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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00429-013-0697-1) contains supplementary material, which is available to authorized users

Distribution of mRNA for the GABA transporter GAT-1 in the rat brain: evidence that GABA uptake is not limited to presynaptic neurons.

Cells containing mRNA for the gamma-aminobutyric acid (GABA) transporter GAT-1 were identified in rat brain by in situ hybridisation. They were found in most of the known locations of GABAergic neurons, as defined by the distribution of mRNA for glutamic acid decarboxylase, the synthetic enzyme for GABA. Within the cerebellum there was substantial labelling of basket and stellate cells in the molecular layer, and of Golgi cells but no others in the granule cell layer. Many Purkinje cells were unlabelled while others, particularly in the hemispheres, were moderately labelled. Many of the Purkinje cells negative for GAT-1 mRNA had adjacent intensely labelled small cells whose size and position corresponded to Bergmann glia. Numerical comparison of cells labelling for GAT-1 mRNA and the mRNAs for the two known isoforms of glutamic acid decarboxylase were made on serial sections of cerebral cortex. Cells positive for GAT-1 mRNA were more numerous, indicating that expression of the transporter is not just limited to GABAergic cells and we suggest that it may also be expressed postsynaptically by some non-GABAergic neurons

Response time as an index for selective auditory cognitive deficits.

The full or partial recovery of cognitive functions following brain lesions is believed to rely on the recruitment of alternative neural networks. This has been shown anatomically for selective auditory cognitive functions (Adriani et al. 2003b). We investigate here behavioral correlates that may accompany the use of alternative processing networks and in particular the resulting increase in response times. The performance of 5 patients with right or left unilateral hemispheric infarction and 6 normal control subjects in sound identification, asemantic sound recognition, sound localization, and sound motion perception was evaluated by the number of correct replies and response times for correct and wrong replies. Performance and response times were compared across patients and normal control subjects. Two patients with left lesions were deficient in sound identification and sound motion perception and normal in sound localization and asemantic sound recognition; one patient with right lesion was deficient in sound localization and sound motion perception and normal in sound identification and asemantic sound recognition; deficient performance was associated with increased response times. The remaining 2 patients (1 with left, 1 with right lesion) had normal performance in all 4 tasks but had significantly longer response times in some (but not all) tasks. Patients with normal or deficient performance tended more often than normal subjects to give faster correct than wrong replies. We propose that increased response time is an indication of processing within an alternative network