Synaptic homeostasis transiently leverages Hebbian mechanisms for a multiphasic response to inactivity

Abstract

Neurons use various forms of negative feedback to maintain their synaptic strengths within an operationally useful range. While this homeostatic plasticity is thought to distinctly counteract the destabilizing positive feedback of Hebbian plasticity, there is considerable overlap in the molecular components mediating both forms of plasticity. The varying kinetics of these components spurs additional inquiry into the dynamics of synaptic homeostasis. We discovered that upscaling of synaptic weights in response to prolonged inactivity is nonmonotonic. Surprisingly, this seemingly oscillatory adaptation involved transient appropriation of molecular effectors associated with Hebbian plasticity, namely CaMKII, L-type Ca2+ channels, and Ca2+-permeable AMPARs, and homeostatic elements such as calcineurin. We created a dynamic model that shows how traditionally "Hebbian" and "homeostatic" mechanisms can cooperate to autoregulate postsynaptic Ca2+ levels. We propose that this combination of mechanisms allows excitatory synapses to adapt to prolonged activity changes and safeguard the capability to undergo future strengthening on demand.

Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors

“…When synaptic excitation is reduced, a mechanism of homeostatic synaptic plasticity is activated, which causes an increase in excitatory synaptic responses in these neurons as a form of compensation ( Miller et al, 2016 ). We and others have previously found that neuronal activity deprivation-induced homeostatic synaptic up-scaling can elevate glutamatergic synaptic activity and Ca 2+ -dependent signaling via the expression of CP-AMPARs ( Thiagarajan et al, 2005 ; Kim et al, 2014 ; Sun et al, 2022 ). CP-AMPARs could thus be an ideal candidate to counteract ketamine-induced NMDAR inhibition in neural plasticity and neuronal Ca 2+ signaling.…”

Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors in the hippocampus

“…When this activity is reduced, a mechanism of homeostatic synaptic plasticity is activated, which causes a rapid increase in excitatory synaptic responses in these neurons as a form of compensation (8). We and others have previously found that neuronal activity deprivation-induced homeostatic synaptic up-scaling can elevate glutamatergic synaptic activity and Ca 2+ -dependent signaling via the expression of CP-AMPARs (35,66,67). CP-AMPARs could thus be an ideal candidate to counteract ketamine-induced NMDAR inhibition in synaptic plasticity and neuronal Ca 2+ signaling.…”