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Brain Advance Access first published online on June 29, 2005
This version published online on July 12, 2005
Brain, doi:10.1093/brain/awh580
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received December 23, 2004
Revised May 30, 2005
Accepted June 3, 2005

Article

Transynaptic effects of tetanus neurotoxin in the oculomotor system

David González-Forero 1, Sara Morcuende 1, Francisco J. Alvarez 2, Rosa R. de la Cruz 1, and Ángel M. Pastor 1*

1 Departamento de Fisiología y Zoología, Universidad de Sevilla, Spain
2 Department of Anatomy and Physiology, Wright State University, OH, USA

* To whom correspondence should be addressed.
Ángel M. Pastor, E-mail: ampastor{at}us.es


  Abstract

The question whether general tetanus arises from the independent sum of multiple local tetani or results from the actions of the transynaptic tetanus neurotoxin (TeNT) in higher brain centres remains unresolved. Despite the blood-borne dissemination of TeNT from an infected wound, the access to the central nervous system is probably prevented by the blood-brain barrier. However, several long-term sequelae (e.g. autonomic dysfunction, seizures, myoclonus, and sleep disturbances) present after the subsidence of muscle spasms might be indicative of central actions that occur farther away from lower motoneurons. Subsequently, the obvious entry route is the peripheral neurons followed by the transynaptic passage to the brain. We aimed at describing the pathophysiological correlates of TeNT translocation using the oculomotor system as a comprehensive model of cell connectivity and neuronal firing properties. In this study, we report that injection of TeNT into the medial rectus muscle of one eye resulted in bilateral gaze palsy attributed to firing alterations found in the contralaterally projecting abducens internuclear neurons. Functional alterations in the abducens-to-oculomotor internuclear pathway resembled in part the classically described TeNT disinhibition. We confirmed the transynaptic targeted action of TeNT by analysing vesicle-associated membrane protein2 (VAMP2) immunoreactivity (the SNARE protein cleaved by TeNT). VAMP2 immunoreactivity decreased by 94.4% in the oculomotor nucleus (the first synaptic relay) and by 62.1% presynaptic to abducens neurons (the second synaptic relay). These results are the first demonstration of physiological changes in chains of connected neurons that are best explained by the transynaptic action of TeNT on premotor neurons as shown with VAMP2 immunoreactivity which serves as an indicator of TeNT activity.

Keywords: deafferentation; neuronal excitability; oculomotor; synaptic plasticity; VAMP2.
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