Long‐term changes in hippocampal physiology and learning ability of rats after intrahippocampal tetanus toxin.

Brace, Helen; Jefferys, John G. R.; Mellanby, Jane

doi:10.1113/jphysiol.1985.sp015861

Cited by 72 publications

(56 citation statements)

References 26 publications

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“…As with the status models injection is followed by a latent period of a week or two before seizures start, after which they recur spontaneously for several weeks (Hawkins and Mellanby, 1987). Over 70% of rats gain seizure remission after 6-8 weeks, but a minority do not, and they all retain permanent behavioural and physiological abnormalities (Brace et al, 1985;Vreugdenhil et al, 2002). The other popular model of chronic epileptogenesis is the cortical undercut.…”

Section: 22mentioning

confidence: 99%

Mechanisms of physiological and epileptic HFO generation

Jefferys

Prida

Wendling

et al. 2012

Progress in Neurobiology

270

238

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High frequency oscillations (HFO) have a variety of characteristics: band-limited or broad-band, transient burst-like phenomenon or steady-state. HFOs may be encountered under physiological or under pathological conditions (pHFO). Here we review the underlying mechanisms of oscillations, at the level of cells and networks, investigated in a variety of experimental in vitro and in vivo models. Diverse mechanisms are described, from intrinsic membrane oscillations to network processes involving different types of synaptic interactions, gap junctions and ephaptic coupling. HFOs with similar frequency ranges can differ considerably in their physiological mechanisms. The fact that in most cases the combination of intrinsic neuronal membrane oscillations and synaptic circuits are necessary to sustain network oscillations is emphasized. Evidence for pathological HFOs, particularly fast ripples, in experimental models of epilepsy and in human epileptic patients is scrutinized. The underlying mechanisms of fast ripples are examined both in the light of animal observations, in vivo and in vitro, and in epileptic patients, with emphasis on single cell dynamics. Experimental observations and computational modeling have led to hypotheses for these mechanisms, several of which are considered here, namely the role of out-ofphase firing in neuronal clusters, the importance of strong excitatory AMPA-synaptic currents and recurrent inhibitory connectivity in combination with the fast time scales of IPSPs, ephaptic coupling and the contribution of interneuronal coupling through gap junctions. The statistical behaviour of fast ripple events can provide useful information on the underlying mechanism and can help to further improve classification of the diverse forms of HFOs.

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Section: 22mentioning

confidence: 99%

Mechanisms of physiological and epileptic HFO generation

Jefferys

Prida

Wendling

et al. 2012

Progress in Neurobiology

270

238

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Section: Introductionmentioning

confidence: 99%

“…The spastic paralysis of tetanus is due to the specific intoxication of the spinal cord inhibitory interneurons by TeNT, which penetrates these cells and blocks the release of inhibitory neurotransmitters (13)(14)(15)(16). In vitro TeNT is active also on other central nervous system (CNS) neurons: it inhibits ␥-aminobutyrate (GABA)-mediated effects in rat hippocampal slices (17) and, when injected in rat ventral hippocampi, it causes an epileptiform syndrome (18,19).The steps involved in TeNT entry and trafficking inside peripheral and central neurons are not known. It is well documented that any form of nerve stimulation, and hence increase in synaptic activity, in the animal or in the phrenic nerve hemidiaphragm preparation, decreases the time of the onset of paralysis (20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

Synaptic vesicle endocytosis mediates the entry of tetanus neurotoxin into hippocampal neurons

Matteoli

Verderio

Rossetto

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

130

105

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Tetanus neurotoxin causes the spastic paralysis of tetanus by blocking neurotransmitter release at inhibitory synapses of the spinal cord. This is due to the penetration of the toxin inside the neuronal cytosol where it cleaves specifically VAMP͞synaptobrevin, an essential component of the neuroexocytosis apparatus. Here we show that tetanus neurotoxin is internalized inside the lumen of small synaptic vesicles following the process of vesicle reuptake. Vesicle acidification is essential for the toxin translocation in the cytosol, which results in the proteolytic cleavage of VAMP͞ synaptobrevin and block of exocytosis.Upon membrane depolarization and calcium entry into nerve terminals, synaptic vesicles (SVs) docked at active zones release their neurotransmitter content into the synaptic cleft (1-4). SVs are then rapidly recycled in an endocytic process that requires dynamin and clathrin (5, 6). The biochemical steps involved in vesicle docking, fusion, and reuptake are actively investigated. Recently, several protein components of the neuroexocytosis apparatus have been identified (4, 7-9), and a model for docking and fusion of vesicles with target membranes has been proposed (10). One of these proteins, a SV membrane protein, VAMP͞ synaptobrevin, is the specific target of the metalloproteinase activity of tetanus neurotoxin (TeNT) (11,12). This neurotoxin consists of two disulfide-linked polypeptide chains: H (100 kDa) mediates the specific binding to the neuronal presynaptic membrane, while L (50 kDa) is responsible for the intracellular proteolytic activity. The spastic paralysis of tetanus is due to the specific intoxication of the spinal cord inhibitory interneurons by TeNT, which penetrates these cells and blocks the release of inhibitory neurotransmitters (13)(14)(15)(16). In vitro TeNT is active also on other central nervous system (CNS) neurons: it inhibits ␥-aminobutyrate (GABA)-mediated effects in rat hippocampal slices (17) and, when injected in rat ventral hippocampi, it causes an epileptiform syndrome (18,19).The steps involved in TeNT entry and trafficking inside peripheral and central neurons are not known. It is well documented that any form of nerve stimulation, and hence increase in synaptic activity, in the animal or in the phrenic nerve hemidiaphragm preparation, decreases the time of the onset of paralysis (20)(21)(22)(23)(24). Indirect evidence suggest that TeNT intoxication of spinal cord neurons involves TeNT transit through an intracellular acidic compartment (25,26). To investigate the route of entry of TeNT inside CNS neurons, we have used primary cultures of hippocampal neurons, which represent a wellcharacterized experimental model (27). These neurons develop in vitro through a stereotyped sequence of events and eventually they form in vitro functional synaptic contacts, characterized by an active SV recycling (28,29). SVs clustered at presynaptic sites of cultured hippocampal neurons internalize antibodies to the intravesicular domain of the SV protein synaptotagmin in a d...

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“…Moreover, the stronger than normal stimulus required to evoke monosynaptic IPSPs in the secondary focus suggested intrinsic changes in the excitability of the interneurones themselves. More than one change may contribute to epileptic discharges in the secondary focus, and these could arise from both the direct action of the toxin and plastic changes of the kind known to be set in train by recurrent epileptic activity (Brace et al 1985;Cain, 1989;Najlerahim et al 1992).…”

Section: Inhibition In a Secondary Epileptic Focusmentioning

confidence: 99%

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

Empson

Jefferys

1993

The Journal of Physiology

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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...

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Long‐term changes in hippocampal physiology and learning ability of rats after intrahippocampal tetanus toxin.

Cited by 72 publications

References 26 publications

Mechanisms of physiological and epileptic HFO generation

Mechanisms of physiological and epileptic HFO generation

Synaptic vesicle endocytosis mediates the entry of tetanus neurotoxin into hippocampal neurons

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

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