Post-ictal depression transiently inhibits induction of LTP in area CA1 of the rat hippocampal slice
Introduction
Temporary memory loss is well documented in epilepsy patients 13, 14, 31, 32and in patients who experience seizures as a consequence of electroconvulsive therapy [26]. This memory loss may include forgetting information learned just prior to the seizure (retrograde amnesia), and/or the inability to retain newly acquired information following the seizure (anterograde amnesia). The presence of the seizure appears to be crucial to the amnestic event [14]; however the mechanisms resulting in seizure-induced memory loss remain unclear.
The hippocampus is involved in the process of memory consolidation [35]. Moreover, the hippocampus is prone to seizure activity. Thus, it is not surprising that memory impairment is especially frequent in patients with temporal lobe epilepsy 14, 32, given that the same networks can be involved in epileptogenesis and memory [13]. Because of the strong link between seizure activity and memory loss and the convergence of these processes in the hippocampus, we have investigated the effects of epileptiform activity on neuroplasticity in the hippocampal slice.
Previously, we characterized a model of stimulus-induced after-discharges (electrographic seizures, or EGSs) in the hippocampal slice which are morphologically similar to complex tonic/clonic seizures observed in vivo 28, 29. The EGSs are elicited in area CA3 and propagated to area CA1. We used this model to study LTP induction in CA1 of the hippocampal formation 6, 19during and following seizures.
The phenomenon of seizure induced amnesia has been successfully modelled in vivo in rodents where seizures induced by electrical stimulation have been shown to inhibit induction 2, 30and maintenance [15]of LTP. Here we demonstrate that LTP induction occurs if the LTP-inducing stimulus is given during the initial phase of the EGS characterized by high frequency firing and tonic postsynaptic depolarization, referred to as the `tonic' phase of the EGS. Surprisingly, LTP does not occur if the stimulus is delivered during the later phase of the EGS characterized by slower, repetitive postsynaptic bursting, referred to as the `clonic' phase. Induction of LTP is strongly inhibited if the stimulus is delivered during the phase of post-seizure depression (the `post-ictal' phase). These results are consistent with the observation that postsynaptic hyperpolarization, during tetanic stimulation, blocks LTP induction [20].
Section snippets
Methods
Hippocampal slices (625 μm) were prepared from 15–22 day old male Sprague–Dawley rats. Rats were anesthetized with halothane, decapitated and hippocampi were dissected free. Transverse slices were cut on a McIlwain tissue chopper in a temporal to septal direction and incubated for at least 1 h in artificial cerebral spinal fluid (ACSF) warmed to 26°C and bubbled with 95% O2, 5% CO2. Slices were then transferred to a submerged recording chamber perfused at 2 ml/min with warmed (30–32°C)
Results
We have demonstrated previously that inducing multiple EGSs in area CA3 results in `epileptogenesis' of the network, i.e. spontaneous interictal activity develops and complex tonic/clonic electrographic seizures can be evoked for the life of the slice. In this model, general network excitability is increased and seizure threshold is lowered. Because epileptogenesis is also considered a neuroplastic process, we first determined whether an EGS evoked from area CA3 potentiated or depressed control
Discussion
Our previous studies have documented several effects of seizure-like activity on neural plasticity in vitro 23, 4. Based on the current view that LTP reflects biological substrates of learning and memory, these effects may underlie seizure-induced amnesia.
We have now determined another possible amnestic mechanism of seizures in that synaptic plasticity is impaired after an ictal event. We show this to be an acute effect of post-ictal depression, lasting for several minutes after the seizure;
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