Characterization of the Mechanism Underlying the Reversal of Long Term Potentiation by Low Frequency Stimulation at Hippocampal CA1 Synapses

Abstract

Reversal of long term potentiation (LTP) may function to increase the flexibility and storage capacity of neuronal circuits; however, the underlying mechanisms remain incompletely understood. We show that depotentiation induced by low frequency stimulation (LFS) (2 Hz, 10 min, 1200 pulses) was input-specific and dependent on Nmethyl-D-aspartate (NMDA) receptor activation. The ability of LFS to reverse LTP was mimicked by a brief application of NMDA. This NMDA-induced depotentiation was blocked by adenosine A 1 receptor antagonist. However, the reversal of LTP by LFS was unaffected by metabotropic glutamate receptor antagonism. This LFS-induced depotentiation was specifically prevented by protein phosphatase (PP)1 inhibitors, okadaic acid, and calyculin A but not by the PP2A or PP2B inhibitors. Furthermore, by using phosphorylation site-specific antibodies, we found that LFS-induced depotentiation is associated with a persistent dephosphorylation of the GluR1 subunit of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor at serine 831, a protein kinase C and calcium/ calmodulin-dependent protein kinase II (CaMKII) substrate, but not at serine 845, a substrate of cAMPdependent protein kinase. This effect was mimicked by bath-applied adenosine or NMDA and was specifically prevented by okadaic acid. Also, the increased phosphorylation of CaMKII at threonine 286 and the decreased PP activity seen with LTP were overcome by LFS, adenosine, or NMDA application. These results suggest that LFS erases LTP through an NMDA receptor-mediated activation of PP1 to dephosphorylate amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and CaMKII in the CA1 region of the hippocampus. Long term potentiation (LTP)1 is a long lasting form of synaptic plasticity that is thought to play important roles in learning and memory in the brain (1). Although LTP is very persistent, current work has provided evidence that various manipulations or pharmacological treatment when applied shortly after LTP induction can reverse it. For example, it has been shown that transient anoxia occurring 1-2 min after LTP induction prevented the stable expression of LTP (2). Such time-dependent reversal of LTP was also effectively induced by low frequency afferent stimulation (1-5 Hz) when delivered within 10 min of LTP induction, both in vivo (3, 4) and in vitro (5-7). In addition, antagonists that prevent cell-cell and cellmatrix interactions were also observed to reverse effectively LTP in a time-dependent manner (8, 9). This reversal of synaptic strength from the potentiated state to pre-LTP levels has been called depotentiation and may provide a mechanism of preventing the saturation of synaptic potentiation and increase the efficiency and the capacity of the information storage of the neuronal networks (10). Although depotentiation has been consistently demonstrated in several brain regions including hippocampus (3-6, 11-14), visual cortex (15), sensorimotor cortex (16), and prefrontal cortex (17), the exact biochemical processes and mol...

Integrin-driven actin polymerization consolidates long-term potentiation

“…3C). Stimulation of adenosine A1 receptors also eliminates recently formed LTP (23) and mediates the time-dependent reversal effect obtained with low-frequency stimulation (20,22). Adenosine proved to be potent in blocking theta-burst-induced actin polymerization when applied immediately after TBS (Fig.…”

“…LTP is vulnerable to a number of treatments, including low-frequency stimulation (11,(20)(21)(22) and adenosine A1 agonists (23) during the 30-to 60-min consolidation period. We tested the effects of each of these manipulations on theta-induced increases in spine actin labeling.…”

Hippocampal Metaplasticity Induced by Deficiency in the Extracellular Matrix Glycoprotein Tenascin-R

“…In an additional series of experiments, the slices were preincubated with ACSF containing one of several compounds for 2 h before transferring slices to the recording chamber and perfusion with normal ACSF. The following reagents were used for in vitro experiments: the GABA A receptor agonists muscimol (1 M) (Akhondzadehet al, 2002) and zolpidem (0.3 M) (Liang et al, 2004) (Saghatelyan et a., 2003), the nicotinic acetylcholine receptor agonist nicotine (1 M) (Fujii et al, 2000), the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (APV; 50 M) (Mockett et al, 2002), the antagonist of metabotropic glutamate receptors (RS)-␣-methyl-4-carboxyphenyglycine (MCPG; 200 M) (Breakwell et al, 1998), the blocker of L-type Ca 2ϩ channels nifedipine (1 M) (He et al, 2001), the inhibitor of protein serine/ threonine phosphatases types 1 and 2A (PP1/2A) calyculin A (1 M) (Huang et al, 2001), and the HNK-1 peptidomimetic or scrambled control peptide (100 g/ml) (Simon-Haldi et al, 2002;Saghatelyan et a., 2003). The use of peptidomimetic has advantages over the native carbohydrate because the peptide is more stable, and considerably more easily synthesized or isolated.…”

“…5 A, C), supporting the view that these channels constitute an important route for Ca 2ϩ entry necessary for induction of metaplasticity. Because sustained Ca 2ϩ entry may stimulate the activity of protein phosphatases, we treated slices with the inhibitor of PP1/2A, calyculin A, known to prevent some forms of metaplasticity (Huang et al, 2001;Woo and Nguyen, 2002;Kang-Park et al, 2003). This treatment dramatically increased LTP in TNRϪ/Ϫ mice to 196.5 Ϯ 19.9%, compared with 157.1 Ϯ 14.0% recorded in TNRϩ/ϩ mice (Fig.…”

Immediate extinction causes a less durable loss of performance than delayed extinction following either fear or appetitive conditioning

“…Depotentiation counteracts most of the effects of LTP, including protein synthesis and phosphorylation of second messenger cascades leading to gene transcription (see e.g., Lin et al 2003aLin et al , 2005. Depotentiation is generally inducible only within intervals less than 1 h after LTP induction (e.g., Stäubli and Chun 1996;Huang et al 2001). Under such conditions, synaptic potentiation (LTP) returns to baseline; this suggests the memory trace might have been erased.…”