Roles of serine/threonine phosphatases in hippocampel synaptic plasticity

Abstract

REVIEWSConsider a busy Manhattan street. Cars and people moving from store to store, apartment to place of business, leaving behind their tyre tracks, coffee cups, oil spills and so on. This rubbish is then steadily cleaned away by street sweepers and janitors. A common school of thought in neuroscience has been much in the same vein -kinases moving from protein to protein within the dendritic spine or presynaptic terminal, phosphorylating these proteins and changing their function, while phosphatases work behind the scenes in a mundane, constitutive custodial role. Increasingly, however, this bias is being challenged, as data now show that phosphatase activity in neurons is dynamically regulated, and that specific phosphatases have important roles in neuronal function. Perhaps in no field is this more apparent than that of hippocampal synaptic plasticity. In the hippocampus, NMDA (N-methyl-D-aspartate)-receptor-dependent longterm potentiation (LTP) and long-term depression (LTD) are robust forms of persistent modifications of synaptic transmission in response to transient stimuli, and are leading cellular candidates for the mediation of aspects of learning and memory. Although it has been clear for some time that protein phosphorylation has a key role in hippocampus-based synaptic plasticity and learning, it has only more recently been appreciated that phosphatases might have an important, active role in governing these processes.In this review, we discuss the roles of phosphatases in synaptic plasticity, focusing on the CA1 region of the hippocampus. First we discuss the enzymes and their regulation, emphasizing their propensity to be regulated by neuronal activity. Then we examine the evidence for a role of phosphatases in synaptic plasticity in area CA1 of the hippocampus, focusing on two broad areas: the effects of manipulating phosphatase activity on synaptic plasticity, and the measurement of phosphatase activation or inactivation in association with synaptic plasticity. We present a discussion of the phosphoproteins and processes on which phosphatases might act in achieving their physiological effects, as well as recent data indicating the behavioural relevance of the phosphatase regulation of plasticity. Finally, we provide a summary model of the roles of phosphatases in the hippocampus, and highlight what we feel to be some important future directions in this rapidly developing area.The regulation of glutamate-mediated excitatory neurotransmission has a critical role in many aspects of behaviour. Great effort has gone into understanding the signal transduction cascades and effectors recruited in these processes, and protein phosphorylation has been identified as an important element. Although initial research in the field focused on the activity-dependent activation of kinases and the kinase dependence of various forms of synaptic plasticity, it has become increasingly clear that phosphatases have an equally dynamic and critical role in the activity-dependent alterations of synaptic transmission. Here, ...

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

“…Serine/threonine protein phosphatases have been implicated in the regulation of synaptic plasticity [70]. A possible role for adenosine in synaptic plasticity is not adequately appreciated given that regulation of extracellular adenosine levels may have important effects in paradigms used to demonstrate plasticity.…”

“…Kinases play important, well documented, roles in the regulation of numerous cellular functions [10,43,67]. The physiological significance of serine/threonine protein phosphatases has also been appreciated, and these enzymes have been implicated in the regulation of ion channels, synaptic plasticity, exocytosis, and apoptosis [31,36,58,70].…”

Interaction of Calcineurin and Type-A GABA Receptor γ2Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

“…The enzymatic activity of CaN in CA1 neurons of the hippocampus is increased by activation of NMDA receptors (Lu et al, 2000). Also, there is extensive evidence showing that CaN plays a critical role in the activitydependent changes of excitatory synaptic transmission in the hippocampus (Winder and Sweatt, 2001). Genetic inhibition of endogenous CaN in the forebrain (CaN transgenic mice), by expressing the auto-inhibitory domain of CaN, showed that LTP at CA1 excitatory synapses induced by subsaturating but not saturating tetanic stimulation was enhanced both in vitro and in vivo (Malleret et al, 2001).…”

Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats

“…When activated by calcium and calmodulin, calcineurin dephosphorylates target proteins such as synapsin I, DARPP32, and CREB, as well as a number of other proteins important for neuronal function including calcium channels, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors, and N-methyl-D-aspartate (NMDA) receptors (Greengard et al 1999;Jovanovic et al 2001;Winder and Sweatt 2001). Thus, calcineurin activity could modulate cocaine-mediated neurotransmitter release and intracellular signaling through actions at several different pre-synaptic and postsynaptic targets.…”