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Homeostatic plasticity in the developing nervous system

Key Points

  • Neuronal activity often leads to changes in synaptic efficacy. However, such plasticity must be accompanied by homeostatic mechanisms that prevent neural activity from being driven towards runaway activity or quiescence. One potential homeostatic mechanism is the adjustment of synaptic excitability so that firing rates remain relatively constant.

  • At the neuromuscular junction, genetic alterations in synaptic transmission lead to compensatory changes. For example, a decrease in the number of synapses leads to a compensatory increase in quantal amplitude. Such mechanisms might normally adjust neuromuscular transmission during development to allow for changes in muscle growth or synaptic drive.

  • Similar phenomena have been seen in cultured networks of central neurons. Blocking spontaneous activity in cortical cultures results in hyperactivity when the block is lifted. One mechanism for such adjustment is the global regulation of excitatory synapses within a given neuron.

  • Synaptic strength can be measured by analysing miniature excitatory postsynaptic currents (mEPSCs), which result from spontaneous release of quanta of transmitter from individual vesicles. Chronic alterations in activity can increase or decrease the amplitude of mEPSCs. The amplitude seems to be scaled so that each synaptic strength is multiplied or divided by the same factor. Such multiplicative scaling should preserve the relative strengths of synapses.

  • Synaptic strength could be regulated through changes in postsynaptic receptor numbers, presynaptic transmitter release or reuptake, or the number of functional synapses. Evidence in favour of a change in receptor number includes the increase in mEPSC amplitude and in the response to glutamate application. It is unclear whether the homeostatic regulation of receptor numbers shares a signalling pathway with the insertion of receptors into the membrane by long-term potentiation (LTP).

  • Presynaptic changes in transmission are involved in homeostatic plasticity at the neuromuscular junction, but it is less clear whether they are involved in homeostasis in central neurons. In some circumstances, such as developing hippocampal cultures, changes in activity cause changes in the frequency of mEPSCs, as well as in their amplitude, indicating presynaptic alterations.

  • It is unclear how homeostatic plasticity is induced. Important questions include: whether homeostatic plasticity is cell-autonomous; how changes in activity are integrated and read out; and what intracellular signalling cascades generate global changes in synaptic strength.

  • The functioning of cortical networks requires a balance between excitatory and inhibitory inputs onto neurons. Homeostasis in recurrent networks seems to involve adjustments in the relative strengths of excitatory and inhibitory feedback. It seems that excitatory and inhibitory synapses are adjusted independently to maintain activity in the face of changes in drive.

  • Evidence that these mechanisms are important in vivo comes from the developing visual system. For example, during development, there is an inverse relationship between mEPSC frequency and amplitude, indicating that as synaptic drive increases, synaptic strength is reduced.

Abstract

Activity has an important role in refining synaptic connectivity during development, in part through 'Hebbian' mechanisms such as long-term potentiation and long-term depression. However, Hebbian plasticity is probably insufficient to explain activity-dependent development because it tends to destabilize the activity of neural circuits. How can complex circuits maintain stable activity states in the face of such destabilizing forces? An idea that is emerging from recent work is that average neuronal activity levels are maintained by a set of homeostatic plasticity mechanisms that dynamically adjust synaptic strengths in the correct direction to promote stability. Here we discuss evidence from a number of systems that homeostatic synaptic plasticity is crucial for processes ranging from memory storage to activity-dependent development.

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Figure 1: The problem of stability in feedforward networks.
Figure 2: Stabilization of firing rates though global, homeostatic regulation of synaptic strengths.
Figure 3: Evidence for firing rate homeostasis in cultured networks.
Figure 4: Synaptic scaling induces a multiplicative change in the distribution of synaptic weights.
Figure 5: Changes in AMPA receptor accumulation.
Figure 6: Homeostatic regulation of the excitation–inhibition balance in cortical networks.

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Correspondence to Gina G. Turrigiano.

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FURTHER INFORMATION

The Nelson/Turrigiano Laboratory of Cortical Physiology

Glossary

QUANTAL AMPLITUDE

The amplitude of the postsynaptic response to a single vesicle of neurotransmitter.

SYNAPTIC COMPETITION

When increasing the strength of a subset of inputs generates a decrease in strength of other inputs.

MINIATURE EXCITATORY POSTSYNAPTIC CURRENT

The postsynaptic current evoked by release of a single vesicle of neurotransmitter – the quantal amplitude.

SYNAPTIC SCALING

Scaling up or down of the quantal amplitude of all synapses onto a postsynaptic neuron in response to long-lasting changes in neuronal activity.

HEBBIAN PLASTICITY

Changes in the connection strength between two neurons as a result of correlated firing.

AMPARS

A subtype of ligand-gated glutamate receptor; these receptors generate the majority of excitatory current at central synapses.

NMDARS

A subtype of ligand- and voltage-gated glutamate receptors that are calcium permeable.

COEFFICIENT OF VARIATION

(CV). A measure of variability — the mean response divided by the standard deviation of the response. The CV of evoked synaptic transmission (determined by repeatedly evoking release and calculating the mean and the standard deviation of the postsynaptic response) depends strongly on neurotransmitter release probability.

PROBABILITY OF TRANSMITTER RELEASE

Release of vesicles at presynaptic release sites is a stochastic process. Generally, when a spike invades the presynaptic terminal the probability that a vesicle will be released is significantly less than one. Increasing this probability would result in more vesicles released/spike (on average) and would therefore increase synaptic strength.

CELL-AUTONOMOUS PLASTICITY

Plasticity in the properties of an individual neuron resulting from changes in its own activity, independent of the activity of other neurons in the network.

BRAIN-DERIVED NEUROTROPHIC FACTOR

A neurotrophin that is expressed at high levels in the central nervous system, and implicated in many forms of synaptic plasticity and maturation, as well as dendritic and axonal growth.

MONOCULAR PRIMARY VISUAL CORTEX

The region of visual cortex in some species (notably rodents) that receives visual input from only one eye.

MONOCULAR DEPRIVATION

Depriving one eye of visual experience, while leaving the other eye unaffected.

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Turrigiano, G., Nelson, S. Homeostatic plasticity in the developing nervous system. Nat Rev Neurosci 5, 97–107 (2004). https://doi.org/10.1038/nrn1327

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