Structural and functional substrates of tetanus toxin in an animal model of temporal lobe epilepsy.
The effects of tetanus toxin (TeNT) both in the spinal cord, in clinical tetanus, and in the brain, in experimental focal epilepsy, suggest disruption of inhibitory synapses. TeNT is a zinc protease with selectivity for Vesicle Associated Membrane Protein (VAMP; previously synaptobrevin), with a reported selectivity for VAMP2 in rats. We found spatially heterogeneous expression of VAMP1 and VAMP2 in the hippocampus. Inhibitory terminals in stratum pyramidale expressed significantly more VAMP1 than VAMP2, while glutamatergic terminals in stratum radiatum expressed significantly more VAMP2 than VAMP1. Intrahippocampal injection of TeNT at doses that induce epileptic foci cleaved both isoforms in tissue around the injection site. The cleavage was modest at 2 days after injection and more substantial and extensive at 8 and 16 days. Whole-cell recordings from CA1 pyramidal cells close to the injection site, made 8-16 days after injection, showed that TeNT decreases spontaneous EPSC frequency to 38 % of control and VAMP2 immunoreactive axon terminals to 37 %. In contrast, TeNT almost completely abolished both spontaneous and evoked IPSCs while decreasing VAMP1 axon terminals to 45 %. We conclude that due to the functional selectivity of the toxin to the relative sparing of excitatory synaptic transmission shifts the network to pathogenically excitable state causing epilepsy.
Neuronal Networks Group, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
Alex S
AS
Ferecskó
Premysl
P
Jiruska
Lucy
L
Foss
Andrew D
AD
Powell
Wei-Chih
WC
Chang
Attila
A
Sik
John G R
JG
Jefferys
D000818:Animals; D001522:Behavior, Animal; D058256:Brain Waves; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D009433:Neural Inhibition; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013702:Temporal Lobe / Q000378:metabolism* / Q000503:physiopathology; D013744:Tetanus Toxin; D013997:Time Factors; D050987:Vesicle-Associated Membrane Protein 1 / Q000378:metabolism*; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism*
D013744:Tetanus Toxin; C494706:Vamp2 protein, rat; D050987:Vesicle-Associated Membrane Protein 1; D050988:Vesicle-Associated Membrane Protein 2; C494705:vesicle-associated membrane protein 1, rat