Mechanisms of Group I mGluR-Dependent Long-Term Depression of NMDA Receptor–Mediated Transmission at Schaffer Collateral–CA1 Synapses

Abstract

Ireland DR, Abraham WC. Mechanisms of group I mGluR-dependent long-term depression of NMDA receptor-mediated transmission at Schaffer collateral-CA1 synapses. J Neurophysiol 101: 1375-1385, 2009. First published December 24, 2008 doi:10.1152/jn.90643.2008. The mechanisms underlying group I metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) of N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic currents (EPSCs NMDAR ) are poorly understood. Here we investigated the effects of (R,S)-3,5-dihydroxyphenylglycine (DHPG), a selective agonist of group I mGluRs, on the EPSCs NMDAR in area CA1 of acute hippocampal slices from 6-to 8-wk Sprague-Dawley rats. DHPG acutely and persistently depressed the isolated EPSC NMDAR and transiently slowed its decay rate. Combined antagonism of mGluR1 and mGluR5 blocked the effects of DHPG. Strong calcium buffering with intracellular BAPTA did not reduce the acute depression or LTD, making the involvement of elevated postsynaptic calcium unlikely. The acute depression and LTD were not mediated by activation of tyrosine kinases or phosphatases, nor were they dependent on protein synthesis. However, the LTD was prevented by the intracellular actin-stabilizer jasplakinolide, raising the possibility that it was associated with a lateral movement of NMDARs. Supporting this hypothesis, when the effective spatial spread of synaptically released glutamate was increased using the glutamate transporter inhibitor TBOA, the resultant EPSC NMDAR did not undergo LTD in response to DHPG. Importantly, isolation of the extrasynaptic EPSC NMDAR by blockade of synaptic NMDARs with MK-801 showed that this was not due to a potentiation of the preexisting extrasynaptic component. These findings indicate that LTD of NMDAR-mediated synaptic transmission occurs via lateral movement of receptors away from the synapse.

Interaction between Ephrins and mGlu5 Metabotropic Glutamate Receptors in the Induction of Long-Term Synaptic Depression in the Hippocampus

“…DHPG-induced LTD at the Schaffer collateral-CA1 synapses is insensitive to inhibitors of phospholipase C␤ (Huang and Hsu, 2006), inhibitors of protein kinase C (Schnabel et al, 1999), intracellular Ca 2ϩ chelators (Fitzjohn et al, 2001;Ireland and Abraham, 2009), or agents that deplete intracellular Ca 2ϩ stores (Schnabel et al, 1999). Thus, it is unlikely that amplification of PI hydrolysis mediates the synergism between clustered EphB1/Fc and DHPG on synaptic depression.…”

Calcium/Calmodulin-Dependent Protein Kinase II Mediates Group I Metabotropic Glutamate Receptor-Dependent Protein Synthesis and Long-Term Depression in Rat Hippocampus

“…), and the brains were removed and chilled in ice-cold oxygenated aCSF for which sucrose was substituted for NaCl (composition in mM: 210 sucrose, 20 glucose, 2.5 KCl, 1.25 NaH 2 PO 4 , 26 NaHCO 3 , 0.5 CaCl 2 , 3 MgCl 2 , 2 ascorbic acid, and 3 Na-pyruvate, pH 7.4, when gassed with 95% O 2 -5% CO 2 ). Transverse hippocampal slices (400 m) were cut on a Vibroslicer (Campden Instruments) and transferred to a static incubation chamber containing oxygenated aCSF (composition in mM: 124 NaCl, 20 glucose, 2.5 KCl, 1.25 NaH 2 PO 4 , 26 NaHCO 3 , 2.5 CaCl 2 , 1.3 MgCl 2 , 2 ascorbic acid, and 3 Na-pyruvate, pH 7.4, when gassed with 95% O 2 -5% CO 2 ) at 34°C where they were placed on a Millicell culture plate insert in interface conditions for 30 min (Ireland and Abraham, 2009). The incubation chamber was then allowed to cool to room temperature and the slices held for an additional 90 min.…”

“…The initial slopes of the fEPSPs were measured and expressed as a percentage change from the baseline level, calculated as the average of the last 15 min of the baseline recording period (Mockett et al, 2002). EPSC peak amplitudes were measured relative to the prestimulus baseline and expressed as a percentage change from the baseline level, calculated from an average of the last 10 min of the baseline recording period (Ireland and Abraham, 2009). The degree of LTD for each experiment was measured as the average of the last 5 min of the post-DHPG recording period, whereas the group means were expressed as the percentage change Ϯ SEM.…”

Fear Memory

“…AMPA receptor trafficking consists of lateral displacements (253), exocytosis (495,565), and/or capture by the postsynaptic density protein PSD95 (593,683). Aging, in which memory deficits are known to take place, has been suggested to involve defective trafficking of AMPA or other receptors (GABA, NMDA) (237).…”