In 1894, Ramón y Cajal first proposed that memory is stored as an anatomical change in the strength of neuronal connections. For the following 60 years, little evidence was recruited in support of this idea. This situation changed in the middle of the twentieth century with the development of cellular techniques for the study of synaptic connections and the emergence of new formulations of synaptic plasticity that redefined Ramón y Cajal's idea, making it more suitable for testing. These formulations defined two categories of plasticity, referred to as homosynaptic or Hebbian activity-dependent, and heterosynaptic or modulatory input-dependent. Here we suggest that Hebbian mechanisms are used primarily for learning and for short-term memory but often cannot, by themselves, recruit the events required to maintain a long-term memory. In contrast, heterosynaptic plasticity commonly recruits long-term memory mechanisms that lead to transcription and to synaptic growth. When jointly recruited, homosynaptic mechanisms assure that learning is effectively established and heterosynaptic mechanisms ensure that memory is maintained.
Modern formulations of synaptic plasticity have led to the definition of two broad categories — homosynaptic or Hebbian activity-dependent and heterosynaptic or modulatory input-dependent. In homosynaptic plasticity, the events responsible for triggering the plastic change occur at the same connection being strengthened or weakened. In heterosynaptic plasticity, the plastic change can occur in the absence of activity of the synapse being strengthened but, instead, as a result of a third, modulatory interneuron.
Homosynaptic Hebbian plasticity in both invertebrate and in mammalian synapses involves the covalent modification of pre-existing synaptic proteins and, when initiated by itself, it often lasts only for one or at most a few hours. In contrast, heterosynaptic mechanisms can readily lead to plastic changes that last for one or more days and can, by themselves, recruit the cellular machinery necessary for the synthesis of new proteins and for the growth of new synapses.
In invertebrate (Aplysia) synapses, the combination of homo- and heterosynaptic mechanisms can result in new categories of synaptic plasticity. For example, when recruited together, the duration of the plastic change can increase in a non-additive way. In addition, the combined mechanisms can restrict the long-term plastic change to a set of synapses smaller than either mechanism alone, thereby sharpening its synapse-specificity.
A similar interaction between homosynaptic and heterosynaptic mechanisms might occur in mammalian synapses but a rigorous demonstration is still missing. Nevertheless, the observation that the blockade of modulatory neurotransmitters prevents the generation of long-lasting changes of synaptic strength indicates that heterosynaptic plasticity probably also contributes to the stabilization of short-term memory in the mammalian brain.
One possible functional significance of this interaction is that homosynaptic mechanisms are used by the nervous system to ensure that learning is effectively established; once learning has taken place, heterosynaptic mechanisms ensure that a long-term memory is maintained.
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We thank Tom Carew, John Koester, Kelsey Martin, James McGaugh, Tom O'Dell, Chris Pittenger, Steve Siegelbaum and Danny Winder for their comments on an earlier version of this manuscript. We thank Harriet Ayers and Millie Pellan for preparation of the manuscript and Charles Lam for assisting with the artwork. C.H.B. is supported by a National Institutes of Health grant. E.R.K. is supported by the Howard Hughes Medical Institute, the G. Harold and Leila Y. Mathers Charitable Foundation and the Lieber Centre for Schizophrenia Research. M.G. is supported by a Human Frontier Science Program Organization fellowship.
ENCYCLOPEDIA OF LIFE SCIENCES
- SYNAPTIC PLASTICITY
A change in the functional properties of a synapse as a result of use.
A strengthening of the response to a wide variety of neutral stimuli following an intense or noxious stimuli.
- CLASSICAL CONDITIONING
Form of associative learning in which a subject learns the relationship between two stimuli.
A decrease in the behavioural response to a repeated, benign stimulus.
- LOCUS COERULEUS
Nucleus of the brainstem. The main supplier of noradrenaline to the brain.
- DORSAL RAPHE
Nucleus of the brainstem. The main supplier of serotonin to the brain.
- VENTRAL TEGMENTAL AREA
Nucleus of the midbrain. The main supplier of dopamine to the cortex.
- STRATUM LUCIDUM
The site of termination of the hippocampal mossy fibres.
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Bailey, C., Giustetto, M., Huang, YY. et al. Is Heterosynaptic modulation essential for stabilizing hebbian plasiticity and memory. Nat Rev Neurosci 1, 11–20 (2000). https://doi.org/10.1038/35036191
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