What happens to synapses during sleep?
During wakefulness, synapses in the brain tend to grow and accumulate glutamate receptors, the proteins that receive excitatory signals. During sleep, this trend reverses: synaptic sizes shrink and glutamate receptor levels decrease, a process that helps reset the brain's circuitry for the next day [2]. This sleep-dependent contraction is driven in part by Homer1a, a protein whose targeting is controlled oppositely by wake- and sleep-promoting signals [2].
Homer1a is an activity-inducible variant of the scaffolding protein Homer. Unlike the long form of Homer, which cross-links receptors and channels at the synapse, Homer1a lacks the ability to dimerize and instead disrupts these links [1]. When Homer1a is upregulated after prolonged neuronal activity, it can affect a large number of synapses, making it well suited for a global scaling-down process like sleep [1].
How does Homer1a lead to glutamate receptor internalization?
Homer1a binds to group I metabotropic glutamate receptors (mGluR1 and mGluR5) and constitutively activates them, meaning they signal even without the usual neurotransmitter trigger [1]. This Homer1a–mGluR complex disrupts the physical links, maintained by long-form Homer, between mGluR1/5 and the Shank–GKAP–PSD-95–ionotropic glutamate receptor network [1]. By breaking these scaffolds, Homer1a can promote the internalization of glutamate receptors from the synaptic membrane, as suggested by studies of scaffold protein redistribution [3] and mGluR5/Homer interactions [4].
The internalization of glutamate receptors reduces the synapse's sensitivity to excitatory signals, effectively scaling down synaptic strength. This mechanism is thought to underlie the homeostatic synaptic scaling observed during sleep, where the goal is to normalize overall activity rather than to store specific information [1][2].
Is this the same as long-term depression (LTD)?
Long-term depression (LTD) is a form of synaptic weakening triggered by specific patterns of activity, such as prolonged low-frequency stimulation. It often involves the internalization of AMPA-type glutamate receptors and can be mediated by mGluR5 signaling [4]. Homer1a has been implicated in LTD-like processes: in Fragile X Syndrome models, disruption of the mGluR5/Homer complex by Homer1a is associated with altered receptor internalization and LTD [4].
However, the scaling down of synapses during sleep is a homeostatic process, meaning it adjusts synaptic strength globally to maintain stability, rather than being input-specific like LTD [1]. While both processes can reduce glutamate receptor levels and may share molecular components like Homer1a and mGluR5, they serve different functions: LTD refines specific connections based on experience, whereas sleep-related scaling down resets the overall balance of excitation [1][2]. The evidence suggests that Homer1a is a key player in both, but the contexts and outcomes differ.
Sources used in this answer
The Complex Formed by Group I Metabotropic Glutamate Receptor (mGluR) and Homer1a Plays a Central Role in Metaplasticity and Homeostatic Synaptic Scaling
The Homer1a–mGluR complex constitutively activates group I mGluRs and disrupts their scaffolding links to ionotropic glutamate receptors, contributing to homeostatic synaptic scaling and metaplasticity, including during sleep.
Homeostasis of synapses: expansion during wakefulness, contraction during sleep
During sleep, synaptic sizes shrink and glutamate receptor levels decrease, driven by Homer1a targeting that is oppositely controlled by wake- and sleep-promoting signals.
… a Redistribution of Scaffold Proteins, NMDAR Subunits, mGluR1, Dopamine Receptor-1, and Their Heterocomplexes Between Synaptic and Extrasynaptic Membranes
Homer1a and other scaffold proteins redistribute between synaptic and extrasynaptic membranes and are associated with glutamate receptor internalization from synapses.
Involvement of mGluR5/Homer crosstalk disruption in the pathophysiology of Fragile X Syndrome
Disruption of the mGluR5/Homer complex by Homer1a is linked to altered agonist-induced internalization of mGluR5 and long-term depression in Fragile X Syndrome models.