Metabotropic glutamate receptor activation modulates epileptiform activity in the hippocampus
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.
References (47)
- et al.
Magnesium-free medium activates seizure-like events in the rat hippocampal slice
Brain Res.
(1986) - et al.
Control of epileptiform burst rate by CA3 hippocampal cell afterhyperpolarizations in vitro
Brain Res.
(1989) - et al.
Selective activation of phosphoinositide hydrolysis by a rigid analogue of glutamate
Neurosci. Lett.
(1990) - et al.
2-amino-4-phosphonobutyrate blocks mossy fiber-CA3 response in guinea pig but not rat hippocampus
Brain Res.
(1984) - et al.
Involvement of non-NMDA receptors in picrotoxin-induced epileptiform activity in the hippocampus
Neurosci. Lett.
(1989) - et al.
Effect of APV and ketamine on epileptiform activity in the CA1 and CA3 regions of the hippocampus
Epilepsy Res.
(1990) - et al.
Trans-ACPD, a selective agonist of the phosphoinositide-coupled excitatory amino acid receptor
Eur. J. Pharmac.
(1989) - et al.
The metabotropic glutamate receptors: Structure and functions
Neuropharmacology
(1995) Noradrenergic modulation of epileptiform activity in the hippocampus
Epilepsy Res.
(1995)- et al.
Activation of hippocampal metabotropic excitatory amino acid receptors leads to seizures and neuronal damage
Neurosci. Lett.
(1992)
Metabotropic glutamate receptors in brain function and pathology
Trends pharmac. Sci.
A family of metabotropic glutamate receptors
Neuron
Phenylglycine derivatives as antagonist of metabotropic glutamate receptors
Trends pharmac. Sci.
Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus
J. Physiol.
Immunocytochemical localization of group III metabotropic glutamate receptors in the hippocampus with subtype-specific antibodies
J. Neurosci.
Modulation of epileptiform activity by metabotropic glutamate receptors in immature rat neocortex
J. Neurophysiol.
Role of EPSPs in initiation of spontaneous synchronized burst firing in rat hippocampal neurons bathed in high potassium
J. Neurophysiol.
Potassium conductances in hippocampal neurons blocked by excitatory amino-acid transmitters
Nature
Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons
Nature
Glutamate metabotropic receptors increase a Ca2+-activated nonspecific cationic current in CA1 hippocampal neurons
J. Neurophysiol.
Excitatory effects of ACPD receptor activation in the hippocampus are mediated by direct effects on pyramidal cells and blockade of synaptic inhibition
J. Neurophysiol.
Involvement of N-methyl-d-aspartate receptors in epileptiform bursting in the rat hippocampus
J. Physiol.
A cyclic AMP-dependent form of associative synaptic plasticity induced by coactivation of B-adrenergic receptors and metabotropic glutamate receptors in rat hippocampus
J. Neurosci.
Cited by (0)
- 1
Current address: Department of Neurology, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, U.S.A.