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Transynaptic Action of Botulinum Neurotoxin Type a at Central Cholinergic Boutons This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Development/Plasticity/Repair Transynaptic action of botulinum neurotoxin type A at central cholinergic boutons Matteo Caleo1, Matteo Spinelli1, Francesca Colosimo1, Ivica Matak2, Ornella Rossetto3, Zdravko Lackovic2 and Laura Restani1 1CNR Neuroscience Institute, Pisa, Italy 2Laboratory of Molecular Neuropharmacology, Department of Pharmacology, University of Zagreb School of Medicine, Šalata 11, 10000 Zagreb, Croatia 3Department of Biomedical Sciences, University of Padua, Italy DOI: 10.1523/JNEUROSCI.0294-18.2018 Received: 30 January 2018 Revised: 6 August 2018 Accepted: 15 August 2018 Published: 12 October 2018 Author contributions: M.C., I.M., and L.R. designed research; M.C., M.S., F.C., I.M., and L.R. performed research; M.C., M.S., F.C., and L.R. analyzed data; M.C. and L.R. wrote the first draft of the paper; M.C., M.S., and L.R. wrote the paper; I.M., O.R., Z.L., and L.R. edited the paper; O.R. contributed unpublished reagents/ analytic tools. Conflict of Interest: The authors declare no competing financial interests. We thank Francesca Biondi for excellent animal care, Silvia Pellicciotta for help in protocol illustrations, Thea Sesardic for providing equine antitoxin to BoNT/A. This work was supported by AIRC Grant IG 18925, CNR (Joint Lab 2018 Project) and Croatian Science Foundation # IP-2014-09-4503. Corresponding authors: Matteo Caleo and Laura Restani: e-mail: [email protected], [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.0294-18.2018 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2018 the authors 1 Transynaptic action of botulinum neurotoxin type A at central cholinergic boutons 2 Matteo Caleo *,1,§, Matteo Spinelli *,1, Francesca Colosimo1, Ivica Matak2, 3 Ornella Rossetto3, Zdravko Lackovic2, Laura Restani1,§ 4 5 1 CNR Neuroscience Institute, Pisa, Italy; 2 Laboratory of Molecular Neuropharmacology, 6 Department of Pharmacology, University of Zagreb School of Medicine, Šalata 11, 10000 Zagreb, 7 Croatia; 3 Department of Biomedical Sciences, University of Padua, Italy 8 9 * MC and MS contributed equally 10 § Corresponding authors: 11 Matteo Caleo and Laura Restani: 12 e-mail: [email protected], [email protected] 13 14 Running title: BoNT/A action at central cholinergic synapses 15 16 Number of figures: 8; Abstract: 199 words; Introduction: 245 words; Discussion: 1221 words 17 18 Conflicts of Interest 19 The authors have no financial interests to disclose. 20 21 Acknowledgements 22 We thank Francesca Biondi for excellent animal care, Silvia Pellicciotta for help in protocol 23 illustrations, Thea Sesardic for providing equine antitoxin to BoNT/A. This work was supported by 24 AIRC Grant IG 18925, CNR (Joint Lab 2018 Project) and Croatian Science Foundation # IP-2014- 25 09-4503. 26 1 27 Abstract 28 Botulinum neurotoxin type A (BoNT/A) is an effective treatment for several movement disorders, 29 including spasticity and dystonia. BoNT/A acts by cleaving synaptosomal-associated protein of 25 30 kDa (SNAP-25) at the neuromuscular junction, thus blocking synaptic transmission and weakening 31 overactive muscles. However, not all the therapeutic benefits of the neurotoxin are explained by 32 peripheral neuroparalysis, suggesting an action of BoNT/A on central circuits. Currently, the specific 33 targets of BoNT/A central activity remain unclear. Here, we show that catalytically active BoNT/A is 34 transported to the facial nucleus (FN) after injection into the nasolabial musculature of rats and 35 mice. BoNT/A-mediated cleavage of SNAP-25 in the FN is prevented by intracerebroventricular 36 delivery of anti-toxin antibodies, demonstrating that BoNT/A physically leaves the motoneurons to 37 enter second-order neurons. Analysis of intoxicated terminals within the FN shows that BoNT/A is 38 transcytosed preferentially into cholinergic synapses. The cholinergic boutons containing cleaved 39 SNAP-25 are associated with a larger size, suggesting impaired neuroexocytosis. Altogether, the 40 present findings indicate a previously unrecognized source of reduced motoneuron drive after 41 BoNT/A via blockade of central, excitatory cholinergic inputs. These data highlight the ability of 42 BoNT/A to selectively target and modulate specific central circuits, with consequent impact on its 43 therapeutic effectiveness in movement disorders. 44 45 Keywords: axonal transport, synaptic transmission, clostridial neurotoxins, transcytosis, dystonia, 46 spasticity, brainstem, motor control 47 2 48 Significance Statement 49 Botulinum neurotoxins are among the most potent toxins known. Despite this, their specific and 50 reversible action, prompted their use in clinical practice, to treat several neuromuscular pathologies 51 (dystonia, spasticity, muscle spasms) characterized by hyperexcitability of peripheral nerve 52 terminals or even in non-pathological applications, i.e. cosmetic use. Substantial experimental and 53 clinical evidence indicates that not all BoNT/A effects can be explained solely by the local action, 54 i.e. silencing of the neuromuscular junction. In particular, there are cases in which the clinical 55 benefit exceeds the duration of peripheral neurotransmission blockade. In this study we 56 demonstrate that BoNT/A is transported to facial motoneurons, released and internalized 57 preferentially into cholinergic terminals impinging onto the motoneurons. Our data demonstrate a 58 direct central action of BoNT/A. 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 3 74 Introduction 75 Botulinum type A (BoNT/A) is one of the most potent toxins known (Pirazzini et al., 2017). It blocks 76 neurotransmission via the specific cleavage of the synaptic protein SNAP-25 (synaptosomal- 77 associated protein of 25 kDa). Intramuscular injection of BoNT/A has been a major advance in the 78 therapy of focal dystonia and spasticity, due to the reversible inhibition of hyperexcitable nerve 79 terminals (Simpson et al., 2008). Several reports indicate that clinical benefit does not always 80 parallel the extent of muscle weakness, e.g. the functional improvement may outstrip peripheral 81 neuroparalysis, pointing to central effects of the neurotoxin (Trompetto et al., 2006; Mazzocchio and 82 Caleo, 2015). One possibility is BoNT/A-mediated blockade of intrafusal fibers, with reduced spindle 83 afferent input to the motoneurons (MNs) (Trompetto et al., 2006). Since BoNT/A is retrogradely 84 transported (Wiegand and Wellhoner, 1977; Antonucci et al., 2008; Restani et al., 2012a), it may 85 also affect central circuits directly via axonal trafficking and transfer to upstream neurons 86 (transcytosis). Indeed, several groups have reported appearance of BoNT/A-cleaved SNAP-25 in 87 distant areas following local delivery of the neurotoxin (Restani et al., 2012a; Wang et al., 2015; 88 Bomba-Warczak et al., 2016). However, it remains unclear whether the catalytically active toxin is 89 transported and transcytosed from MNs to functionally connected synapses in vivo. There is also a 90 lack of information on the central neurons that are affected following intramuscular BoNT/A. Here 91 we have exploited an animal model to gain novel insights into the mechanisms and potential 92 therapeutic relevance of BoNT/A central activity. 93 94 95 Materials and Methods 96 Ethics statement 97 All procedures were performed in compliance with the EU Council Directive 2010/63/EU on the 98 protection of animals used for scientific purposes, and approved by the Italian Ministry of Health (for 99 experiments carried out on C57/Bl6 mice and Long-Evans rats, protocol n. 346/2013-B) and 4 100 Croatian Ministry of Agriculture (for experiments with Wistar rats, protocol n. EP 24-2/2015). 101 102 Experimental Design and Statistical analysis 103 We injected BoNT/A or onabotulinumtoxin A into the naso-labial musculature (whisker pad) of 104 rodents to investigate trafficking and effects of the toxins in distant regions, such as the facial 105 nucleus. 106 All statistical tests were performed using SigmaPlot 12.0 (Systat Software Inc, USA). For 107 comparison between three groups, One-Way ANOVA on ranks was used, followed by a 108 Bonferroni’s test. Mann-Whitney Rank Sum test was used for comparison between two groups. All 109 the sections collected from animals in each experimental group were pooled together for the 110 statistical analyses (alpha value 0.05). No samples were excluded from analysis. 111 112 Procedures 113 A total of 45 C57BL6J mice and 15 rats of both sexes (age range: 3-6 months) were used. An initial 114 set of experiments were carried out in rats (Long-Evans and Wistar rats), then we turned to mice as 115 this is the species that is currently mostly employed to monitor peripheral neuroparalysis and 116 toxicity of BoNTs (Keller, 2006; Morbiato et al., 2007; Kutschenko et al., 2017). We estimated the 117 number of animals to be used for the different experiments based on the results of our previous 118 papers on BoNT/A trafficking in the visual system (Restani et al., 2011, 2012b). All experimental 119 animals were included in the analysis. The number of animals and the species/strain used for each 120 experiment is indicated in the Figure legends. 121 BoNT/A injection into the whisker pad, immunohistochemistry for cleaved SNAP-25 and synaptic 122 markers were performed as previously reported (Antonucci et al., 2008; Matak et al., 2011; Restani 123 et al., 2011, 2012a). A laboratory preparation of BoNT/A, lacking accessory proteins (kind gift of C. 124 Montecucco, University of Padua), was injected in Long-Evans rats and mice (75 and 7.5 pg in a 125 volume of 500 nl and 100 nl, respectively). This toxin batch displays a LD50 of 0.25 ng/Kg (see 5 126 Pirazzini et al., 2017).
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