1. “ Modelli sperimentali di distonia: implicazioni per la patogenesi” Antonio Pisani Clinica Neurologica , Università di Roma “Tor Vergata”; Fondazione Santa Lucia, IRCCS Roma XLI Congresso Società Italiana di Neurologia Catania, 25 Ottobre 2010 Associazione Italiana di Neuropatologia- AINP

2. Prima che la DBS diventi l’unica scelta....

3. Trattamento farmacologico: cosa abbiamo a disposizione?

5. Approccio multidisciplinare

8. Modelli animali

9. Modelli Farmacologici LeDoux, in press

10. Modelli con mutazioni spontanee

11. Modelli genetici

13. Modelli murini di DYT1 Distonia Knock-out Knock-down Wild-type Cortex-, Cerebellum-, Striatum-, dopaminergic neuron-specific Knock-out of Dyt1 ∆ GAG Knock-in Mice

16. Motor Learning in TorsinA transgenic mice N. Sharma, 2005

17. La plasticità sinaptica come endofenotipo specifico per la DYT1 dystonia

18. Motor learning Synaptic plasticity Analisi della fisiologia striatale

21. Methods: coronal slice preparation and morphology

22. Methods: parasagittal slice preparation and morphology

23. Medium spiny neuron Confocal microscope image of a spiny neuron from a DYT1 mutant mouse, filled during electrophysiological recordings with biocytin

26. Bidirectional long-term plasticity at corticostriatal synapses HFS Time (sec) -1000 0 1000 2000 3000 4000 40 80 120 160 200 240 E P S P a m p l i t u d e ( % o f c o n t r o l ) 0 20 LFS HFS = LTD LTP

27. Bidirectional impairment of synaptic plasticity in hMT mice Martella et al., 2009

28. Bidirectional impairment of synaptic plasticity in hMT mice Martella et al., 2009

29. Interim summary a “ loss of inhibition ” characterizes the impairment of synaptic plasticity

30. Quali meccanismi alla base di questa “loss of inhibition”?

31. DA Cholinergic Interneuron Medium Spiny Neuron LTP LTD HFS

32. DA Pisani et al., 2006 enhanced LTP no LTD HFS

33. Interactions between Medium Spiny Neuron and Cholinergic Interneuron Pisani et al., 2007

34. Role of endogenous acetylcholine Martella et al., 2009

35. Role of endogenous acetylcholine: treatment with (Artane®) Martella et al., 2009

36. Martella et al., 2009 Lowering ACh tone rescues SD

37. Increased AChE activity In collaboration with E. Cacci and S. Biagioni, University of Rome “La Sapienza”

40. Università di Roma “Tor Vergata” Giorgio Bernardi Giusy Martella Paola Platania Grazia Madeo Tommaso Schirinzi Fondazione Santa Lucia, Roma Paola Bonsi Giuseppe Sciamanna Annalisa Tassone Georgia Mandolesi Francesca Puglisi Vladimiro Batocchi

41. A special thank to our Collaborators! University of Alabama at Birmingham, USA David G. Standaert, Yuking Li Harvard Medical School, USA Nutan Sharma, Xandra O. Breakefield CEINGE, Italy Alessandro Usiello Karolinska Inst., Sweden Gilberto Fisone