Central effects of BoNT

Abstract

Botulinum neurotoxins A and E (BoNT/A and BoNT/E) are bacterial enzymes that exert a long-lasting inhibition of transmitter release via the cleavage of the synaptic protein SNAP-25. We have studied the trafficking and functional effects of BoNT/A and BoNT/E after in vivo injection into the rodent hippocampus and visual cortex. We found that BoNT/A and BoNT/E inhibit glutamate release and silence the activity of pyramidal neurons. BoNT/A, but not BoNT/E, exhibits retrograde axonal transport following uptake at the nerve terminal. This retrograde spread has important implications for the clinical applications of BoNT/A. We have exploited the silencing effects of BoNT/E in two lines of research. First, we have demonstrated the anti-epileptic effects of in vivo administration of BoNT/E. Indeed, BoNT/E prevents spontaneous recurrent seizures in a mouse model of temporal lobe epilepsy. Second, we have used BoNT/E to address the role of intrinsic neural activity in maturation of the visual cortex during the developmental critical period. Unilateral, intracortical injections of BoNT/E were made in rat pups at the time of eye opening and resulted in the silencing of the treated, but not contralateral, hemisphere for a period of 2 weeks. We found that visual acuity was permanently reduced in the blocked hemisphere, and the critical period for ocular dominance plasticity persisted into adulthood.