Long‐Term Depression in the Hippocampus In Vivo Is Associated with Protein Phosphatase‐Dependent Alterations in Extracellular Signal‐Regulated Kinase

Abstract

There is growing evidence that activation of either protein kinases or protein phosphatases determines the type of plasticity observed after different patterns of hippocampal stimulation. Because activation of the extracellular signal-regulated kinase (ERK) has been shown to be necessary for long-term potentiation, we investigated the regulation of ERK in long-term depression (LTD) in the adult hippocampus in vivo. We found that ERK immunoreactivity was decreased following the induction of LTD and that this decrease required NMDA receptor activation. The LTD-associated decrease in ERK immunoreactivity could be simulated in vitro via incubation of either purified ERK2 or hippocampal homogenates with either protein phosphatase 1 or protein phosphatase 2A. The protein phosphatase-dependent decrease in ERK immunoreactivity was inhibited by microcystin. Intrahippocampal administration of the protein phosphatase inhibitor okadaic acid blocked the LTD-associated decrease in ERK2, but not ERK1, immunoreactivity. Collectively, these data demonstrate that protein phosphatases can decrease ERK immunoreactivity and that such a decrease occurs with ERK2 during LTD. These observations provide the first demonstration of a biochemical alteration of ERK in LTD. Key Words: HippocampusLong-term depression-Protein phosphatase 1-Protein phosphatase 2A-Extracellular signal-regulated kinase-Plasticity. J. Neurochem. 74, 192-198 (2000).It has been hypothesized that experience-dependent changes at the neuronal level are supported by changes in synaptic strength (Hebb, 1949;Kandel and Schwartz, 1982;Lynch and Baudry, 1984;Bliss and Collingridge, 1993;Chen and Tonegawa, 1997). There have been numerous studies exploring multiple signaling cascades that underlie synaptic plasticity. Previous studies have shown that an increase in synaptic strength, i.e., longterm potentiation, is accompanied by an increase in the activity of various protein kinases (for a review, see Roberson et al., 1996) and a decrease in basal protein phosphatase activity (Blitzer et al., 1998). In contrast, a decrease in synaptic strength, i.e., long-term depression (LTD), is dependent on protein phosphatases (Mulkey et al., 1993(Mulkey et al., , 1994 and is accompanied by an increase in the activity of serine/threonine protein phosphatases (Thiels et al., 1998).We are interested in determining whether two serine/ threonine protein phosphatases, protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), regulate protein kinases in synaptic plasticity. Of particular interest is the extracellular signal-regulated kinase (ERK). ERK activity has been shown to be increased following the induction of long-term potentiation and to be necessary for the expression of longterm potentiation (English and Sweatt, 1997). In addition, ERK activity has been shown to increase with and be necessary for hippocampal-dependent associative-fear conditioning (Atkins et al., 1998) and spatial learning (Blum et al., 1999).ERK is activated by mitogen-activated protein kinase kinas...

Identification of Process-Localized mRNAs from Cultured Rodent Hippocampal Neurons

“…In Drosophila oocytes, the hnRNP A/B homolog, Hrp48, has been shown to bind the 5Ј-and 3Ј-untranslated regions of oskar mRNA and repress its translation during transport (Huynh et al, 2004;Yano et al, 2004). Last, protein phosphatase 2a (PP2a), a protein with a potential role in plasticity (Norman et al, 2000;Winder and Sweatt, 2001;Belmeguenai and Hansel, 2005), is also known to dephosphorylate EF2 kinase, which stimulates translation (Redpath and Proud, 1989).…”

Behavioral Stress Modifies Hippocampal Synaptic Plasticity through Corticosterone-Induced Sustained Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase Activation

“…Our findings establish one possible mechanism by which the sustained activation of ERK1/2 after stress experience is reversed by LFS. In fact, LTD in the hippocampal CA1 region in vivo can lead to a protein phosphatasedependent decrease in ERK1/2 activity (Norman et al, 2000).…”

γ-Aminobutyric acid type A receptors modulate cAMP-mediated long-term potentiation and long-term depression at monosynaptic CA3–CA1 synapses

“…Several investigators have proposed that hippocampal LTD involves activation of protein phosphatases (23,24). We therefore tested whether the LTD induced by concurrent application of Sp-cAMPS and picrotoxin was mediated through protein phosphatases.…”