Different NMDA receptor subtypes mediate induction of long‐term potentiation and two forms of short‐term potentiation at CA1 synapses in rat hippocampus in vitro

Abstract

Key points• N -Methyl-D-aspartate receptor (NMDAR)-dependent potentiation of synaptic transmission is widely accepted as a cellular model of learning and memory.• It is most often studied in the CA1 area of rat hippocampal slices where it comprises a decremental and a sustained phase, which are commonly referred to as short-term potentiation (STP) and long-term potentiation (LTP), respectively.• In this study we show for the first time that STP and LTP are triggered by the activation of different classes of NMDARs and that STP itself comprises two pharmacologically and kinetically distinct components.• We suggest that the mechanistic separation of STP and LTP is likely to have important functional implications in that these two forms of synaptic plasticity can subserve unique physiological functions in a behaving animal.Abstract Potentiation at synapses between CA3 and the CA1 pyramidal neurons comprises both transient and sustained phases, commonly referred to as short-term potentiation (STP or transient LTP) and long-term potentiation (LTP), respectively. Here, we utilized four subtype-selective N -methyl-D-aspartate receptor (NMDAR) antagonists to investigate whether the induction of STP and LTP is dependent on the activation of different NMDAR subtypes. We find that the induction of LTP involves the activation of NMDARs containing both the GluN2A and the GluN2B subunits. Surprisingly, however, we find that STP can be separated into two components, the major form of which involves activation of NMDARs containing both GluN2B and GluN2D subunits. These data demonstrate that synaptic potentiation at CA1 synapses is more complex than is commonly thought, an observation that has major implications for understanding the role of NMDARs in cognition. A. Volianskis and N. Bannister contributed equally to this work.

BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation

“…BDNF enhances the expression and trafficking of GluN2A in cultured cortical and hippocampal neurons, and induces the phosphorylation of GluN2A subunit in PSD of rat spinal cord (Di et al, 2001;Hayashi et al, 2000), which is associated with an increase in NMDA receptor activity (Caldeira et al, 2007b;Small et al, 1998), whereas absence of BDNF induces a reduction of GluN2A level in the visual cortex of BDNF knock-out mice (Margottil and Domenici, 2003). Involvement of GluN2A-containing NMDA (GluN2A-NMDA) receptor in the development of LTP is supported by the findings that pharmacological inhibition of GluN2A by NVP-AAM077 blocks the induction of LTP in multiple brain regions including the hippocampus (Bartlett et al, 2007;Fox et al, 2006;Jin and Feig, 2010;Li et al, 2007;Liu et al, 2004;Volianskis et al, 2013), the cortex (Massey et al, 2004) as well as the amygdala (Dalton et al, 2012;Muller et al, 2009) and the nucleus accumbens (Schotanus and Chergui, 2008). Deletion of GluN2A subunit in mice results in a impaired induction of postsynaptic LTP in the dentate gyrus (Kannangara et al, 2014) and the visual cortex (Philpot et al, 2007), and at the mossy fiber to granule cell synapse in the cerebellum (Andreescu et al, 2011).…”

Ephenidine: A new psychoactive agent with ketamine-like NMDA receptor antagonist properties

“…Recordings of extracellular synaptic activity were made (Ceolin et al., 2012, Volianskis et al., 2013) using a bipolar electrode to deliver stimuli (0.03 Hz) to the Schaffer collateral pathway to evoke field excitatory postsynaptic potentials (fEPSPs) recorded from a glass microelectrode (3–6 MΩ) in the stratum radiatum of area CA1. The NMDA receptor-mediated component of the fEPSP (NMDA-fEPSP) was isolated by adding 3 μM NBQX, 50 μM picrotoxin and 1 μM CGP 55845 to the aCSF, which abolished AMPA and GABA receptor mediated transmission.…”

Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain

“…Although many studies have investigated which NMDAR subunit composition is required to trigger LTP in hippocampal area CA1, there is still some controversy regarding the relative role of the GluN2A-and GluN2B-containing NMDAR subtypes. Indeed, recent work suggests a predominant role for NMDAR tri-heteromers, which consist of GluN2A and GluN2B (together with the obligatory pair of GluN1 subunits), in the induction of LTP in area CA1 of adult tissue 58 . In the ACC, it has been shown that LTP, as detected by whole-cell patch-clamp recording, is sensitive to both GluN2A-preferring and GluN2B-preferring antagonists 57 , suggesting that tri-heteromers of the NMDAR may also be the dominant form of the receptor that contributes to LTP at these synapses.…”