- Email: [email protected]
Activation of glutamate metabotropic receptors induces long-term potentiation
European Journal of Pharmacology, 214 (1992) 297-298
297
© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00
EJP 0342R
Rapid communication
Activation of glutamate metabotropic receptors induces long-term potentiation Z u n e r A. B o r t o l o t t o a n d G r a h a m L. Collingridge Department of Pharmacology, The Medical School, Universityof Birmingham, Edgbaston, Birmingham B15 2TT UK Received 12 March 1992, accepted 18 March 1992
The specific glutamate metabotropic receptor agonist 1S,3R-aminocyclopentane dicarboxylate (ACPD), but not its inactive enantiomer 1R,3S-ACPD, induced a slowly developing potentiation of synaptic transmission in rat hippocampal slices. This effect was independent of its ability to potentiate responses mediated by the activation of N-methyI-D-aspartate receptors. Perfusion with 1S,3R-ACPD provides, therefore, a means of chemically inducing a form of long-term potentiation. 1S,3R-ACPD (1S,3R-aminocyclopentane dicarboxylate); Metabotropic receptors; Long-term potentiation (LTP)
It has been reported that activation of glutamate metabotropic receptors (mGluRs) can facilitate tetanus-induced long-term potentiation (LTP) in the CA1 region of the hippocampus (McGuinness et al., 1991). We now report that activation of these receptors can induce LTP in this region without the need for tetanic stimulation. Experiments were performed on rat hippocampal slices (400 /xm thick) that were prepared using standard techniques and maintained in an interface chamber at 30°C perfused with medium containing (mM): NaC1 124; KC1 3; NaHCO 3 26; CaC12 2; MgSO 4 1; D-glucose 10; N a H 2 P O 4 1.25, bubbled with a 95% 0 2 - 5 % CO 2 mixture. Extracellular recordings were obtained from stratum radiatum in response to low frequency stimulation (0.033 Hz, 20 /zs, 3 - 8 V) of Schaffer collateral-commissural fibres. Bath perfusion of 10/~M 1S,3R-aminocyclopentane dicarboxylate (ACPD) for 20 min resulted in a slowly developing potentiation of synaptic transmission in all 13 slices tested. In contrast, the 1R,3S enantiomer was inactive in the four slices examined. The effect of 1S,3R-ACPD was detected within a few minutes but took over 1 h to reach its maximum. A typical example of the time course and magnitude of the potentiation is illustrated in fig. 1. Two previous reports have shown that ACPD can augment tetanus-induced LTP, but in these studies when ACPD was applied without a tetanus LTP was not observed (McGuinness et al., 1991; Otani and
Correspondence to: G.L. Collingridge, Department of Pharmacology, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K. Tel. 44.21.414 4506, fax 44.21.414 4509.
1
2
3
20 ms
2.5 ~o 2.0 to
IS, 3 R - A C P D
m
o. 1.5 = 1.0
.%*.%*
..._..--1
~ 0.5 0
./-:2
2 i
i
i
20
40
60
i
i
i
80 1 0 0 1 2 0
Time (mln)
Fig. 1. 1S,3R-ACPD induces LTP. The graph plots the slope of the field EPSP versus time and shows the slowly developing potentiation induced by the addition of 1S,3R-ACPD (applied for the duration of the bar). Representative traces (averages of four are shown for the times indicated by 1-3.
Ben-Ari, 1991). The reason for the failure of these studies to detect this ACPD-induced LTP is not clear. The one methodological difference is that we used the 1S,3R enantiomer, which is the active form at mGluRs (Irving et al., 1990), whereas the earlier studies used the racemic mixture of the 1S,3R and 1R,3S isomers. The ability of ACPD to augment tetanus-induced LTP will relate, in part, to its ability to facilitate responses mediated by the activation of N-methyl-D-aspartate (NMDA) receptors (Harvey et al., 1991; Kelso et al., in press). However, the potentiation described in the present study does not involve the activation of N M D A receptors. Thus, at no time was there the appearance
298 o f t h e slow N M D A r e c e p t o r - m e d i a t e d c o m p o n e n t o f t h e synaptic r e s p o n s e . F u r t h e r m o r e , i d e n t i c a l p o t e n t i a tion can be i n d u c e d in t h e p r e s e n c e o f the N M D A receptor antagonist, D-2-amino-5-phosphonopentan o a t e ( u n p u b l i s h e d observations). In conclusion, o u r w o r k has shown t h a t s t i m u l a t i o n o f m G l u R s by A C P D can i n d u c e a f o r m o f L T P w i t h o u t t h e n e e d for a tetanus. Interestingly, A C P D , unlike a tetanus, d o e s not p r o d u c e a r a p i d e n h a n c e m e n t o f synaptic efficiency. Its t i m e c o u r s e p a r a l l e l s t h a t o f t h e k i n a s e - d e p e n d e n t p h a s e of t e t a n u s - i n d u c e d LTP, which is a s s o c i a t e d with an i n c r e a s e in A M P A r e c e p t o r sensitivity ( R e y m a n n et al., 1990). This suggests that A C P D m a y specifically i n d u c e a p o s t s y n a p t i c c o m p o n e n t o f L T P , possibly t h r o u g h the activation of p r o t e i n k i n a s e C.
Acknowledgements Supported by the MRC. ZAB acknowledges support from CAPES CNPq.
References Harvey, J., B.G. Frenguelli, D.C. Sunter, J.C. Watkins and G.L. Collingridge, 1991, The actions of 1S,3R-ACPD, a glutamate metabotropic receptor agonist, in area Cal of rat hippocampus, Br. J. Pharmacol. 104, c79. Irving, A.J., J.G. Schofield, J.C. Watkins, D.C. Sunter and G.L. Collingridge, 1990, 1S,3R-ACPD stimulates and L-AP3 blocks Ca 2+ mobilization in rat cerebellar neurons, Eur. J. Pharmacol. 186, 363. Kelso, S.R., T.E. Nelson and J.P. Leonard, Protein kinase C-mediated enhancement of NMDA currents by metabotropic glutamate receptors in Xenopus oocytes, J. Physiol. (London) (in press). McGuinness, N., R. Anwyl and M. Rowan, 1991, Trans-ACPD enhances long-term potentiation in the hippocampus, Eur. J. Pharmacol. 197, 231. Otani, S. and Y. Ben-Ari, 1991, Metabotropic receptor-mediated long-term potentiation in rat hippocampal slices, Eur. J. Pharmacol. 205, 325. Reymann, K.G., S.N. Davies, H. Matthies, H. Kase and G.L. Collingridge, 1990, Activation of a K-252b-sensitive protein kinase is necessary for a post-synaptic phase of long-term potentiation in area Cal of rat hippocampus, Eur. J. Neurosci. 2, 481.
297
© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00
EJP 0342R
Rapid communication
Activation of glutamate metabotropic receptors induces long-term potentiation Z u n e r A. B o r t o l o t t o a n d G r a h a m L. Collingridge Department of Pharmacology, The Medical School, Universityof Birmingham, Edgbaston, Birmingham B15 2TT UK Received 12 March 1992, accepted 18 March 1992
The specific glutamate metabotropic receptor agonist 1S,3R-aminocyclopentane dicarboxylate (ACPD), but not its inactive enantiomer 1R,3S-ACPD, induced a slowly developing potentiation of synaptic transmission in rat hippocampal slices. This effect was independent of its ability to potentiate responses mediated by the activation of N-methyI-D-aspartate receptors. Perfusion with 1S,3R-ACPD provides, therefore, a means of chemically inducing a form of long-term potentiation. 1S,3R-ACPD (1S,3R-aminocyclopentane dicarboxylate); Metabotropic receptors; Long-term potentiation (LTP)
It has been reported that activation of glutamate metabotropic receptors (mGluRs) can facilitate tetanus-induced long-term potentiation (LTP) in the CA1 region of the hippocampus (McGuinness et al., 1991). We now report that activation of these receptors can induce LTP in this region without the need for tetanic stimulation. Experiments were performed on rat hippocampal slices (400 /xm thick) that were prepared using standard techniques and maintained in an interface chamber at 30°C perfused with medium containing (mM): NaC1 124; KC1 3; NaHCO 3 26; CaC12 2; MgSO 4 1; D-glucose 10; N a H 2 P O 4 1.25, bubbled with a 95% 0 2 - 5 % CO 2 mixture. Extracellular recordings were obtained from stratum radiatum in response to low frequency stimulation (0.033 Hz, 20 /zs, 3 - 8 V) of Schaffer collateral-commissural fibres. Bath perfusion of 10/~M 1S,3R-aminocyclopentane dicarboxylate (ACPD) for 20 min resulted in a slowly developing potentiation of synaptic transmission in all 13 slices tested. In contrast, the 1R,3S enantiomer was inactive in the four slices examined. The effect of 1S,3R-ACPD was detected within a few minutes but took over 1 h to reach its maximum. A typical example of the time course and magnitude of the potentiation is illustrated in fig. 1. Two previous reports have shown that ACPD can augment tetanus-induced LTP, but in these studies when ACPD was applied without a tetanus LTP was not observed (McGuinness et al., 1991; Otani and
Correspondence to: G.L. Collingridge, Department of Pharmacology, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K. Tel. 44.21.414 4506, fax 44.21.414 4509.
1
2
3
20 ms
2.5 ~o 2.0 to
IS, 3 R - A C P D
m
o. 1.5 = 1.0
.%*.%*
..._..--1
~ 0.5 0
./-:2
2 i
i
i
20
40
60
i
i
i
80 1 0 0 1 2 0
Time (mln)
Fig. 1. 1S,3R-ACPD induces LTP. The graph plots the slope of the field EPSP versus time and shows the slowly developing potentiation induced by the addition of 1S,3R-ACPD (applied for the duration of the bar). Representative traces (averages of four are shown for the times indicated by 1-3.
Ben-Ari, 1991). The reason for the failure of these studies to detect this ACPD-induced LTP is not clear. The one methodological difference is that we used the 1S,3R enantiomer, which is the active form at mGluRs (Irving et al., 1990), whereas the earlier studies used the racemic mixture of the 1S,3R and 1R,3S isomers. The ability of ACPD to augment tetanus-induced LTP will relate, in part, to its ability to facilitate responses mediated by the activation of N-methyl-D-aspartate (NMDA) receptors (Harvey et al., 1991; Kelso et al., in press). However, the potentiation described in the present study does not involve the activation of N M D A receptors. Thus, at no time was there the appearance
298 o f t h e slow N M D A r e c e p t o r - m e d i a t e d c o m p o n e n t o f t h e synaptic r e s p o n s e . F u r t h e r m o r e , i d e n t i c a l p o t e n t i a tion can be i n d u c e d in t h e p r e s e n c e o f the N M D A receptor antagonist, D-2-amino-5-phosphonopentan o a t e ( u n p u b l i s h e d observations). In conclusion, o u r w o r k has shown t h a t s t i m u l a t i o n o f m G l u R s by A C P D can i n d u c e a f o r m o f L T P w i t h o u t t h e n e e d for a tetanus. Interestingly, A C P D , unlike a tetanus, d o e s not p r o d u c e a r a p i d e n h a n c e m e n t o f synaptic efficiency. Its t i m e c o u r s e p a r a l l e l s t h a t o f t h e k i n a s e - d e p e n d e n t p h a s e of t e t a n u s - i n d u c e d LTP, which is a s s o c i a t e d with an i n c r e a s e in A M P A r e c e p t o r sensitivity ( R e y m a n n et al., 1990). This suggests that A C P D m a y specifically i n d u c e a p o s t s y n a p t i c c o m p o n e n t o f L T P , possibly t h r o u g h the activation of p r o t e i n k i n a s e C.
Acknowledgements Supported by the MRC. ZAB acknowledges support from CAPES CNPq.
References Harvey, J., B.G. Frenguelli, D.C. Sunter, J.C. Watkins and G.L. Collingridge, 1991, The actions of 1S,3R-ACPD, a glutamate metabotropic receptor agonist, in area Cal of rat hippocampus, Br. J. Pharmacol. 104, c79. Irving, A.J., J.G. Schofield, J.C. Watkins, D.C. Sunter and G.L. Collingridge, 1990, 1S,3R-ACPD stimulates and L-AP3 blocks Ca 2+ mobilization in rat cerebellar neurons, Eur. J. Pharmacol. 186, 363. Kelso, S.R., T.E. Nelson and J.P. Leonard, Protein kinase C-mediated enhancement of NMDA currents by metabotropic glutamate receptors in Xenopus oocytes, J. Physiol. (London) (in press). McGuinness, N., R. Anwyl and M. Rowan, 1991, Trans-ACPD enhances long-term potentiation in the hippocampus, Eur. J. Pharmacol. 197, 231. Otani, S. and Y. Ben-Ari, 1991, Metabotropic receptor-mediated long-term potentiation in rat hippocampal slices, Eur. J. Pharmacol. 205, 325. Reymann, K.G., S.N. Davies, H. Matthies, H. Kase and G.L. Collingridge, 1990, Activation of a K-252b-sensitive protein kinase is necessary for a post-synaptic phase of long-term potentiation in area Cal of rat hippocampus, Eur. J. Neurosci. 2, 481.