CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Molecular Neuropathology

Overview

Epilepsy and autism are among the most common neurological disorders, affecting about 1-2% of human population worldwide. Our research aims at investigating the cellular and molecular bases of these two diseases, which remain largely unknown. The ultimate goal of our studies is to identify novel molecular substrates for therapeutic strategies against epilepsy and autism.

Research directions

We use a multidisciplinary approach, ranging from pharmacological to genetic animal models, to study epilepsy and autism. Specific projects are:

     
  • Developmental basis of epilepsy and autism. Mutations of genes involved in brain development have been associated to human syndromes characterised by the occurrence of epileptic seizures and autistic phenotype. We study how the altered expression of neural genes during embryonic brain development can impact epilepsy susceptibility during postnatal and adult life. In detail, we study mice carrying mutations in the homeobox-containing gene Engrailed2 (En2), which is crucially involved in the early specification of selected neuronal populations of the brain, and whose mutation has been associated to autism. In our recent study (Tripathi et al., 2009) we showed increased seizure susceptibility in En2 knockout mice, likely due to altered GABAergic connectivity in the hippocampus.
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  • Antiepileptic treatment in mouse models of genetic epilepsy. Sodium channel mutations are known to be associated to severe epileptic syndromes of genetic origin in humans. We are studying a mouse model of intractable temporal lobe epilepsy (SCN2A transgenic mice) in order to characterize the neuropathological consequences of seizures and to develop novel therapeutic strategies.
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  • Dopamine signaling in epilepsy-induced cell death. Altered dopamine signalling markedly influences seizure susceptibility. Indeed, drugs interfering with dopamine receptors can modify seizure threshold in humans and experimental animals. We showed that deficient signalling through dopamine D2 receptors (D2R) results in increased susceptibility to seizures and seizure-induced neuronal death. Our current studies are aimed at investigating the biochemical pathways downstream of D2R involved in seizure-induced neuronal death.

Publications

  • Tripathi PP, Santorufo G, Brilli E, Borrelli E, Bozzi Y (2010) Kainic acid-induced seizures activate GSK-3beta in the hippocampus of D2R-/- mice. Neuroreport 21:846-50.
  • Coremans V, Ahmed T, Balschun D, D'Hooge R, DeVriese A, Cremer J, Antonucci F, Moons M, Baekelandt V, Reumers V, Cremer H, Eisch A, Lagace D, Janssens T, Bozzi Y, Caleo M, Conway EM (2010) Impaired neurogenesis, learning and memory and low seizure threshold associated with loss of neural precursor cell survivin. BMC Neurosci 11:2.
  • Tripathi PP, Sgadò P, Scali M, Viaggi C, Casarosa S, Simon HH, Vaglini F, Corsini GU, Bozzi Y (2009) Increased susceptibility to kainic acid-induced seizures in Engrailed-2 knockout mice. Neuroscience 159:842-9.
  • Antonucci F, Bozzi Y, Caleo M (2009) Intrahippocampal infusion of botulinum neurotoxin E (BoNT/E) reduces spontaneous recurrent seizures in a mouse model of mesial temporal lobe epilepsy. Epilepsia 50:963-6.
  • Brilli E, Scali M, Casarosa S, Köhler M, Bozzi Y (2009) Seizures increase importin-beta1 expression in NG2+ cells in the rat hippocampus. J. Neurosci. Res. 87:636-43.
  • Tripathi PP, Di Giovannantonio LG, Viegi A, Wurst W, Simeone A, Bozzi Y (2008) Serotonin hyperinnervation abolishes seizure susceptibility in Otx2 conditional mutant mice. J. Neurosci. 28:9271-6.
  • Chyczewski L, Walkowiak B, Chyczewska E (1991) Megakaryocyte cumulation in rabbit lungs after intraperitoneal administration of casein. Patol Pol 42:24-6.
  • Antonucci F, Di Garbo A, Novelli E, Manno I, Sartucci F, Bozzi Y, Caleo M (2008) Botulinum neurotoxin E (BoNT/E) reduces CA1 neuron loss and granule cell dispersion, with no effects on chronic seizures, in a mouse model of temporal lobe epilepsy. Exp. Neurol. 210:388-401.
  • Pozzi D, Condliffe S, Bozzi Y, Chikhladze M, Grumelli C, Proux-Gillardeaux V, Takahashi M, Franceschetti S, Verderio C, Matteoli M (2008) Activity-dependent phosphorylation of Ser187 is required for SNAP-25-negative modulation of neuronal voltage-gated calcium channels. Proc. Natl. Acad. Sci. U.S.A. 105:323-8.
  • Pozzi D, Condliffe S, Bozzi Y, Chikhladze M, Grumelli C, Proux-Gillardeaux V, Takahashi M, Franceschetti S, Verderio C, Matteoli M (2008) Activity-dependent phosphorylation of Ser187 is required for SNAP-25-negative modulation of neuronal voltage-gated calcium channels. Proc. Natl. Acad. Sci. U.S.A. 105:323-8.
  • Errico F, Nisticò R, Palma G, Federici M, Affuso A, Brilli E, Topo E, Centonze D, Bernardi G, Bozzi Y, D'Aniello A, Di Lauro R, Mercuri NB, Usiello A (2008) Increased levels of d-aspartate in the hippocampus enhance LTP but do not facilitate cognitive flexibility. Mol. Cell. Neurosci. 37:236-46.
  • Bozzi Y, Borrelli E (2006) Dopamine in neurotoxicity and neuroprotection: what do D2 receptors have to do with it? Trends Neurosci. 29:167-74.
  • Costantin L, Bozzi Y, Richichi C, Viegi A, Antonucci F, Funicello M, Gobbi M, Mennini T, Rossetto O, Montecucco C, Maffei L, Vezzani A, Caleo M (2005) Antiepileptic effects of botulinum neurotoxin E. J. Neurosci. 25:1943-51.
  • Kobayashi M, Iaccarino C, Saiardi A, Heidt V, Bozzi Y, Picetti R, Vitale C, Westphal H, Drago J, Borrelli E (2004) Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice. Proc. Natl. Acad. Sci. U.S.A. 101:11465-70.
  • Bozzi Y, Borrelli E (2002) Dopamine D2 receptor signaling controls neuronal cell death induced by muscarinic and glutamatergic drugs. Mol. Cell. Neurosci. 19:263-71.
  • Bozzi Y, Vallone D, Borrelli E (2000) Neuroprotective role of dopamine against hippocampal cell death. J. Neurosci. 20:8643-9.

Grants

2010–2011: Research grant, Italian Ministry of University and Research (MIUR), PRIN 2008 Program. “Neuroanatomical and behavioural characterization of Engrailed-2 knockout mice, a model for autism spectrum disorders”

2010–2011: Research grant, Italian Ministry of Health, “Ricerca Finalizzata” Program. “Role of inflammation in the genesis of late-onset epilepsies: gene expression studies in animal models and mutation analysis in epileptic patients”

2008–2009: Research grant, National Research Council (CNR, Italy) – “Ricerche Spontanee a Tema Libero" (RSTL). “Identification of novel genes involved in epileptogenesis through DNA microarrays technology”

2007–2008: Research grant, Parents Against Childhood Epilepsy (PACE, USA). "Suppression of a seizure focus by infusion of botulinum neurotoxin in mouse models of temporal lobe epilepsy"

Collaborations

  • Emiliana Borrelli, Department of Pharmacology, University of California, Irvine, USA.
  • Matteo Caleo
  • Giovanni Umberto Corsini, Department of Pharmacology, University of Pisa, Italy.
  • David Henshall, Department Physiology, Royal College of Surgeons, Dublin, Ireland.
  • Alexandra Joyner, Memorial Sloan-Kettering Cancer Center, New York, USA.
  • Michela Matteoli
  • Miriam Meisler, Department of Human Genetics, University of Michigan, Ann Arbor, USA.
  • Antonio Simeone, CEINGE-IGB CNR, Naples, Italy.

 

PI photo

Yuri Bozzi

Contact information

email  E-mail

email  +39 0461 883651

Participating staff

Mark Dunleavy
Post-doc

Sacha Genovesi
Post-doc

Giovanni Provenzano
Post-doc

Paola Sgadò
Post-doc

 

The Laboratory of Molecular Neuropathology of the CNR Institute of Neuroscience (CNR-IN) was established in 2009 through an agreement between the CNR-IN and the Centre for Integrative Biology (CIBIO) of the University of Trento, Italy. The Laboratory is located at CIBIO. More information is available at BozziLab.