In an attempt to improve behavioral memory, we devised a strategy to amplify the signal-to-noise ratio of the cAMP pathway, which plays a central role in hippocampal synaptic plasticity and behavioral memory. Multiple highfrequency trains of electrical stimulation induce long-lasting long-term potentiation, a form of synaptic strengthening in hippocampus that is greater in both magnitude and persistence than the short-lasting long-term potentiation generated by a single tetanic train. Studies using pharmacological inhibitors and genetic manipulations have shown that this difference in response depends on the activity of cAMPdependent protein kinase A. Genetic studies have also indicated that protein kinase A and one of its target transcription factors, cAMP response element binding protein, are important in memory in vivo. These findings suggested that amplification of signals through the cAMP pathway might lower the threshold for generating long-lasting long-term potentiation and increase behavioral memory. We therefore examined the biochemical, physiological, and behavioral effects in mice of partial inhibition of a hippocampal cAMP phosphodiesterase. Concentrations of a type IV-specific phosphodiesterase inhibitor, rolipram, which had no significant effect on basal cAMP concentration, increased the cAMP response of hippocampal slices to stimulation with forskolin and induced persistent long-term potentiation in CA1 after a single tetanic train. In both young and aged mice, rolipram treatment before training increased long-but not short-term retention in freezing to context, a hippocampus-dependent memory task.The second messenger, cAMP, and cAMP-dependent protein kinase A (PKA) have been implicated in short-and longlasting synaptic plasticity in Aplysia and in short-and longlasting behavioral learning in Aplysia and Drosophila (1, 2). Recently, convergent pharmacological and genetic evidence has also implicated the cAMP system in short-lasting longterm potentiation (LTP) at the mossy fiber-CA3 synapse of rodent hippocampus (3-6), and, strikingly, in the stronger longer-lasting intermediate and late phases of long-lasting LTP (L-LTP) that follow three to four trains of tetanic stimulation in all three hippocampal pathways: the perforant, the mossy fiber, and the Schaeffer collateral (CA3-CA1) (3,(7)(8)(9)(10)(11)(12)(13)(14). LTP is a well studied example of synaptic plasticity in mammals, thought to be a candidate cellular mechanism for mediating some forms of explicit hippocampus-dependent memory (15, 16). L-LTP has been of particular interest in regard to this behavioral correlation, because it is much more persistent than the short-lasting long-term potentiation that follows a single tetanic train (7,8,9). L-LTP persists as long as it has been observed, up to 29 hr in vitro, and depends at later time points not only on PKA activity but also on transcription and translation (3,6,8,9), much like behavioral long-term memory.The dependence of L-LTP, in hippocampal slices and behavioral memory, on PKA a...
MAP kinase (ERK) translates cell surface signals into alterations in transcription. We have found that ERK also regulates hippocampal neuronal excitability during 5 Hz stimulation and thereby regulates forms of long-term potentiation (LTP) that do not require macromolecular synthesis. Moreover, ERK-mediated changes in excitability are selectively required for some forms of LTP but not others. ERK is required for the early phase of LTP elicited by brief 5 Hz stimulation, as well as for LTP elicited by more prolonged 5 Hz stimulation when paired with beta1-adrenergic receptor activation. By contrast, ERK plays no role in LTP elicited by a single 1 s 100 Hz train. Consistent with these results, we find that ERK is activated by beta-adrenergic receptors in CA1 pyramidal cell somas and dendrites.
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, ...
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