Synaptic inhibition in primary and secondary chronic epileptic foci induced by intrahippocampal tetanus toxin in the rat.

Abstract

SUMMARY1. Injecting twelve mouse minimum lethal doses of tetanus toxin into one hippocampus of a rat leads to the development of chronic epileptic foci in both hippocampi. These generate intermittent epileptic discharges for 6-8 weeks. Here we compare GABAergic inhibition, 10-18 days after injection, in slices prepared from the injected and contralateral hippocampi (respectively the primary and the secondary or 'mirror' foci), using both neurochemical and electrophysiological methods.2. Epileptic activity was recorded from slices of both hippocampi from all tetanus toxin-injected rats. Evoked epileptic discharges were similar on the two sides, but spontaneous epileptic discharges were more common contralaterally.3. Ca2"-dependent, K+-stimulated (synaptic) release of radiolabelled GABA was depressed in slices from the injected hippocampus, compared with vehicle-injected controls. In contrast, slices from the contralateral hippocampus had normal levels of Ca2"-dependent, K+-stimulated GABA release, even though adjacent slices were epileptogenic.4. Intracellular recordings revealed that both fast and slow stimulus-evoked inhibitory postsynaptic potentials (IPSPs) were abolished in CA3 pyramidal cells in the primary focus. In the secondary focus, however, fast IPSPs were seen in seven of twenty-five cells, and slow IPSPs were seen in all cells if the stimulus was strong enough.5. Monosynaptic IPSPs were isolated pharmacologically by blocking glutamatergic excitatory postsynaptic potentials (EPSPs) with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and D(-)-2-amino-5-phosphopentanoic acid . No monosynaptic IPSPs were uncovered in cells from the primary focus at any stimulus strength. Monosynaptic IPSPs were evoked in all cells from both the secondary focus and control slices. The estimated conductances of monosynaptic fast IPSPs were similar in cells from the secondary focus and from the controls, although the former required twice the stimulus strength.6. Slow IPSPs were found in the secondary focus and in controls, but not in the primary focus. They were sensitive to 3-amino-2-(4-chlorophenyl)-2-hydroxypropylsulphonic acid (2-OH saclofen). The estimated conductances of slow IPSPs M1S 1729 R. MI. E2JPSON AND J. G. R. JEFFERYS evoked by weak stimuli in the secondary focus were much smaller than in the controls. However, stimuli that could trigger epileptic discharges in the secondary focus, evoked 2-OH saclofen-sensitive slow IPSPs with estimated conductances approaching the controls. This marked increase in the slow IPSP did not occur when EPSPs, and epileptic bursts, were blocked with CNQX and AP-5, suggesting that a strong barrage of excitation is needed to generate full-sized slow IPSPs in the secondary focus. 7. The chronic epileptic foci induced by tetanus toxin in the injected and contralateral hippocampi have distinct mechanisms. The ipsilateral focus behaved as expected from the acute actions of tetanus toxin; the synaptic release of GABA was disrupted and IPSPs were abolished, providing a probable mechanism f...

A comparison of the efficacy of carbamazepine and the novel anti‐epileptic drug levetiracetam in the tetanus toxin model of focal complex partial epilepsy

“…Furthermore, synaptic inhibition in the ipsilateral focus (at the site of injection of tetanus toxin) drops to 10% of controls during the first 2 weeks, but there is a subsequent recovery. In contrast, the loss of synaptic inhibition in the contralateral mirror focus never drops below 50% (Empson & Jefferys, 1993; Whittington & Jefferys, 1994). Thus, these studies suggest a more complex mechanism of action of the tetanus toxin and/or the induced focus than just the blockade of inhibitory (GABA and glycine) neurotransmission.…”

“…Tetanus toxin is a potent clostridal neurotoxin, which blocks preferentially the presynaptic release of GABA and glycine, the two major inhibitory neurotransmitters of the CNS. Indeed, several studies have reported on the decrease in GABA release and of the associated reduction in the size of IPSPs (Whittington & Jefferys, 1994; Jordan & Jefferys, 1992; Empson & Jefferys, 1993). These effects are considered to be the consequence of the cleavage of synaptobrevin by tetanus toxin (Schiavo et al ., 1992).…”

Hormonal Effects on the Brain

“…In experimental models of epilepsy, manipulations that selectively affect the hippocampus can produce chronic seizure syndromes (see, e.g., ref. 33,34), and seizure-inducing drugs alter electrical discharge of hippocampal neurons (35).…”

Amygdala‐kindling induces alterations in neuronal density and in density of degenerated fibers

“…Mirror foci can also be recorded in animal models of epilepsy. For example, injection of low doses of tetanus toxin into one hippocampus of a rat leads to the development of chronic epileptic foci in both hippocampi (Empson and Jefferys, 1993). The left and right basolateral amygdala are interconnected and thus, one side of the amygdala may rapidly activate the contralateral side.…”