NMDA receptor‐mediated metaplasticity during the induction of long‐term depression by low‐frequency stimulation

Abstract

Metaplasticity refers to the activity-dependent modification of the ability of synapses to undergo subsequent synaptic plasticity. Here, we have addressed the question of whether metaplasticity contributes to the induction of long-term depression (LTD) by low-frequency stimulation (LFS). The experiments were conducted using standard extracellular recording techniques in stratum radiatum of area CA1 in hippocampal slices made from adult Sprague-Dawley rats. The degree of LTD induction was found to be a nonlinear function of the number of pulses during a 1-Hz LFS. Little LTD was observed following 600 or 900 pulses, but a significant LTD occurred following 1200 pulses of LFS, whether delivered in one episode, or in two bouts of 600 pulses given 10 min apart. A similar pattern was observed for 3 Hz LFS. The data support the suggestion that pulses occurring early in the LFS train prime synapses for LTD induction, as triggered by later occurring stimuli. The priming effect lasted at least 120 min, when tested by giving two bouts of 1 Hz LFS (600 pulses each) at different intervals. Neither heterosynaptic nor homosynaptic stimulation by itself was sufficient to prime LTD. However, a combination of the stimuli, induced by increased stimulus strength during the LFS, appeared necessary for inducing the effect. An N-methyl-d-aspartate (NMDA) receptor antagonist markedly reduced total LTD induction, regardless of whether it was administered during the first or second LFS in a protocol employing two bouts of 600 pulse LFS, 30 min apart. These findings strongly support the hypothesis that NMDA receptor-dependent metaplasticity processes contribute to the induction of LTD during standard LFS protocols.

Low-Frequency Stimulation Depresses the Primate Anterior-Cingulate-Cortex and Prevents Spontaneous Recovery of Aversive Memories

“…In contrast to studies that abolish the spontaneous activity of the PL by HFS (Vidal-Gonzalez et al, 2006), or Muscimol (Blum et al, 2006;Corcoran and Quirk, 2007;Laurent and Westbrook, 2009), the local effect of LFS is brief and minor (Hashimoto et al, 2003;Maurice et al, 2003;Bar-Gad et al, 2004); yet LFS has a long-term accumulating effect on the region's responsiveness, as shown here (Mockett et al, 2002). Further, stimulation was not coupled with presentation and therefore did not affect behavioral expression and CS-related responses.…”

Metaplastic Regulation of Long-Term Potentiation/Long-Term Depression Threshold by Activity-Dependent Changes of NR2A/NR2B Ratio

“…However, it is still unclear whether prior activity without producing persistent changes could exert influence on subsequent synaptic activity, although a few studies hint that it might occur (Mockett et al, 2002). In the present study, we address this question by setting the intensity to produce one-fifth maximal fEPSPs.…”

“…PSs across a range of frequencies (1,5,10,20,50, and 100 Hz) was delivered to the Schaffer's fibers of hippocampal slices. The pulse number for the stimulation at each frequency was fixed at 600 Wang and Wagner, 1999;Mockett et al, 2002). The intensity of the PSs was set to produce one-fifth maximal fEPSPs.…”

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

“…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).…”