Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function

Abstract

Neural circuits must maintain stable function in the face of many plastic challenges, including changes in synapse number and strength, during learning and development. Recent work has shown that these destabilizing influences are counterbalanced by homeostatic plasticity mechanisms that act to stabilize neuronal and circuit activity. One such mechanism is synaptic scaling, which allows neurons to detect changes in their own firing rates through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of glutamate receptors at synaptic sites. Additional homeostatic mechanisms may allow local changes in synaptic activation to generate local synaptic adaptations, and network-wide changes in activity to generate network-wide adjustments in the balance between excitation and inhibition. The signaling pathways underlying these various forms of homeostatic plasticity are currently under intense scrutiny, and although dozens of molecular pathways have now been implicated in homeostatic plasticity, a clear picture of how homeostatic feedback is structured at the molecular level has not yet emerged. On a functional level, neuronal networks likely use this complex set of regulatory mechanisms to achieve homeostasis over a wide range of temporal and spatial scales.

Figure 1.

Homeostasis of neuronal firing through homeostatic synaptic plasticity. (A) Cartoon illustration of the phenomenon of firing rate homeostasis in dissociated neocortical networks; perturbing firing in either direction results in the homeostatic regulation of synaptic and intrinsic properties so that baseline firing rates are restored. (B) One mechanism contributing to the firing rate homeostasis illustrated in A is synaptic scaling. When activity is perturbed (illustrated here as the potentiation of some inputs through Hebbian mechanisms) this triggers synaptic scaling, which produces a proportional reduction in strength at all synapses of the right magnitude to return firing to baseline levels. Note that, because this mechanism scales synaptic strength up or down proportionally, the relative difference in synaptic strengths induced by Hebbian mechanisms is preserved.

Figure 2.

Calcium-dependent pathways regulate both scaling up and scaling down. (A) At a particular average level of somatic calcium influx, scaling up and scaling down will balance each other, and the resulting synaptic equilibrium will help determine the firing rate set point of the neuron. (B) If activity decreases (owing to sensory deprivation, learning-induced LTD, or other factors) then average somatic calcium will also decrease; this will enhance scaling up and reduce scaling down and restore firing to baseline. (C) Conversely, if firing increases and average somatic calcium increases, this will enhance scaling down and reduce scaling up, again restoring firing to baseline.