Review
More than synaptic plasticity: role of nonsynaptic plasticity in learning and memory

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Decades of research on the cellular mechanisms of memory have led to the widely held view that memories are stored as modifications of synaptic strength. These changes involve presynaptic processes, such as direct modulation of the release machinery, or postsynaptic processes, such as modulation of receptor properties. Parallel studies have revealed that memories might also be stored by nonsynaptic processes, such as modulation of voltage-dependent membrane conductances, which are expressed as changes in neuronal excitability. Although in some cases nonsynaptic changes can function as part of the engram itself, they might also serve as mechanisms through which a neural circuit is set to a permissive state to facilitate synaptic modifications that are necessary for memory storage.

Introduction

Cellular and molecular studies implicate modulation of synaptic strength as the basis of learning and memory 1, 2, 3, 4, 5. Changes in synaptic strength occur via a wide range of mechanisms that act at the level of the presynaptic neuron (e.g. direct modulation of release process and subsequent changes in amount of neurotransmitter released) or at the level of the postsynaptic neuron (e.g. modifications in function and/or number of neurotransmitter receptors) (Figure 1a). However, it is now clear that different forms of learning and patterns of neuronal activity also produce diverse and widespread nonsynaptic changes by modulating membrane components, including resting and voltage-dependent channels and ion pumps, which are often expressed as changes in excitability (Box 1; Figure 1b). Despite the growing number of studies reporting nonsynaptic changes, several aspects of this form of plasticity remain elusive. What is its relationship to synaptic plasticity and what is its functional relevance? Are nonsynaptic changes part of the engram (see Glossary) itself or do they act as a permissive mechanism to facilitate synaptic mechanisms? How can nonsynaptic changes achieve high degrees of specificity similar to those expressed by synaptic modifications? Here we review selected examples of early and more recent evidence of learning- and activity-induced nonsynaptic changes and we discuss their potential relevance.

Section snippets

Changes in excitability produced by learning

Although the role of synaptic changes in learning dates back to Ramón y Cajal [6] and Tanzi [7], data supporting both the role of synaptic and nonsynaptic changes began to emerge in the 1970 s and 1980 s. The breakthroughs occurred with the development of several model systems in which it was possible to monitor changes in neuronal properties produced by learning (see Ref. [1] for early review).

Woody and his colleagues 8, 9 provided early evidence for learning-dependent nonsynaptic plasticity in

Nonsynaptic changes associated with LTP and long-term depression (LTD)

Specific patterns of neuronal stimulation induce either enhancement (LTP) or reduction (LTD) of synaptic strength 56, 57, cellular phenomena that are believed to underlie aspects of learning and memory 3, 56, 57, 58, 59. Although research on LTP and LTD largely focuses on the mechanisms underlying modulation of synaptic strength, several lines of evidence indicate that both LTP and LTD are accompanied by modifications of intrinsic excitability.

Bliss and Lømo [60] found an increase in the

Site-specific changes in excitability

In contrast with mechanisms of memory storage based on changes in synaptic strength that have a potentially massive storage capacity, global changes in excitability would theoretically alter the throughput of all the synaptic inputs impinging on a neuron and have limited storage capacity. Recent findings could help to reconcile differences between models of memory storage based on synaptic versus intrinsic plasticity. Dendritic integration (i.e. spatial and temporal summation of synaptic

Concluding remarks

Theories of memory storage have been inspired by the unique features of the synapse and its plasticity. However, analyses in both vertebrate and invertebrate model systems indicate that learning and memory, as well as patterns of electrical stimulation of neurons and neural pathways, also produce changes in excitability. These changes can be neuron-wide or restricted to specific cellular compartments such as individual dendrites, thus affecting neuronal function and signal integration either

Acknowledgments

We thank D. Baxter, T. Crow, D. Johnston and M. Clarke for comments on an earlier draft of the manuscript. This research was supported by National Institutes of Health grants NS019895, NS038310, and MH058321.

Glossary

Associative learning
refers to the formation of an association either between two stimuli (i.e. classical conditioning) or between a behavior and a stimulus (i.e. operant conditioning).
Classical conditioning
is the ability to associate a predictive stimulus with a subsequent salient event. In classical conditioning procedures, a novel or weak stimulus (conditioned stimulus, CS) is paired with a stimulus that generally elicits a reflexive response (unconditioned stimulus and response,

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