Synaptic tagging

Abstract: Changing the strength of connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. In its most general form, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the infor- mation storage underlying the type of memory mediated by the brain area in which that plasticity is observed." We outline a set of criteria by which this hypothesis can be judged and describe a range of experimental strategies used to investigate it. We review both classical and newly discovered properties of synaptic plasticity and stress the importance of the neural architecture and synaptic learning rules of the network in which it is embedded. The greater part of the article focuses on types of memory mediated by the hippocampus, amygdala, and cortex. We conclude that a wealth of data supports the notion that synaptic plasticity is necessary for learning and memory, but that little data currently supports the notion of sufficiency.

Abstract: Repeated stimulation of hippocampal neurons can induce an immediate and prolonged increase in synaptic strength that is called long-term potentiation (LTP)—the primary cellular model of memory in the mammalian brain1. An early phase of LTP (lasting less than three hours) can be dissociated from late-phase LTP by using inhibitors of transcription and translation2–8. Because protein synthesis occurs mainly in the cell body9–12, whereas LTP is input-specific, the question arises of how the synapse specificity of late LTP is achieved without elaborate intracellular protein trafficking. We propose that LTP initiates the creation of a short-lasting protein-synthesis-independent 'synaptic tag' at the potentiated synapse which sequesters the relevant protein(s) to establish late LTP. In support of this idea, we now show that weak tetanic stimulation, which ordinarily leads only to early LTP, or repeated tetanization in the presence of protein-synthesis inhibitors, each results in protein-synthesis-dependent late LTP, provided repeated tetanization has already been applied at another input to the same population of neurons. The synaptic tag decays in less than three hours. These findings indicate that the persistence of LTP depends not only on local events during its induction, but also on the prior activity of the neuron.

Abstract: Two general forms of synaptic plasticity that operate on different timescales are thought to contribute to the activity-dependent refinement of neural circuitry during development: (1) long-term potentiation (LTP) and long-term depression (LTD), which involve rapid adjustments in the strengths of individual synapses in response to specific patterns of correlated synaptic activity, and (2) homeostatic synaptic scaling, which entails uniform adjustments in the strength of all synapses on a cell in response to prolonged changes in the cell's electrical activity. Without homeostatic synaptic scaling, neural networks can become unstable and perform suboptimally. Although much is known about the mechanisms underlying LTP and LTD, little is known about the mechanisms responsible for synaptic scaling except that such scaling is due, at least in part, to alterations in receptor content at synapses. Here we show that synaptic scaling in response to prolonged blockade of activity is mediated by the pro-inflammatory cytokine tumour-necrosis factor-alpha (TNF-alpha). Using mixtures of wild-type and TNF-alpha-deficient neurons and glia, we also show that glia are the source of the TNF-alpha that is required for this form of synaptic scaling. We suggest that by modulating TNF-alpha levels, glia actively participate in the homeostatic activity-dependent regulation of synaptic connectivity.