Synaptic Plasticity

mGlu Receptors in LTP

Hippocampus

The most studied part of the brain in relation to synaptic plasticity is the hippocampus. The involvement of mGlu receptors in LTP was first shown in this region (Bashir et al 1993) where (S)-MCPG, a groupI/II mGlu receptor antagonist, was shown to block both NMDAR-dependent and NMDAR-independent LTP. However, subsequent work showed that application of LY341495, at a concentration where it acts as a broad-spectrum mGlu receptor antagonist, did not block either form of LTP in the hippcampus (Fitzjohn et al 1998). In addition, neither blockade of Group I receptors or their knockout affects the induction of LTP in hippocampal CA1 neurons (Doherty et al 2000; Conqeut et al 1994; Bortolotto et al 2005). Thus the identity of the receptor blocked by (S)-MCPG is still unkown.

Metaplasticity - The Molecular Switch

Molecular SwitchThe Molecular Switch: MCPG blocks the induction of LTP in experimentally naïve inputs (blue) but not in inputs that have experienced prior LTP (red)

While the known mGlu receptors may not play a role in the direct induction or expression of hippocampal LTP, they are crucial for a form of metaplasticity known as the Molecular Switch (Bortolotto et al 1994). This phenomenon is where the ability of (S)-MCPG to block the induction of LTP in a particular pathway is determined by the previous experience of LTP induction in that pathway . Thus, (S)-MCPG can only block LTP induction in a pathway that has not previously experienced LTP induction - a naive pathway. The particular mGlu receptor subtype involved in this process has been shown to be the mGlu5 receptor as it is blocked by MPEP, activated by (RS)-CHPG and absent in mGlu5-/- mice (Bortolotto et al 2005). We have also shown that the molecular switch is set at a much lower level of stimulus than LTP itself (Bortolotto et al 2008), with as few as 10 shocks at 5Hz able to set the switch but not to induce LTP.

mGlu Receptors in LTD

Unlike LTP, mGlu receptors are directly involved in a diverse range of LTD mechanisms.

DHPG-dependent LTD

DHPG-LTDDHPG-dependent LTD. Application of DHPG leads to a long-lasting depression of synaptic transmission (red circles). This effect can be totally blocked by the tyrosine phosphatase inhibitor PAO (blue circels). After: Moult et al (2002) Neuropharmacology 43; 175-180 © Elsevier Ltd
This form of LTD was first reported in 1997 ( Palmer et al 1997), where it was shown that DHPG could induce a long lasting depression of synaptic transmission in the CA1 region of the hippocampus. It was later shown that induction was also induced by the mGlu5 receptor agonist, CHPG ( Fitzohn et al 1999). This form of LTD is different to that induced by a standard low frequency stimulus (LFS, eg 1200 shocks @ 2 Hz) as it is still evident once LFS-induced LTD has been saturated ( Palmer et al 1997).

The expression mechanism for DHPG-induced LTD is via phosphorylation/dephosphorylation cycles. It is unaffected by PKC or PKA inhibitors ( Schanbel et al 1999, 2000), but broad spectrum protein phosphatase inhibitors have been shown to facilitate LTD while protein tyrosine phosphatase (PTP) inhibitors have been shown to inhibit this form of LTD ( Schnabel et al 2001; Moult et al 2002, 2006). This is the same as the requirements for a form of synaptic LTD that is induced by paired-pulses ( Moult et al 2008). It is thus likely that these two forms of LTD are infact the same, but induced in different ways.
Orthovanadate inhibition of DHPG-induced AMPAR internalisationOrthovanadate, a PTP inhibitor, blocks DHPG-induced loss of surface expressed AMPA receptors. From: Moult et al (2006) J. Neuroscience 26; 2852-2861© Society for Neuroscience
The cellular effects of these molecular events appears to be a loss of surface expressed AMPA receptors and possibly also NMDA receptors. DHPG induces an increase in the failure rate of dendritically recorded, AMPA receptor-mediated EPSCs under minimal stimulation ( Fitzjohn et al 2001). Another study has shown more directly that DHPG induces the internalisation of both AMPA and NMDA receptors in cultured hippocampal neurons ( Synder et al 2001), while more recent immunocytochemical investigations have shown that loss of AMPA receptors from the neuronal surface is blocked by PTP inhibitors ( Moult et al 2006). Thus, although the induction and expression mechanisms of mGluR- and NMDAR-dependent LTD are different, the end result may be the same, i.e. a loss of surface expressed receptors.

The effect of DHPG-induced LTD is not confined to an acute increase in AMPA receptor internalisation, but it also has a regulatory role in protein synthesis (Synder et al 2001).

Synaptically induced mGlu receptor-dependent LTD

Low frequency stimulation-induced LTD (LFS-LTD)

Role of NCS1 and PICK1 in mGlu-dependent LTDIt is well known that delivery of a low frequency stimulus to hippocampal neurons (eg 900 stimuli @ 1Hz) results in a form of LTD that is dependent on NMDA receptors. In the perirhinal cortex, raising the frequency of stimulation to 5Hz results in the induction of a NMDA receptor independent form of LTD that is dependent on mGlu receptors instead (Jo et al 2006). This form of LTD requires the activation of PKC, PICK1 and a neuronal Ca2+ sensing protein, NCS-1 (Jo et al 2008). NCS-1 and PICK1 were shown to interact in a mGlu receptor dependent manner. It is hypothesised that NCS-1 acts to target PICK1 and thus PKC to the AMPA receptor, resulting in phosphorylation and internalisation. This analagous to the role hippocalcin (another Ca2+ sensing protein) plays in NMDAR-mediated AMPA receptor internalisation, where it targets AP2 to the GluA2 subunit as part of the internalisation process.

Paired pulse-induced LTD (PP-LTD)

A train of paired stimuli given at low frequency, can generate LTD in adults that is independent of NMDA receptors (Kemp & Bashir 1997) and is blocked by the mGlu receptor antagonists LY341495 and CPCCOEt when used in combination with the AMPA/Kainate antagonist CNQX,(Kemp & Bashir 1999; Note: although CPCCOEt is generally regarded as a mGlu1 receptor selective antagonist, the mGlu5 receptor is the predominant form of Group I mGlu receptor in the CA1 region of the hippocampus). In this induction protocol, the stimulation produces paired pulse facilitation, a form of short term plasticity in which the post-synaptic response to the second stimulation pulse is larger that the first. This is most likely due to increased glutamate release and will result in a stronger activation of the post-synaptic receptors, resulting in the observed LTD.

Such results suggest that mGlu receptors play a role in this form of LTD, a notion that is confirmed by the finding that paired pulse-induced LTD is absent in mice that lack the mGlu5 receptor (Huber et al 2001). More recently, PP-LTD was shown to be blocked by the mGlu5 receptor antagonist MPEP while being unaffected by the mGlu1 receptor antagonist LY367385 (Moult et al 2008), thus confirming that this form of LTD requires the activation of mGlu5 receptors. This study also demonstrated that PP-LTD  requires co-activation of both protein tyrosine phosphatase cascades and the p38 MAPK pathway. This suggests a new level of complexity in the signalling pathways that lead to AMPA receptor internalisation and LTD.