Tetanus toxin induces long-term changes in excitation and inhibition in the rat hippocampal CA1 area

Intrahippocampal tetanus toxin induces a period of chronic recurrent limbic seizures in adult rats, associated with a failure of inhibition in the hippocampus. The rats normally gain remission from their seizures after 6-8 weeks, but show persistent cognitive impairment. In this study we assessed which changes in cellular and network properties could account for the enduring changes in this model, using intracellular and extracellular field recordings in hippocampal slices from rats injected with tetanus toxin or vehicle, 5 months previously. In CA1 pyramidal neurones from toxin-injected rats, the slope of the action potential upstroke was reduced by 32%, the fast afterhyperpolarisation by 32% and the slow afterhyperpolarisation by 54%, suggesting changes in voltage-dependent conductances. The excitatory postsynaptic potential slope was reduced by 60% and the population synaptic potential slope was reduced at all stimulus intensities, suggesting a reduced afferent input in CA1. Paired-pulse stimulation showed an increase of the excitability ratio and an increase of cellular excitability only for the second pulse, suggesting a reduced inhibition. The polysynaptic inhibitory postsynaptic potential was reduced by 34%, whereas neither the inhibitory postsynaptic potential at subthreshold stimulus intensities,nor the pharmacologically isolated monosynaptic inhibitory postsynaptic potential were different in toxin-injected rats, suggesting a reduced synaptic excitation of interneurones. Stratum radiatum stimuli in toxin-injected rats, and not in controls, evoked antidromic activation of CA1 neurones, demonstrating axonal sprouting into areas normally devoid of CA1 pyramidal cell axons.We conclude that this combination of enduring changes in cellular and network properties, both pro-epileptic (increased recurrent excitatory connectivity, reduced recurrent inhibition and reduced afterhyperpolarisations) and anti-epileptic (impaired firing and reduced excitation), reaches a balance that allows remission of seizures, perhaps at the price of persistent cognitive impairment.