Long-Term Potentiation Induced by θ Frequency Stimulation Is Regulated by a Protein Phosphatase-1-Operated Gate

Abstract

Long-term potentiation (LTP) can be induced in the Schaffer collateral3CA1 synapse of hippocampus by stimulation in the frequency range (5-12 Hz), an effect that depends on activation of the cAMP pathway. We investigated the mechanisms of the cAMP contribution to this form of LTP in the rat hippocampal slice preparation. pulse stimulation (TPS; 150 stimuli at 10 Hz) by itself did not induce LTP, but the addition of either the ␤-adrenergic agonist isoproterenol or the cAMP analog 8-bromocAMP (8-Br-cAMP) enabled TPS-induced LTP. The isoproterenol effect was blocked by postsynaptic inhibition of cAMPdependent protein kinase. Several lines of evidence indicated that cAMP enabled LTP by blocking postsynaptic protein phosphatase-1 (PP1). Activators of the cAMP pathway reduced PP1 activity in the CA1 region and increased the active form of inhibitor-1, an endogenous inhibitor of PP1. Postsynaptic injection of activated inhibitor-1 mimicked the LTP-enabling effect of cAMP pathway stimulation. TPS evoked complex spiking when isoproterenol was present. However, complex spiking was not sufficient to enable TPS-induced LTP, which additionally required the inhibition of postsynaptic PP1. PP1 inhibition seems to promote the activation of Ca 2ϩ /calmodulin-dependent protein kinase (CaMKII), because (1) a CaMKII inhibitor blocked the induction of LTP by TPS paired with either isoproterenol or activated inhibitor-1 and (2) CaMKII in area CA1 was activated by the combination of TPS and 8-Br-cAMP but not by either stimulus alone. These results indicate that the cAMP pathway enables TPS-induced LTP by inhibiting PP1, thereby enhancing Ca 2ϩ -independent CaMKII activity. Key words: LTP induction; cAMP-dependent protein kinase; inhibitor-1; protein phosphatase-1; Ca 2ϩ /calmodulin-dependent protein kinase; gating; complex spikesMany synapses in the CNS can be strengthened or weakened by repetitive stimulation. This phenomenon has been intensively studied in the rodent hippocampus, particularly at the synapse between the pyramidal cells of areas CA3 and CA1 (Bliss and Collingridge, 1993;Malenka and Nicoll, 1999), and many of these studies have investigated how particular patterns of stimulation give rise to different forms of synaptic plasticity. Such factors as the frequency, intensity, and duration of the stimulation determine whether the synapse is strengthened or weakened, as well as the persistence of the synaptic change. Remarkably, even when two different patterns induce seemingly similar synaptic changes, they may do so via different molecular mechanisms. Efforts to understand the role of the pattern of stimulation in synaptic plasticity may prove particularly valuable, because pronounced spontaneous frequency variations characterize hippocampal neuronal activity in behaving animals (Fenton and Muller, 1998). Studies in hippocampal slices have established that the pattern of stimulation determines the mechanism of synaptic change, so it is reasonable to speculate that the natural patterns of the hippocampus in vivo may give ri...

Cytoplasmic Polyadenylation Element Binding Protein-Dependent Protein Synthesis Is Regulated by Calcium/Calmodulin-Dependent Protein Kinase II

“…When phosphorylated, these inhibitors suppress PP1 activity. During early-phase LTP, activation of CaMKII is accompanied by PP1 inhibition through this mechanism, and this could result in prolonged phosphorylation of CPEB and stronger stimulation of protein synthesis than occurs with depolarizing stimulation alone (Blitzer et al, 1998;Makhinson et al, 1999;Brown et al, 2000). DARPP-32 is dephosphorylated by calcineurin, a calciumdependent protein phosphatase, which responds to moderate levels of calcium (Winder and Sweatt, 2001).…”

Postsynaptic Application of a Peptide Inhibitor of cAMP-Dependent Protein Kinase Blocks Expression of Long-Lasting Synaptic Potentiation in Hippocampal Neurons

“…NMDA receptor-mediated currents are also increased by PKA-mediated phosphorylation (Raman et al, 1996;Leonard and Hell, 1997). PKA-mediated phosphorylation of a protein phosphatase inhibitor, I-1, could allow for the suppression of protein phosphatase-1, and the subsequent disinhibition of CaMKII may gate the expression of long-lasting LTP at postsynaptic sites (Blitzer et al, 1995(Blitzer et al, , 1998Brown et al, 2000). Finally, fusion proteins, consisting of PKI and nuclear localization signals, are capable of blocking long-lasting LTP in hippocampal slices when they are delivered into the nuclear compartment of neurons (Matsushita et al, 2001).…”

Protein Phosphatases and Calcium/Calmodulin-Dependent Protein Kinase II-Dependent Synaptic Plasticity: Figure 1.

“…In parallel, Thr 286 phosphorylation of CaMKII was induced only when the two stimuli were paired. Inhibition of PP1 was therefore suggested to "gate" CaMKII autophosphorylation at Thr 286 in this LTP paradigm (Blitzer et al, 1998;Brown et al, 2000). Thus, potentiation of LTP induction by ␤-adrenergic receptor agonists (Thomas et al, 1996;Winder et al, 1999;Brown et al, 2000;Yang et al, 2002) and other cAMP-coupled neurotransmitter receptors (Otmakhova and Lisman, 1996;Cai et al, 2002;Svenningsson et al, 2002;Li et al, 2003;Wang et al, 2003) may require PP1 inhibition by inhibitor-1 (or DARPP-32) to enhance CaMKII autophosphorylation.…”