Elsevier

Brain Research

Volume 955, Issues 1–2, 15 November 2002, Pages 98-103
Brain Research

Research report
Cysteamine pre-treatment reduces pentylenetetrazol-induced plasticity and epileptiform discharge in the CA1 region of rat hippocampal slices

https://doi.org/10.1016/S0006-8993(02)03371-1Get rights and content

Abstract

The effects of prior treatment of cysteamine, a somatostatin inhibitor, on pentylenetetrazol (PTZ) induced epileptic and plastic changes in CA1 excitability were examined. Population spikes were evoked by activation of Schaffer collaterals with a range of stimulation intensities. Changes in the population spike and epileptiform amplitudes were used as indices to quantify the effects of PTZ exposure in the control and cysteamine pre-treated slices. Cysteamine pre-treatment decreased baseline CA1 population spike amplitude following high intensity stimulation of Schaffer collaterals. Following PTZ application directly to the slices, cysteamine diminished the increased population spike and epileptiform amplitudes which were normally observed following collateral stimulation. Magnesium-free medium induced epileptiform activity was also significantly reduced with cysteamine pre-treatment. It is concluded that somatostatin may be involved in PTZ-induced epileptic and plastic changes in CA1 excitability.

Introduction

The hippocampus is directly involved in the development of epilepsy and other types of adaptive behavior such as learning and memory [16], [31]. It has been reported that some subregions of the hippocampus are more likely to initiate epileptiform activity than others. In the hippocampus, the site of origin of ictal-like activity appears to be located in area cornus ammonis 1 (CA1), while interictal-like activity has been found in the CA2–CA3 region [9].

Pentylenetetrazol (PTZ) is one of the most extensively used epileptogenic agents. It induces absence-type seizures (with a dose of ∼25 mg/kg) or convulsions (with ≥50 mg/kg) [23]. However, its mechanism of action has not yet been completely determined. Experimental data have indicated that PTZ blocks GABAergic mechanism [24].

Exposure to PTZ in hippocampal slices results in the appearance of spontaneous interictal-like discharges and alteration of orthodromically induced field potentials of repetitive burst discharges [12]. Bingmann and Speckmann described prolonged seizure-like events after repeated application of high concentrations of PTZ [3]. However, such events were not seen in other experiments [12]. We have shown that a transient PTZ application produces a long-lasting increase in population spike amplitude [18].

Somatostatin, a neuropeptide, is widely distributed throughout the brain including the hippocampal formation [6], [8], [27]. The hippocampal CA1 area, in particular, has an unusually rich collection of somatostatinergic neurons and fibers [4]. Microiontophoretic application of somatostatin elicits excitatory responses in neocortical, hippocampal and striatal neurons in vivo [17] as well as in hippocampal slices [6]. It has been shown that levels of immunoreactive somatostatin are increased in certain brain regions of rat kindled by focal amygdala stimulation [7]. Also somatostatin augments the spread of limbic seizures from hippocampus [21]. The absence of a specific somatostatin receptor antagonist is an important limitation to the study of this peptides’ functional role in the brain [27]. However, cysteamine, an agent which causes depletion of brain and gastrointestinal immunoreactive somatostatin [14], [19], [25], is a useful tool for the blockade of the actions of the peptide in the central nervous system. Cysteamine suppresses the development of long-term potentiation in the mossy fiber-CA3 pathway [15] and potentiates dentate granule cell responsiveness to perforant path activation [30]. In PTZ-kindled rats, systemic cysteamine causes a significant and long-lasting decrease in the severity of convulsive responses to PTZ [1]. It also acts to prevent attainment of the kindled state when applied before or during the kindling paradigm [2]. These findings suggest that brain endogenous somatostatin may play a role in seizure susceptibility and synaptic plasticity. Therefore, the current experiments were designed to determine whether a prior treatment with cysteamine would prevent PTZ-induced potentiation and epileptiform activity in hippocampal CA1.

Section snippets

Animals

The subjects were male albino rats weighting 100–160 g. They were housed five per cage and kept in the animal care facility under controlled temperature and lighting (lights on: 8 a.m.–8 p.m.) with food and water freely available.

Slice preparation

Under ether anesthesia, rats were decapitated and their right hippocampus was rapidly dissected. Transverse slices (450 μm) were prepared by a standard method [13] and then placed in a prechamber containing an aerated artificial cerebrospinal fluid (ACSF) which

Baseline CA1 synaptic response

Electrical stimulation of the afferent fibers in the stratum radiatum elicited a synchronous response from the CA1 pyramidal cells which could be measured extracellularly. There was no frequency potentiation at the test stimulation rate of 0.1 Hz. Fig. 1A presents mean size of baseline PSA over all stimulus intensities for the two groups. The difference between two groups was generally significant (F1, 132=8.07, P=0.005). Post hoc analysis indicated that this difference was concentrated at

Discussion

Activity dependent changes in synaptic efficacy are critical for the development of appropriate neural circuits and for many forms of neural plasticity [10]. These changes in synaptic activity can elicit persistent neural responses which are critical mechanisms for lasting changes in brain function. We have reported that a transient PTZ application causes a long-lasting potentiation of population spike amplitude in hippocampal CA1 [18]. The current experiments were designed to determine whether

References (31)

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