Elsevier

Brain Research

Volume 776, Issues 1–2, 21 November 1997, Pages 75-87
Brain Research

Research report
Action of a metabotropic glutamate receptor agonist in rat lateral septum: induction of a sodium-dependent inward aftercurrent

https://doi.org/10.1016/S0006-8993(97)00945-1Get rights and content

Abstract

The mechanism by which (1S,3R)-ACPD, a metabotropic glutamate receptor agonist, induces burst firing in lateral septal neurons of the rat was investigated in coronal brainstem slices. Membrane currents were characterized in voltage clamp using whole-cell recordings. In the presence of (1S,3R)-ACPD, following depolarizing voltage jumps, repolarization towards the holding potential generated an inward aftercurrent. It could have a plateau-like phase and decayed exponentially. This (1S,3R)-ACPD-dependent inward aftercurrent was accompanied by an increase in cell conductance and was reduced following partial replacement of extracellular sodium by N-methyl-d-glucamine. It was unaffected by TEA or barium, and persisted in Cs-loaded neurons or following partial replacement of extracellular chloride by isethionate. This suggests that it was mainly carried by sodium. Loading neurons with the calcium chelator, BAPTA, or blocking transmembrane calcium currents, suppressed the (1S,3R)-ACPD-dependent aftercurrent. By contrast, partial replacement of extracellular sodium by lithium did not affect it. Thus, this current was dependent upon calcium influx but was not due to a sodium/calcium exchanger. It was probably mediated by G protein activation. Indeed, in neurons loaded with GTP-γ-S, following depolarizing voltage jumps, repolarization towards the holding potential revealed an inward aftercurrent having properties similar to those of the (1S,3R)-ACPD-dependent current. We suggest that (1S,3R)-ACPD induced calcium-activated non-selective channels. In the presence of this agonist, a depolarization-evoked calcium influx could thus evoke a cationic inward current. This current probably promotes the burst firing observed in lateral septal neurons in current clamp.

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).

References (39)

Cited by (18)

  • Tale of tail current

    2020, Progress in Biophysics and Molecular Biology
    Citation Excerpt :

    The tail sometimes is referred to as ‘aftercurrent’ and is also recorded upon to −50 mV in lateral septum − LS neurons (Raggenbass et al., 1997). The metabotropic agonist of glutamatergic receptors 10 μM (1S,3R)-ACPD facilitates inward tails in a depolarization-dependent way (Raggenbass et al., 1997). This is an ‘all or none’ effect as it is absent at −30 mV, while similar long-lasting and saturating responses are observed between −20 and + 10 mV.

  • Metabotropic glutamate receptors 1 and 5 differentially regulate bulbar dopaminergic cell function

    2010, Brain Research
    Citation Excerpt :

    Second, the process involved phosphoinositide hydrolysis by phospholipase C, as the PLC inhibitor U73122 inhibited the DHPG-induced depolarization/inward current. The final outcome of the intracellular Ca2+ increase promoted by mGluR1 activation can involve several processes, including Ca2+-dependent, non-selective cationic conductances (Congar et al., 1997; Crepel et al., 1994; Guerineau et al., 1995; Raggenbass et al., 1997), and a Na+/Ca2+ exchanger (Keele et al., 1997; Lee and Boden, 1997; Staub et al., 1992). The increase of intracellular Ca2+ does not involve modifications of membrane conductances for Ca2+ (it is not blocked by extracellular Cd+), or K+ (it is not blocked by intracellular Cs+-TEA).

  • Suppression of potassium channels elicits calcium-dependent plateau potentials in suprachiasmatic neurons of the rat

    2005, Brain Research
    Citation Excerpt :

    In striatal cholinergic neurons, Ca++-mediated plateau potentials can be recorded in the presence of TEA [14,44]. In the lateral septum, the induction of Ca++-dependent plateau potentials requires the presence of metabotropic glutamate receptor agonists [45,64,65]. Metabotropic glutamate receptor-dependent and muscarinic receptor-dependent plateau potentials have also been characterized in the hippocampus [12,16,32,39], in the subiculum [25], and in the entorhinal cortex [15,31].

  • Block of hippocampal CAN channels by flufenamate

    2000, Brain Research
    Citation Excerpt :

    Ca2+-activated non-selective cation (CAN) channels are activated by cytoplasmic Ca2+ and, when activated, cause a membrane depolarization (e.g., Ref. [13]). CAN currents underlie such slow depolarizing processes as bursting [16], slow afterdepolarization [6], and plateau potentials [18]. These channels can be potentiated through a process that depends on cytoplasmic Ca2+ stores and, when potentiated, CAN channels may play a role in the ‘amplification’ phase of excitotoxicity [11].

  • TRPC channels and epilepsy

    2017, Advances in Experimental Medicine and Biology
View all citing articles on Scopus
1

Present address: Laboratoire de Physiologie Cellulaire et Moléculaire, CNRS UMR 6548, Université de Nice-Sophia Antipolis, 06108 Nice Cedex 2, France.

View full text