Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology
Abstract
1. Introduction
2. Action of BoNTs on Central Synaptic Terminals
3. BoNTs for the Study of Brain Physiology
4. Exploiting BoNTs in Pathological Brain Conditions
5. Intracerebral BoNTs: Future Directions
Author Contributions
Acknowledgments
Conflicts of Interest
References
- Van der Kloot, W.; Molgó, J. Quantal acetylcholine release at the vertebrate neuromuscular junction. Physiol. Rev. 1994, 74, 899–991. [Google Scholar] [CrossRef] [PubMed]
- Rossetto, O.; Pirazzini, M.; Montecucco, C. Botulinum neurotoxins: Genetic, structural and mechanistic insights. Nat. Rev. Microbiol. 2014, 12, 535–549. [Google Scholar] [CrossRef] [PubMed]
- Pirazzini, M.; Rossetto, O.; Eleopra, R.; Montecucco, C. Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology. Pharmacol. Rev. 2017, 69, 200–235. [Google Scholar] [CrossRef] [PubMed]
- Akaike, N.; Shin, M.-C.; Wakita, M.; Torii, Y.; Harakawa, T.; Ginnaga, A.; Kato, K.; Kaji, R.; Kozaki, S. Transsynaptic inhibition of spinal transmission by A2 botulinum toxin. J. Physiol. 2013, 591, 1031–1043. [Google Scholar] [CrossRef] [PubMed]
- Whitemarsh, R.C.M.; Tepp, W.H.; Bradshaw, M.; Lin, G.; Pier, C.L.; Scherf, J.M.; Johnson, E.A.; Pellett, S. Characterization of botulinum neurotoxin A subtypes 1 through 5 by investigation of activities in mice, in neuronal cell cultures, and in vitro. Infect. Immun. 2013, 81, 3894–3902. [Google Scholar] [CrossRef] [PubMed]
- Peck, M.W.; Smith, T.J.; Anniballi, F.; Austin, J.W.; Bano, L.; Bradshaw, M.; Cuervo, P.; Cheng, L.W.; Derman, Y.; Dorner, B.G.; et al. Historical Perspectives and Guidelines for Botulinum Neurotoxin Subtype Nomenclature. Toxins 2017, 9. [Google Scholar] [CrossRef] [PubMed]
- Schiavo, G.; Matteoli, M.; Montecucco, C. Neurotoxins affecting neuroexocytosis. Physiol. Rev. 2000, 80, 717–766. [Google Scholar] [CrossRef] [PubMed]
- Montal, M. Botulinum neurotoxin: A marvel of protein design. Annu. Rev. Biochem. 2010, 79, 591–617. [Google Scholar] [CrossRef] [PubMed]
- Scott, A.B.; Rosenbaum, A.; Collins, C.C. Pharmacologic weakening of extraocular muscles. Investig. Ophthalmol. 1973, 12, 924–927. [Google Scholar]
- Bozzi, Y.; Costantin, L.; Antonucci, F.; Caleo, M. Action of botulinum neurotoxins in the central nervous system: Antiepileptic effects. Neurotox. Res. 2006, 9, 197–203. [Google Scholar] [CrossRef] [PubMed]
- Dong, M.; Yeh, F.; Tepp, W.H.; Dean, C.; Johnson, E.A.; Janz, R.; Chapman, E.R. SV2 is the protein receptor for botulinum neurotoxin A. Science 2006, 312, 592–596. [Google Scholar] [CrossRef] [PubMed]
- Verderio, C.; Rossetto, O.; Grumelli, C.; Frassoni, C.; Montecucco, C.; Matteoli, M. Entering neurons: Botulinum toxins and synaptic vesicle recycling. EMBO Rep. 2006, 7, 995–999. [Google Scholar] [CrossRef] [PubMed]
- Harper, C.B.; Papadopulos, A.; Martin, S.; Matthews, D.R.; Morgan, G.P.; Nguyen, T.H.; Wang, T.; Nair, D.; Choquet, D.; Meunier, F.A. Botulinum neurotoxin type-A enters a non-recycling pool of synaptic vesicles. Sci. Rep. 2016, 6, 19654. [Google Scholar] [CrossRef] [PubMed]
- Kroken, A.R.; Blum, F.C.; Zuverink, M.; Barbieri, J.T. Entry of Botulinum Neurotoxin Subtypes A1 and A2 into Neurons. Infect. Immun. 2017, 85. [Google Scholar] [CrossRef] [PubMed]
- Restani, L.; Giribaldi, F.; Manich, M.; Bercsenyi, K.; Menendez, G.; Rossetto, O.; Caleo, M.; Schiavo, G. Botulinum Neurotoxins A and E Undergo Retrograde Axonal Transport in Primary Motor Neurons. PLoS Pathog. 2012, 12. [Google Scholar] [CrossRef] [PubMed]
- Bomba-Warczak, E.; Vevea, J.D.; Brittain, J.M.; Figueroa-Bernier, A.; Tepp, W.H.; Johnson, E.A.; Yeh, F.L.; Chapman, E.R. Interneuronal Transfer and Distal Action of Tetanus Toxin and Botulinum Neurotoxins A and D in Central Neurons. Cell Rep. 2016, 16, 1974–1987. [Google Scholar] [CrossRef] [PubMed]
- Antonucci, F.; Rossi, C.; Gianfranceschi, L.; Rossetto, O.; Caleo, M. Long-distance retrograde effects of botulinum neurotoxin A. J. Neurosci. 2008, 28, 3689–3696. [Google Scholar] [CrossRef] [PubMed]
- Restani, L.; Novelli, E.; Bottari, D.; Leone, P.; Barone, I.; Galli-Resta, L.; Strettoi, E.; Caleo, M. Botulinum neurotoxin A impairs neurotransmission following retrograde transynaptic transport. Traffic 2012, 13, 1083–1089. [Google Scholar] [CrossRef] [PubMed]
- Ashton, A.C.; Dolly, J.O. Characterization of the inhibitory action of botulinum neurotoxin type A on the release of several transmitters from rat cerebrocortical synaptosomes. J. Neurochem. 1988, 50, 1808–1816. [Google Scholar] [CrossRef] [PubMed]
- Verderio, C.; Grumelli, C.; Raiteri, L.; Coco, S.; Paluzzi, S.; Caccin, P.; Rossetto, O.; Bonanno, G.; Montecucco, C.; Matteoli, M. Traffic of botulinum toxins A and E in excitatory and inhibitory neurons. Traffic 2007, 8, 142–153. [Google Scholar] [CrossRef] [PubMed]
- Garbelli, R.; Inverardi, F.; Medici, V.; Amadeo, A.; Verderio, C.; Matteoli, M.; Frassoni, C. Heterogeneous expression of SNAP-25 in rat and human brain. J. Comp. Neurol. 2008, 506, 373–386. [Google Scholar] [CrossRef] [PubMed]
- Verderio, C.; Pozzi, D.; Pravettoni, E.; Inverardi, F.; Schenk, U.; Coco, S.; Proux-Gillardeaux, V.; Galli, T.; Rossetto, O.; Frassoni, C.; et al. SNAP-25 Modulation of Calcium Dynamics Underlies Differences in GABAergic and Glutamatergic Responsiveness to Depolarization. Neuron 2004, 41, 599–610. [Google Scholar] [CrossRef]
- Beske, P.H.; Scheeler, S.M.; Adler, M.; McNutt, P.M. Accelerated intoxication of GABAergic synapses by botulinum neurotoxin A disinhibits stem cell-derived neuron networks prior to network silencing. Front. Cell. Neurosci. 2015, 9, 159. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Capogna, M.; McKinney, R.A.; O’Connor, V.; Gähwiler, B.H.; Thompson, S.M. Ca2+ or Sr2+ partially rescues synaptic transmission in hippocampal cultures treated with botulinum toxin A and C, but not tetanus toxin. J. Neurosci. 1997, 17, 7190–7202. [Google Scholar] [CrossRef] [PubMed]
- Sutton, M.A.; Wall, N.R.; Aakalu, G.N.; Schuman, E.M. Regulation of dendritic protein synthesis by miniature synaptic events. Science 2004, 304, 1979–1983. [Google Scholar] [CrossRef] [PubMed]
- Costantin, L.; Bozzi, Y.; Richichi, C.; Viegi, A.; Antonucci, F.; Funicello, M.; Gobbi, M.; Mennini, T.; Rossetto, O.; Montecucco, C.; et al. Antiepileptic effects of botulinum neurotoxin E. J. Neurosci. 2005, 25, 1943–1951. [Google Scholar] [CrossRef] [PubMed]
- Antonucci, F.; Di Garbo, A.; Novelli, E.; Manno, I.; Sartucci, F.; Bozzi, Y.; Caleo, M. 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. 2008, 210, 388–401. [Google Scholar] [CrossRef] [PubMed]
- Montecucco, C.; Schiavo, G.; Pantano, S. SNARE complexes and neuroexocytosis: How many, how close? Trends Biochem. Sci. 2005, 30, 367–372. [Google Scholar] [CrossRef] [PubMed]
- Keller, J.E.; Neale, E.A. The role of the synaptic protein snap-25 in the potency of botulinum neurotoxin type A. J. Biol. Chem. 2001, 276, 13476–13482. [Google Scholar] [CrossRef] [PubMed]
- Caleo, M.; Restani, L.; Vannini, E.; Siskova, Z.; Al-Malki, H.; Morgan, R.; O’Connor, V.; Perry, V.H. The role of activity in Synaptic degeneration in a protein misfolding disease, prion disease. PLoS ONE 2012, 7. [Google Scholar] [CrossRef] [PubMed]
- Caleo, M.; Restani, L.; Perry, V.H. Silencing synapses: A route to understanding synapse degeneration in chronic neurodegenerative disease. Prion 2013, 7, 147–150. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Wree, A.; Mix, E.; Hawlitschka, A.; Antipova, V.; Witt, M.; Schmitt, O.; Benecke, R. Intrastriatal botulinum toxin abolishes pathologic rotational behaviour and induces axonal varicosities in the 6-OHDA rat model of Parkinson’s disease. Neurobiol. Dis. 2011, 41, 291–298. [Google Scholar] [CrossRef] [PubMed]
- Hawlitschka, A.; Holzmann, C.; Witt, S.; Spiewok, J.; Neumann, A.-M.; Schmitt, O.; Wree, A.; Antipova, V. Intrastriatally injected botulinum neurotoxin-A differently effects cholinergic and dopaminergic fibers in C57BL/6 mice. Brain Res. 2017, 1676, 46–56. [Google Scholar] [CrossRef] [PubMed]
- Davletov, B.; Bajohrs, M.; Binz, T. Beyond BOTOX: Advantages and limitations of individual botulinum neurotoxins. Trends Neurosci. 2005, 28, 446–452. [Google Scholar] [CrossRef] [PubMed]
- Luvisetto, S.; Marinelli, S.; Rossetto, O.; Montecucco, C.; Pavone, F. Central injection of botulinum neurotoxins: Behavioural effects in mice. Behav. Pharmacol. 2004, 15, 233–240. [Google Scholar] [CrossRef] [PubMed]
- Luvisetto, S.; Marinelli, S.; Lucchetti, F.; Marchi, F.; Cobianchi, S.; Rossetto, O.; Montecucco, C.; Pavone, F. Botulinum neurotoxins and formalin-induced pain: Central vs. peripheral effects in mice. Brain Res. 2006, 1082, 124–131. [Google Scholar] [CrossRef] [PubMed]
- Cui, M.; Khanijou, S.; Rubino, J.; Aoki, K.R. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 2004, 107, 125–133. [Google Scholar] [CrossRef] [PubMed]
- Bach-Rojecky, L.; Lacković, Z. Central origin of the antinociceptive action of botulinum toxin type A. Pharmacol. Biochem. Behav. 2009, 94, 234–238. [Google Scholar] [CrossRef] [PubMed]
- Matak, I.; Lacković, Z. Botulinum toxin A, brain and pain. Prog. Neurobiol. 2014, 119–120, 39–59. [Google Scholar] [CrossRef] [PubMed]
- Caleo, M.; Restani, L.; Gianfranceschi, L.; Costantin, L.; Rossi, C.; Rossetto, O.; Montecucco, C.; Maffei, L. Transient synaptic silencing of developing striate cortex has persistent effects on visual function and plasticity. J. Neurosci. 2007, 27, 4530–4540. [Google Scholar] [CrossRef] [PubMed]
- Takesian, A.E.; Hensch, T.K. Balancing plasticity/stability across brain development. Prog. Brain Res. 2013, 207, 3–34. [Google Scholar] [PubMed]
- Ando, S.; Kobayashi, S.; Waki, H.; Kon, K.; Fukui, F.; Tadenuma, T.; Iwamoto, M.; Takeda, Y.; Izumiyama, N.; Watanabe, K.; et al. Animal model of dementia induced by entorhinal synaptic damage and partial restoration of cognitive deficits by BDNF and carnitine. J. Neurosci. Res. 2002, 70, 519–527. [Google Scholar] [CrossRef] [PubMed]
- Spalletti, C.; Alia, C.; Lai, S.; Panarese, A.; Conti, S.; Micera, S.; Caleo, M. Combining robotic training and inactivation of the healthy hemisphere restores pre-stroke motor patterns in mice. Elife 2017, 6. [Google Scholar] [CrossRef] [PubMed]
- Rogawski, M.A. Convection-enhanced delivery in the treatment of epilepsy. Neurotherapeutics 2009, 6, 344–351. [Google Scholar] [CrossRef] [PubMed]
- Gasior, M.; Tang, R.; Rogawski, M.A. Long-lasting attenuation of amygdala-kindled seizures after convection-enhanced delivery of botulinum neurotoxins A and B into the amygdala in rats. J. Pharmacol. Exp. Ther. 2013, 346, 528–534. [Google Scholar] [CrossRef] [PubMed]
- Zhang, C.; Mastorakos, P.; Sobral, M.; Berry, S.; Song, E.; Nance, E.; Eberhart, C.G.; Hanes, J.; Suk, J.S. Strategies to enhance the distribution of nanotherapeutics in the brain. J. Control. Release 2017, 267, 232–239. [Google Scholar] [CrossRef] [PubMed]
- Barua, N.U.; Gill, S.S.; Love, S. Convection-enhanced drug delivery to the brain: Therapeutic potential and neuropathological considerations. Brain Pathol. 2014, 24, 117–127. [Google Scholar] [CrossRef] [PubMed]
- Cunningham, C.; Deacon, R.; Wells, H.; Boche, D.; Waters, S.; Diniz, C.P.; Scott, H.; Rawlins, J.N.P.; Perry, V.H. Synaptic changes characterize early behavioural signs in the ME7 model of murine prion disease. Eur. J. Neurosci. 2003, 17, 2147–2155. [Google Scholar] [CrossRef] [PubMed]
- Van Vliet, E.A.; Aronica, E.; Gorter, J.A. Role of blood-brain barrier in temporal lobe epilepsy and pharmacoresistance. Neuroscience 2014, 277, 455–473. [Google Scholar] [CrossRef] [PubMed]
- Antonucci, F.; Bozzi, Y.; Caleo, M. Intrahippocampal infusion of botulinum neurotoxin E (BoNT/E) reduces spontaneous recurrent seizures in a mouse model of mesial temporal lobe epilepsy. Epilepsia 2009, 50, 963–966. [Google Scholar] [CrossRef] [PubMed]
- Antonucci, F.; Cerri, C.; Maya Vetencourt, J.F.; Caleo, M. Acute neuroprotection by the synaptic blocker botulinum neurotoxin E in a rat model of focal cerebral ischaemia. Neuroscience 2010, 169, 395–401. [Google Scholar] [CrossRef] [PubMed]
- Manno, I.; Antonucci, F.; Caleo, M.; Bozzi, Y. BoNT/E prevents seizure-induced activation of caspase 3 in the rat hippocampus. Neuroreport 2007, 18, 373–376. [Google Scholar] [CrossRef] [PubMed]
- Kato, K.; Akaike, N.; Kohda, T.; Torii, Y.; Goto, Y.; Harakawa, T.; Ginnaga, A.; Kaji, R.; Kozaki, S. Botulinum neurotoxin A2 reduces incidence of seizures in mouse models of temporal lobe epilepsy. Toxicon 2013, 74, 109–115. [Google Scholar] [CrossRef] [PubMed]
- Dorfer, C.; Widjaja, E.; Ochi, A.; Carter Snead, O., III; Rutka, J.T. Epilepsy surgery: Recent advances in brain mapping, neuroimaging and surgical procedures. J. Neurosurg. Sci. 2015, 59, 141–155. [Google Scholar] [PubMed]
- Mehlan, J.; Brosig, H.; Schmitt, O.; Mix, E.; Wree, A.; Hawlitschka, A. Intrastriatal injection of botulinum neurotoxin-A is not cytotoxic in rat brain—A histological and stereological analysis. Brain Res. 2016, 1630, 18–24. [Google Scholar] [CrossRef] [PubMed]
- Wedekind, F.; Oskamp, A.; Lang, M.; Hawlitschka, A.; Zilles, K.; Wree, A.; Bauer, A. Intrastriatal administration of botulinum neurotoxin A normalizes striatal D2R binding and reduces striatal D1R binding in male hemiparkinsonian rats. J. Neurosci. Res. 2018, 96, 75–86. [Google Scholar] [CrossRef] [PubMed]
- Mann, T.; Zilles, K.; Dikow, H.; Hellfritsch, A.; Cremer, M.; Piel, M.; Rösch, F.; Hawlitschka, A.; Schmitt, O.; Wree, A. Dopamine, Noradrenaline and Serotonin Receptor Densities in the Striatum of Hemiparkinsonian Rats following Botulinum Neurotoxin-A Injection. Neuroscience 2018, 374, 187–204. [Google Scholar] [CrossRef] [PubMed]
- Ungerstedt, U.; Butcher, L.L.; Butcher, S.G.; Andén, N.E.; Fuxe, K. Direct chemical stimulation of dopaminergic mechanisms in the neostriatum of the rat. Brain Res. 1969, 14, 461–471. [Google Scholar] [CrossRef]
- Pellett, S.; Bradshaw, M.; Tepp, W.H.; Pier, C.L.; Whitemarsh, R.C.M.; Chen, C.; Barbieri, J.T.; Johnson, E.A. The Light Chain Defines the Duration of Action of Botulinum Toxin Serotype A Subtypes. MBio 2018, 9. [Google Scholar] [CrossRef] [PubMed]
- Scheps, D.; López de la Paz, M.; Jurk, M.; Hofmann, F.; Frevert, J. Design of modified botulinum neurotoxin A1 variants with a shorter persistence of paralysis and duration of action. Toxicon 2017, 139, 101–108. [Google Scholar] [CrossRef] [PubMed]
- Ferrari, E.; Maywood, E.S.; Restani, L.; Caleo, M.; Pirazzini, M.; Rossetto, O.; Hastings, M.H.; Niranjan, D.; Schiavo, G.; Davletov, B. Re-assembled botulinum neurotoxin inhibits CNS functions without systemic toxicity. Toxins 2011, 3, 345–355. [Google Scholar] [CrossRef] [PubMed]
- Ferrari, E.; Gu, C.; Niranjan, D.; Restani, L.; Rasetti-Escargueil, C.; Obara, I.; Geranton, S.M.; Arsenault, J.; Goetze, T.A.; Harper, C.B.; et al. Synthetic self-assembling clostridial chimera for modulation of sensory functions. Bioconjug. Chem. 2013, 24, 1750–1759. [Google Scholar] [CrossRef] [PubMed]
Disease | Animal Model | Species | BoNT Serotype | Reported Effects | Reference |
---|---|---|---|---|---|
Epilepsy | intrahippocampal KA | rat | BoNT/E | decreased number and duration of seizures triggered by KA; decreased neuronal loss | Costantin et al, 2005 [26] |
intrahippocampal KA | rat | BoNT/E | downregulation of caspase 3 | Manno et al, 2007 [52] | |
intrahippocampal KA | mouse | BoNT/E | decreased neuronal loss and dispersion of granule cells (BoNT/E tested during epileptogenesis) | Antonucci et al, 2008 [27] | |
intrahippocampal KA | mouse | BoNT/E | reduction of total seizure duration and frequency (BoNT/E tested during chronic phase) | Antonucci et al, 2009 [50] | |
amygdala kindling model | rat | BoNT/A BoNT/B | anti-convulsant effects of both toxins (BoNT/B also at behavioral level) | Gasior et al, 2013 [45] | |
amygdala kindling model | mouse | BoNT/A2 | decreased seizures (in 50% of animals) | Kato et al, 2013 [53] | |
Ischemia | endothelin 1 | rat | BoNT/E | neuroprotective effect (decrease of glutamate release) | Antonucci et al, 2010 [48] |
phototrombotic stroke | mouse | BoNT/E | synaptic silencing of contralateral hemisphere improved motor recovery | Spalletti et al, 2017 [43] | |
Parkinson’s disease | 6-OHDA model | rat | BoNT/A | abolished pathologic rotational behavior; induced ChAT and TH axonal varicosities | Wree et al, 2011 [32] |
6-OHDA model | rat | BoNT/A | induced ChAT and TH axonal varicosities; no changes in ChAT-positive neurons | Mehlan et al, 2016 [55] | |
6-OHDA model | mouse | BoNT/A | induced ChAT axonal varicosities; | Hawlitschka et al, 2017 [33] | |
6-OHDA model | rat | BoNT/A | changes in receptor expression (rebalance of D2/D3 receptor density) | Mann et al, 2018 [57] | |
Prion disease | ME7 prion disease | mouse | BoNT/A | electrical activity does not impact on synaptic degeneration | Caleo et al, 2012 [30] |
Pain | formalin-induced pain | mouse | BoNT/A | decreased licking response in the second phase of formalin test | Luvisetto et al, 2006 [36] |
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Caleo, M.; Restani, L. Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology. Toxins 2018, 10, 175. https://doi.org/10.3390/toxins10050175
Caleo M, Restani L. Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology. Toxins. 2018; 10(5):175. https://doi.org/10.3390/toxins10050175
Chicago/Turabian StyleCaleo, Matteo, and Laura Restani. 2018. "Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology" Toxins 10, no. 5: 175. https://doi.org/10.3390/toxins10050175
APA StyleCaleo, M., & Restani, L. (2018). Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology. Toxins, 10(5), 175. https://doi.org/10.3390/toxins10050175