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

Chiung-Chun Huang, Ying-Ching Liang, Kuei-Sen Hsu
2001 Journal of Biological Chemistry  
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
more » ... y 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-5methyl-4-isoxazolepropionic acid receptors and CaMKII in the CA1 region of the hippocampus. Long term potentiation (LTP) 1 is a long lasting form of syn-aptic 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 molecular mechanisms responsible for this synaptic plasticity are incomplete. We have demonstrated previously that the LFS-induced depotentiation at Schaffer collateral-CA1 synapses may attribute to an increase of extracellular adenosine acting on the A 1 adenosine receptors to interrupt the cAMP-PKA-dependent signaling cascades leading to the development of LTP (7). In addition, the induction of depotentiation requires the activation of PP-coupled cascades. In this study, we describe experiments in the CA1 region of rat hippocampus designed to characterize further this form of synaptic plasticity using both electrophysiological and biochemical techniques. In particular, we addressed the following questions. 1) Is the LFS-induced depotentiation input-specific and dependent on NMDA and/or mGluR activation? 2) Does the pharmacological activation of NMDA receptors mimic the LFS to elicit a time-dependent reversal of LTP? 3) What is the kind of PP participating in LFS-induced depotentiation, and what might be its substrate(s) after its activation during depotentiation? We provide evidence that a PP1-mediated dephosphorylation of GluR1 subunit of AMPA receptors at serine 831, known as a substrate of CaMKII and PKC, may be a major expression mechanism for NMDA receptor-dependent homosynaptic LFS-induced depotentiation. These results also imply that PP1 may serve as the sensor of the level of neuronal activity and in turn regulates the development of LTP at Schaffer collateral-CA1 synapses. . 1 The abbreviations used are: LTP, long term potentiation; LFS, low frequency stimulation; NMDA, N-methyl-D-aspartate; PKA, protein kinase A; PKC, protein kinase C; PP, protein phosphatase; AMPA, ?; CaMKII, calcium/calmodulin-dependent protein kinase II; ACSF, artificial cerebral spinal fluid; fEPSPs, field excitatory postsynaptic potentials; DPCPX, 8-Cyclopentyl-1,3-dipropylxanthine; D-APV, D-2-amino-5-phosphonovalerate; AIDA, aminoindan-1,5-dicarboxylic acid; mGluR, metabotropic glutamate receptor; MCPG, ␣-methyl-4-carboxyphenylglycine; MAP, mitogen-activated protein.
doi:10.1074/jbc.m106388200 pmid:11679581 fatcat:6oeejceoizfg7f6cuinnxv6tli