Stimulus reinforcement strengthens learning. Intervals between reinforcement affect both the kind of learning that occurs and the amount of learning. Stimuli spaced by a few minutes result in more effective learning than when massed together. There are several synaptic correlates of repeated stimuli, such as different kinds of plasticity and the amplitude of synaptic change. Here we study the role of signalling pathways in the synapse on this selectivity for spaced stimuli. Using the in vitro hippocampal slice technique we monitored long-term potentiation (LTP) amplitude in CA1 for repeated 100-Hz, 1-s tetani. We observe the highest LTP levels when the inter-tetanus interval is 5-10 min. We tested biochemical activity in the slice following the same stimuli, and found that extracellular signal-regulated kinase type II (ERKII) but not CaMKII exhibits a peak at about 10 min. When calcium influx into the slice is buffered using AM-ester calcium dyes, amplitude of the physiological and biochemical response is reduced, but the timing is not shifted. We have previously used computer simulations of synaptic signalling to predict such temporal tuning from signalling pathways. In the current study we consider feedback and feedforward models that exhibit temporal tuning consistent with our experiments. We find that a model incorporating post-stimulus build-up of PKM zeta acting upstream of mitogen-activated protein kinase is sufficient to explain the observed temporal tuning. On the basis of these combined experimental and modelling results we propose that the dynamics of PKM activation and ERKII signalling may provide a mechanism for functionally important forms of synaptic pattern selectivity.
Synaptic plasticity provides a record of neuronal activity and is a likely basis for memory. The early apparent simplicity of the process of synaptic plasticity has been lost in a flood of experimental data that now implicates some 200 signaling molecules in cellular memory. It is now clear that these signaling networks perform surprisingly sophisticated cellular decisions that weigh factors such as input patterns, location of stimulus, history of activity, and context. Computer models have followed experiments into this maze of molecular detail, often matching closely with their experimental counterparts, but perhaps losing simplicity in the process. Here, we suggest that the merger of models and experiment have begun to restore the earlier simplicity by outlining a few key functional roles for signaling networks in synaptic plasticity. In this review, we discuss the current state of understanding of synaptic plasticity in terms of models and experiments.
How ready is biology for systems biology? This review surveys some 250 models and supporting experiments to assess how well major signaling pathways have been quantified. The review traces the family tree of MAPK models to show how modeling can evolve and has influenced the field.
Strong inputs to neurons trigger complex biochemical events leading to synaptic plasticity. These biochemical events occur at many spatial scales, ranging from submicron dendritic spines to signals that propagate hundreds of microns from dendrites to the nucleus. ERKII is an important signaling molecule that is involved in many aspects of plasticity, including local excitability, communication with the nucleus, and control of local protein synthesis. We observed that ERKII activation spreads long distances in apical dendrites of stimulated hippocampal CA1 pyramidal neurons. We combined experiments and models to show that this >100 mum spread was too large to be explained by biochemical reaction-diffusion effects. We show that two modes of calcium entry along the dendrite contribute to the extensive activation of ERKII. We predict the occurrence of feedback between biophysical events resulting in calcium entry, and biochemical events resulting in ERKII activation. This feedback causes a switch-like propagation of ERKII activation, coupled with enhanced electrical excitability, along the apical dendrite. We propose that this propagating switch forms zones on dendrites in which plasticity is facilitated.
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