi A, Feurra M, Berardi N, Pizzorusso T, Zaccara G, Cincotta M (2008) Disruption of the prefrontal cortex function by rTMS produces a category-specific enhancement of the reaction times during visual object identification. Neuropsychologia 46:2725-31.
  • Boggio EM, Putignano E, Sasso√®-Pognetto M, Pizzorusso T, Giustetto M (2007) Visual stimulation activates ERK in synaptic and somatic compartments of rat cortical neurons with parallel kinetics. PLoS ONE 2:e604.
  • Pizzorusso T, Berardi N, Maffei L (2007) A richness that cures. Neuron 54:508-10.
  • Putignano E, Lonetti G, Cancedda L, Ratto G, Costa M, Maffei L, Pizzorusso T (2007) Developmental downregulation of histone posttranslational modifications regulates visual cortical plasticity. Neuron 53:747-59.
  • Pizzorusso T, Medini P, Landi S, Baldini S, Berardi N, Maffei L (2006) Structural and functional recovery from early monocular deprivation in adult rats. Proc. Natl. Acad. Sci. U.S.A. 103:8517-22.
  • Berardi N, Pizzorusso T, Maffei L (2004) Extracellular matrix and visual cortical plasticity: freeing the synapse. Neuron 44:905-8.
  • van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, Cesetti T, van de Ven RC, Tottene A, van der Kaa J, Plomp JJ, Frants RR, Ferrari MD (2004) A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41:701-10.
  • Cancedda L, Putignano E, Impey S, Maffei L, Ratto GM, Pizzorusso T (2003) Patterned vision causes CRE-mediated gene expression in the visual cortex through PKA and ERK. J. Neurosci. 23:7012-20.
  • Berardi N, Pizzorusso T, Ratto GM, Maffei L (2003) Molecular basis of plasticity in the visual cortex. Trends Neurosci. 26:369-78.
  • Bartoletti A, Cancedda L, Reid SW, Tessarollo L, Porciatti V, Pizzorusso T, Maffei L (2002) Heterozygous knock-out mice for brain-derived neurotrophic factor show a pathway-specific impairment of long-term potentiation but normal critical period for monocular deprivation. J. Neurosci. 22:10072-7.
  • Pizzorusso T, Medini P, Berardi N, Chierzi S, Fawcett JW, Maffei L (2002) Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298:1248-51.
  • Di Cristo G, Berardi N, Cancedda L, Pizzorusso T, Putignano E, Ratto GM, Maffei L (2001) Requirement of ERK activation for visual cortical plasticity. Science 292:2337-40.

Grants

2009-2012 Telethon Italia

2009-2013 FP7 Project PLASTICISE

2010-2013 Project Seed IIT

2010-2011 Italian Ministry of University and Scientific Research, PRIN

Collaborations

  • A. Barco, Instituto de Neurosciencias, Alicante, Spain.
  • G.M. Ratto, NEST Scuola Normale Superiore, Pisa, Italy.
  • M. Giustetto, Università di Torino, Italy.
  • Daniela Pietrobon
  • K. Kostarelos, UCL, London, United Kingdom.
  • J. Verhaagen, Netherlands Institute for Brain Research, Amsterdam, The Netherlands.
  • J. Fawcett, Centre for Brain Repair Cambridge, United Kingdom.
  • G. Cioni, Fondazione Stella Maris IRCCS, Calambrone (PI), Italy.

 

no PI photo

Tommaso Pizzorusso

Contact information

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Participating staff
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