Elsevier

Neuroscience Research

Volume 45, Issue 4, April 2003, Pages 363-367
Neuroscience Research

Update article
On long-term depression induced by activation of G-protein coupled receptors

https://doi.org/10.1016/S0168-0102(03)00002-6Get rights and content

Abstract

In this mini-review I consider the mechanisms by which activation of glutamate and acetylcholine metabotropic receptors can result in the induction of long-term depression. Two regions of the CNS will receive particular attention; the CA1 region of hippocampus and the perirhinal cortex.

Section snippets

Glutamate

Glutamate is the neurotransmitter at most excitatory synapses within the central nervous system and acts via ionotropic and metabotropic receptors, located both postsynaptically and presynaptically. Ionotropic glutamate receptors (NMDA, AMPA and kainate) directly mediate ion flux across the plasma membrane of neurones whilst metabotropic glutamate (mGlu) receptors couple to their effector mechanisms via G proteins. mGlu receptors are divided into groups I, II and III based on sequence homology,

Acetylcholine

Acetylcholine-producing (cholinergic) neurones are principally located in the basal forebrain system and project diffusely to the cortex. Acetylcholine, like glutamate, acts via ionotropic (nicotinic) and metabotropic (muscarinic) receptors that are both pre and postsynaptically located. To date, five muscarinic receptor types have been identified; M1–M5 (see Kerlavage et al., 1987 for review). M1, 3 and 5 couple to activation of the phospholipase C pathway (and hence IP3 and DAG production)

Synaptic plasticity

Synaptic efficacy can be both increased and decreased in a long-term manner (long-term potentiation; LTP and long-term depression; LTD, respectively). LTD is a long-lasting decrease in the efficiency of synaptic transmission and is a generic term for several distinct forms of synaptic plasticity (Kemp and Bashir, 2001, Bear and Malenka, 1994, Bear and Abraham, 1996). For example, LTD can reverse LTP and this form of depression is referred to as depotentiation. Synaptic depression of

Synaptically induced mGlu receptor-dependent LTD in CA1 region of hippocampus

An unequivocal role for mGlu receptors in the induction of LTD was first demonstrated following the discovery of selective mGlu receptor antagonists, in particular α-methyl-4-carboxyphenylglycine (MCPG) (Bashir et al., 1993). Thus it was shown that the group I/II mGlu receptor antagonist MCPG prevented the induction of depotentiation normally induced by low frequency stimulation (LFS; 900 stimuli, 1 Hz) in the CA1 region of the hippocampus in vitro (Bashir et al., 1993, Bashir and Collingridge,

Synaptically induced mGlu receptor-dependent LTD in perirhinal cortex

A novel form of LTD dependent on the activation of both NMDA and mGlu receptors in the perirhinal cortex was recently described (Cho et al., 2000, Cho and Bashir, 2002). This form of LTD was novel for two reasons. Firstly, in contrast to virtually all forms of LTD described in the CA1 region there was a requirement for the activation of both NMDA and mGlu receptors. The second novel finding was the requirement of both group I and group II mGlu receptors at resting membrane potentials. Thus both

LTD induced by mGlu receptor agonists in hippocampus and perirhinal cortex

The application of mGlu receptor agonists, in particular the group I mGlu receptor agonist dihydroxyphenylglycine (DHPG), can result in LTD of synaptic transmission in different regions including the CA1 (Fitzjohn et al., 1996, Overstreet et al., 1997, Palmer et al., 1997, Schnabel et al., 1999, Huber et al., 2000, Watabe et al., 2002) and perirhinal cortex (McCaffery et al., 1999). Interestingly, DHPG-induced LTD does not require afferent stimulation (Fitzjohn et al., 1999, Huber et al., 2001

Biochemical mechanisms of mGlu receptor-dependent LTD

In the following section the mechanisms of synaptically induced and agonist induced mGlu LTD will be considered together.

In contrast to the mechanisms of activity-dependent NMDA receptor LTD, which are fairly well established, the mechanisms of mGlu receptor-mediated LTD are still a matter of some considerable debate. Interestingly, the saturation of DHPG-induced LTD does not prevent the subsequent induction of NMDA receptor-dependent LTD, and vice versa (Palmer et al., 1997, Huber et al., 2001

The locus of expression of mGlu receptor-dependent LTD

There is evidence that synaptically-induced (Bolshakov and Siegelbaum, 1994, Oliet et al., 1997) and DHPG-induced LTD (Fitzjohn et al., 2001, Watabe et al., 2002) are expressed presynaptically, as a decrease in the probability of glutamate release. In contrast however, it has recently been suggested that both DHPG-induced LTD and synaptically induced mGlu LTD are at least partly postsynaptic since both these forms are blocked by postsynaptically delivered protein synthesis inhibitors (Huber et

A role for other neurotransmitters in LTD?

Although the vast majority of studies show that LTD in the CA1 region can be blocked by either NMDA or mGlu receptor antagonists, there are some studies, which show no requirement for either of these receptors. For example, 5–10 Hz stimulation can result in the induction of LTD that is not blocked by a combination of NMDA and AMPA receptor antagonists nor by mGlu receptor antagonists (Berretta and Cherubini, 1998). The transmitters/receptors involved in this form of LTD have not been

LTD induced by muscarinic receptor activation in perirhinal cortex

The data above suggest that the major role of non-glutamatergic receptors might be to modulate the induction of LTD indirectly by for example regulating glutamate receptor activity. However, activation of acetylcholine receptors has now been shown to result directly in the induction of LTD. Thus in perirhinal cortex the application of acetylcholine (200 μM) or the non-hydrolysable analogue carbachol (50 μM) resulted in a large transient depression of synaptic transmission followed by LTD (

Future questions for acetylcholine and mGlu LTD

One important question for the study of G-protein receptor LTD is what is the role of tyrosine dephosphorylation in LTD? It is known that tyrosine phosphorylation can promote acetylcholine receptor clustering at the neuromuscular junction (Sanes and Lichtman, 1999) and that tyrosine dephosphorylation is involved in dispersal of acetylcholine receptor clusters (Dai and Peng, 1998). Therefore a dispersal of acetylcholine receptors, or dispersal of mGlu receptors, by tyrosine dephosphorylation

Conclusions

In this mini-review I have considered how activation of glutamate metabotropic receptors and acetylcholine metabotropic receptors couple to similar intracellular 2nd messengers and how this activation can result in the induction of long-term depression. While the understanding of mGlu LTD is further advanced than for acetylcholine LTD it would appear that there are parallels in the detailed intracellular mechanisms. It remains to be determined whether other transmitter receptors that couple to

Acknowledgements

Supported by the BBSRC, MRC and Wellcome Trust.

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