Elsevier

Neuroscience

Volume 81, Issue 4, 10 October 1997, Pages 927-935
Neuroscience

Metabotropic glutamate receptor activation modulates epileptiform activity in the hippocampus

https://doi.org/10.1016/S0306-4522(97)00264-9Get rights and content

Abstract

Synchronous neuronal activity that resembles interictal epileptiform discharges occurs in hippocampal slices if there is an imbalance of inhibitory and excitatory synaptic activity. Antagonists of the GABAA receptor and agonists of the ionotropic glutamate receptors are convulsants that produce epileptiform discharges in hippocampal slices. We evaluated the effects of activation of the metabotropic class of glutamate receptors on epileptiform activity produced by convulsants. The metabotropic glutamate agonist (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD, 30–100 μM) accelerated the rate of interictal epileptiform discharges produced by either bicuculline methiodide or 4-aminopyridine and had minimal effects on discharges produced by high [K+]o. The increase in rate was associated with a significant decrease in the amplitude and duration of the afterhyperpolarization that follows the paroxysmal depolarizing shift, the intracellular correlate of the interictal epileptiform discharge. A modest increase in input resistance (∼10%) accompanied the rate increase. β-adrenergic or muscarinic agonists, neurotransmitters that also decrease the afterhyperpolarization, acted synergistically with ACPD (100 μM) to increase the control rate of bicuculline-induced interictal discharges by more than eight-fold. Antagonists of β-adrenergic or muscarinic receptors reduced, but did not block, the acceleration of bicuculline-induced discharge rate produced by 30 μM ACPD.

The results show that metabotropic glutamate receptors enhance the rate of interictal epileptiform discharges produced by bicuculline or 4-aminopyridine. ACPD had no effect on interictal epileptiform activity induced by high [K+]o, a finding that may indicate that in high [K+]o conditions the metabotropic receptor is activated or that the effects of high [K+]o already reduced the effect of depolarizing currents that are enhanced by ACPD. The acceleration in interictal discharge rate was associated with a reduction in the afterhyperpolarization that follows the paroxysmal depolarizing shift and this action appears to be important in determining the synchronization of neurons and the rate of interictal epileptiform discharges. Furthermore, interaction between mGluR activation and either muscarinic or β-adrenergic activation may be important for seizure generation.

Section snippets

Experimental procedures

Sprague–Dawley rats (Harlan) weighing 125–250 g were decapitated after ether anaesthesia and the brain was removed quickly. The hippocampus was dissected and hippocampal slices (400–500 μm-thick) were prepared using a McIlwain tissue chopper. Slices were incubated for greater than 60 min in an interface chamber while perfused with artificial cerebrospinal fluid (ACSF) at 32–34°C that was bubbled with carboxygen (95% O2 and 5% CO2). The composition of the control ACSF in mM was: NaCl 124, KCl 2.5,

ACPD effects on epileptiform activity

ACPD accelerated the rate of epileptiform discharges produced by 10 μM BMI in a concentration-dependent manner. A 140% increase in the rate was observed following bath application of 30 μM ACPD and over a 300% increase in rate occurred after bath application of 100 μM ACPD (Fig. 1). These effects were readily reversible following return to control BMI ACSF. The duration of the extracellular field discharge was significantly shortened by both 30 μM ACPD (153.3±11.3 to 129.1±12.24 ms, n=10, P=0.0027)

Metabotropic receptors accelerated epileptiform discharges

The racemic mixture of the metabotropic glutamate agonist ACPD at concentrations of 30–100 μM produced an increase in the rate of CA3 hippocampal interictal epileptiform discharges produced by either bicuculline or 4-AP. ACPD also shortened the duration of the extracellularly recorded bicuculline-induced epileptiform discharges. Merlin et al. found that 5 μM of the selective ACPD isomer (1S,3R) increased the discharge rate of epileptiform bursting produced by the GABA antagonist picrotoxin in

Conclusions

Activation of metabotropic receptors accelerated the rate of spontaneously occurring interictal epileptiform discharges produced by blocking GABAA or potassium currents but not when produced by high [K+]o alone. The increase in discharge rate was correlated with a decrease in the AHP that follows the PDS and supports the hypothesis that potassium currents, especially the slow AHP produced by calcium-activated potassium channels, help to determine the rate of interictal epileptiform discharges.

Acknowledgements

Supported by the NIH (NS28580) and VA Research. The authors thank Drs Peter Lipton, William Lytton, Robert Pearce, and Thomas Sutula for comments on drafts of the manuscript.

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    Current address: Department of Neurology, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, U.S.A.

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