Elsevier

Epilepsy Research

Volume 93, Issues 2–3, February 2011, Pages 192-196
Epilepsy Research

Short communication
Valproate decreases frequency facilitation at mossy fiber—CA3 synapses after status epilepticus

https://doi.org/10.1016/j.eplepsyres.2010.11.006Get rights and content

Summary

Mossy fiber to CA3 synapses exhibit metaplasticity during the development of epilepsy, and valproate in control animals can modulate long-term plasticity at this synapse. Here we show that valproate alters frequency facilitation (short-term plasticity) at this synapse in hippocampal slices from post-status epilepticus but not control animals. This indicates that valproate can have specific actions in the “epileptic” brain.

Introduction

The development of epilepsy (epileptogenesis) following a brain insult or kindling results from molecular, cellular and network alterations (Herman, 2002, Walker et al., 2002). These changes not only culminate in epilepsy but also can modify the response to drugs. For example, amygdala kindled rats are more likely than nonkindled rats to develop phencyclidine-like behavioural side-effects with competitive NMDA receptor antagonists (Löcher and Hönack, 1991), and, similarly, patients with epilepsy had behavioural and motor adverse events following exposure to a NMDA receptor antagonist that were not observed in healthy volunteers (Sveinbjornsdottir et al., 1993). This effect is not restricted to NMDA receptor antagonists, as there is a higher incidence of side-effects of other antiepileptic drugs in amygdala-kindled compared to normal rats (Hönack and Löscher, 1995). Furthermore, levetiracetam is ineffective in many seizure models in naive animals but is effective against seizures in animals with chronic epilepsy (Klitgaard et al., 1998).

Epileptogenesis results in metaplasticity, a change in the ability of the system to undergo synaptic plasticity (Goussakov et al., 2000). This has been observed at the mossy fiber to CA3 synapse where the ability to elicit mossy fiber long-term potentiation (LTP) is compromised in post-status epilepticus rats (Goussakov et al., 2000). One possible explanation for this observation is that the cAMP/protein kinase A signalling system is overstimulated during epileptogenesis, so occluding mossy fiber LTP.

Valproic acid (VPA) has multiple modes of action (Löscher, 2002). It has recently been shown to modulate the protein kinase A signalling pathway (Boeckeler et al., 2006, Chang et al., 2010), and to impair PKA-dependent LTP at the mossy fiber synapse to CA3 region (Chang et al., 2010). We therefore, asked whether VPA would differentially affect baseline transmission and short-term plasticity, measured as frequency facilitation, at this synapse in post-status epilepticus animals.

Here we show that VPA has no effect on baseline transmission or frequency facilitation at the mossy fiber to CA3 synapse in control animals but, in contrast, affects frequency facilitation in post-status epilepticus animals.

Section snippets

Seizure induction

Male Sprague–Dawley rats, weighing between 250 g and 330 g, were used. Rats were kept under controlled environmental conditions (24–25 °C; 50–60% humidity; 12 h light/dark cycle) with free access to food and tap water. All experiments followed the Home Office regulations under the Animal (Scientific Procedures) Act, 1986.

Status epilepticus (SE) was induced in experimental animals by the administration of pilocarpine (320 mg/kg, ip), a muscarinic cholinergic agonist. Twenty minutes before and after

Results

Rats following SE were killed at least two weeks after SE at a time when metaplasticity at mossy fibers has been previously described (Goussakov et al., 2000). Slices from these animals were compared against those from control (non-SE) animals. We first tested the effects of VPA (1 mM) on baseline transmission (0.05 Hz) and on increasing stimulation from 0.05 Hz to 1 Hz in slices from epileptic (SE-slices) and control animals. During stimulation at 0.05 Hz, there was no significant effect of VPA (1 

Discussion

Here we tested the effects of VPA on baseline transmission and frequency facilitation, a form of short-term potentiation (STP), in control and post-status epilepticus tissue. Unexpectedly, VPA had no significant effect on baseline transmission but decreased STP in slices from post-status epilepticus animals.

Frequency facilitation is the hallmark of mossy fiber to CA3 transmission (Salin et al., 1996). Frequency facilitation is dependent on a rise of Ca2+ ions in the presynaptic terminal both

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Cited by (3)

  • Seizure-induced reduction in PIP<inf>3</inf> levels contributes to seizure-activity and is rescued by valproic acid

    2014, Neurobiology of Disease
    Citation Excerpt :

    One important corollary of the data described here is that VPA may have specific effects only visible during seizure activity, as VPA did not affect PIP3 levels under control conditions. This observation is consistent with previous studies that show that VPA only affects frequency facilitation of synaptic transmission in epileptic but not control animals (Chang and Walker, 2011). The impact of this is that it may be essential to employ seizure-inducing conditions in subsequent experiments to identify the primary target(s) of current treatments and to develop new therapies for seizure control.

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