Research reportAction of a metabotropic glutamate receptor agonist in rat lateral septum: induction of a sodium-dependent inward aftercurrent
Introduction
Glutamate mediates fast excitatory transmission in the brain by acting on α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA), kainate and N-methyl-d-aspartate (NMDA) receptors 12, 17. In the mid-1980s, it was discovered that glutamate can also activate a second messenger [26]and that this action is mediated by receptors of a new type [28], currently called metabotropic glutamate receptors (mGluRs). To date, eight different subtypes of mGluRs have been cloned 16, 18, 21: mGluR1 and mGluR5, of which three and two splice variants have been identified, respectively, are coupled to Gq/11 proteins, whereas the other subtypes are coupled to Gi/o proteins.
Activation of mGluRs can directly increase neuronal excitability by blocking or reducing potassium currents or by generating non-specific cationic currents. It can also regulate voltage-activated calcium channels and depress excitatory or inhibitory transmission by acting presynaptically. In addition, mGluRs can affect synaptic plasticity, by modulating long-term potentiation and long-term depression, and may play a role in neuronal death 16, 18, 20, 21, 23, 31.
The lateral septum of the rat contains large amounts of mGluR1 and mGluR5 1, 24, 25, and work done by Gallagher and collaborators has shown that mGluR agonists exert a variety of effects on lateral septal neurons [8]. Thus, mGluR activation can potentiate a slow afterdepolarization [34]and can increase the efficiency of synaptic transmission in the septum [35]. In these neurons, mGluR agonists can also evoke both a slow membrane depolarization and burst firing [32]. Burst firing, but not the slow depolarization, can be blocked by nickel or cobalt [33]and is mediated by a pertussis toxin-sensitive G protein [36]. This suggests that the membrane mechanisms responsible of the mGluR-dependent slow membrane depolarization and burst firing are distinct. But whereas the membrane currents underlying the slow depolarization have been studied in some detail 37, 39, the ionic basis of mGluR-dependent burst firing activity is not fully understood [36].
In the present study, we have attempted to unravel the membrane mechanism by which (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD), an agonist of mGluRs, induces burst firing in lateral septal neurons. We have used coronal slices containing the septal region, obtained either from newborn or from young adult rats. Membrane currents were characterized under voltage clamp conditions, using patch pipettes and the whole-cell recording technique.
Section snippets
Brain slices
The animals used were either newborn (5- to 10-day-old) or young adult (3- to 4-week-old) male rats from the Sivz strain, a Sprague-Dawley-derived strain. They were stunned and decapitated, the brain was excised and a block of tissue containing the septum was prepared. Two to three coronal slices, 300 to 400 μm thick, were cut using a vibrating microtome (Campden Instruments, Loughborough, UK) and incubated in a thermoregulated (33–34°C) recording chamber of the interface type [22]. They were
Results
When recorded with K-gluconate-containing pipettes, the neurons studied had all resting membrane potentials more negative than −50 mV. In young adults, the cell input resistance, Rin, was 160±13 MΩ (n=23; range: 55 to 313 MΩ). In newborn animals, Rin was 380±30 MΩ (n=15; range: 222 to 646 MΩ), a significantly higher value (P<0.001). This suggests that neurons from newborn animals were smaller in size.
In preliminary experiments, the effect of (1S,3R)-ACPD was tested on some lateral septal
Discussion
We have found that in the presence of (1S,3R)-ACPD, depolarizing voltage jumps could generate a TTX-insensitive inward aftercurrent in lateral septal neurons of the rat. This current was mainly carried by sodium ions and in order to be elicited, it required calcium influx from the extracellular medium. However, it was probably not due to the activation of a sodium/calcium exchanger. Thus, though this current was calcium-dependent, calcium was not its main carrier. Interestingly, in preliminary
Acknowledgements
We thank Dr. J.J. Dreifuss for reading of the manuscript and Ms. D. Machard for excellent technical assistance. This work was supported in part by the Swiss National Science Foundation (Grant 31.43436.95). D.M. acknowledges support from the French Medical Research Foundation and P.P. from the COTRAO (Communauté de Travail des Alpes Occidentales).
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Present address: Laboratoire de Physiologie Cellulaire et Moléculaire, CNRS UMR 6548, Université de Nice-Sophia Antipolis, 06108 Nice Cedex 2, France.