Subtype-specific involvement of metabotropic glutamate receptors in two forms of long-term potentiation in the dentate gyrus of freely moving rats

doi:10.1016/S0306-4522(98)00111-0

Neuroscience

Volume 86, Issue 3, 8 June 1998, Pages 709-721

https://doi.org/10.1016/S0306-4522(98)00111-0 Get rights and content

Abstract

In this study, the role of metabotropic glutamate receptors in N-methyl-d-aspartate receptor-dependent and voltage-gated calcium channel-dependent long-term potentiation in the dentate gyrus of freely moving rats was investigated. Antagonists for group 1 metabotropic glutamate receptors ((S)-4-carboxyphenylglycine), group 1/2 metabotropic glutamate receptors ((RS)-α-methyl-4-carboxyphenylglycine) and group 2 metabotropic glutamate receptors ((RS)-α-methylserine O-phosphate monophenylester) were used. The N-methyl-d-aspartate receptor antagonist, d(−)-2-amino-5-phosphonopentanoic acid, and the L-type voltage-gated calcium channel antagonist, methoxyverapamil were used to investigate the N-methyl-d-aspartate receptor and voltage-gated calcium channel contribution to the long-term potentiation recorded. Field excitatory postsynaptic potential slope function and population spike amplitude were measured. Drugs were applied, prior to tetanus, via a cannula implanted into the lateral cerebral ventricle.

200 Hz tetanization produces an long-term potentiation which is inhibited by application of d(−)-2-amino-5-phosphonopentanoic acid and (RS)-α-methyl-4-carboxyphenylglycine. In this study, a dose-dependent inhibition of 200 Hz long-term potentiation expression was obtained with (S)-4-carboxyphenylglycine. Long-term potentiation induced by 400 Hz tetanization was not inhibited by d(−)-2-amino-5-phosphonopentanoic acid, although the amplitude of short-term potentiation was reduced. (RS)-α-methyl-4-carboxyphenylglycine and (S)-4-carboxyphenylglycine, both in the presence and absence of d(−)-2-amino-5-phosphonopentanoic acid, inhibited the development of 400 Hz long-term potentiation. (RS)-α-methylserine O-phosphate monophenylester had no significant effect on long-term potentiation induced by either 200 or 400 Hz tetanization. Application of methoxyverapamil significantly inhibited 400 Hz long-term potentiation, but had no effect on 200 Hz long-term potentiation.

These data suggest that 400 Hz long-term potentiation, induced in the presence of d(−)-2-amino-5-phosphonopentanoic acid, requires activation of L-type calcium channels. Furthermore, these results strongly support a critical role for group 1 metabotropic glutamate receptors in both N-methyl-d-aspartate receptor- and voltage-gated calcium channel-dependent long-term potentiation.

Section snippets

Experimental procedures

Under sodium pentobarbitone anaesthesia (“Nembutal”, 40 mg/kg, i.p.), seven-week-old male Wistar rats underwent implantation of a monopolar recording and a bipolar stimulating electrode into the dentate gyrus granule cell layer and perforant path, respectively, as described previously.[24]A cannula was implanted into the lateral cerebral ventricle, through which drug application was made. The animals were allowed between seven to 10 days to recover from surgery before experiments were conducted.

[³H]d(−)-2-amino-5-phosphonopentanoic acid application and drug diffusion

Application of [³H]AP5 (100 nmol and 40 μCi in 5 μl) followed by brain removal 30 min later, demonstrated that by this time-point a highly localized diffusion of the drug into the hippocampus had occurred (Fig. 1). The highest concentration of the drug was seen in the lateral cerebral ventricle, followed by the hippocampus. Some weaker radioactivity was noted in the areas surrounding the third ventricle, which comprised the hypothalamic nuclei and lateral habenular nucleus. 60 min following [³H]AP5

Drug application via the lateral cerebral ventricle results in diffusion to the hippocampus

Application of [³H]AP5 illustrated that 30 min following injection into the lateral cerebral ventricle, a localized diffusion of the drug to the hippocampus occurred. One can thus assume that at the point of tetanization (30 min following drug injection), not only had the drug reached the hippocampus, but in addition, minimal extrahippocampal effects of the compound could occur. 60 min following drug application the drug was still predominantly localized in the hippocampus, although some diffusion

Conclusion

The findings of this study highlight the versatility of mGluRs in synaptic plasticity and offer further insight into the nature of NMDAR- dependent and independent forms of LTP in the hippocampus. Thus, this study indicates that it is possible to induce both NMDAR- and VGCC-dependent LTP in the dentate gyrus of freely moving rats (using 200 and 400 Hz stimulation, respectively), and that VGCC-dependent LTP requires activation of L-type calcium channels. In addition, both forms of LTP critically

Acknowledgements

The authors would like to thank Ms S. Vieweg, Ms K. Schuhmacher and Ms G. Behnisch for expert technical assistance, and Ms K. Lohmann for assistance with computer graphics. This work was supported in part by grants to KGR from the Biomed II programme (BMH4-CT96-0228) and the Deutsche Forschungsgemeinschaft (SFB 426).

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Subtype-specific involvement of metabotropic glutamate receptors in two forms of long-term potentiation in the dentate gyrus of freely moving rats

Abstract

Section snippets

Experimental procedures

[3H]d(−)-2-amino-5-phosphonopentanoic acid application and drug diffusion

Drug application via the lateral cerebral ventricle results in diffusion to the hippocampus

Conclusion

Acknowledgements

Neuroscience

Neuropharmacology

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Eur. J. Pharmac. molec. Pharmac.

Neurosci. Lett.

Eur. J. Pharmac.

Neuroscience

Neuroscience

Neuropharmacology

Trends pharmac. Sci.

Novel form of long-term potentiation produced by K+ channel blocker in the hippocampus

Nature

Induction of LTP in hippocampus needs synaptic activation of glutamate metabotropic receptors

Nature

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

(R,S)-α-methyl-4-carboxyphenylglycine neither prevents induction of LTP nor antagonizes metabotropic glutamate receptors in CA1 hippocampal neurons

J. Neurophysiol.

[³H]d(−)-2-amino-5-phosphonopentanoic acid application and drug diffusion

Novel form of long-term potentiation produced by K⁺ channel blocker in the hippocampus