Cellular And Molecular Mechanisms Underlying Homeostatic Synaptic Plasticity
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It is well established that modification of sensory cortices of animals is integral to many functions of the brain. While input-specific synaptic plasticity mechanisms are thought to underlie developmental refinement of synaptic connectivity with sensory experience, theoretical analyses suggest that slower global homeostatic mechanisms are required to stabilize dynamic neural networks. One of the homeostatic mechanisms that have been proposed is synaptic scaling, where a prolonged increase in neural activity globally scales down excitatory synaptic responses, while a chronic decrease in activity scales them up. This phenomenon has been demonstrated by pharmacological manipulations in cultured neurons, as well as in vivo visual cortex by several days of visual deprivation. However, whether restoring vision could reverse these changes and the molecular mechanisms of visual experience-induced homeostatic synaptic plasticity were not known. Moreover, whether there are more global regulations beyond one sensory modality was unknown. Several human studies demonstrated that loss of vision is usually accompanied by increased functionality of other sensory modalities. We found that visual deprivation produces synaptic changes in primary somatosensory and auditory cortices, opposite to that seen in the visual cortex. The reversible homeostatic synaptic modification in primary sensory cortices by visual experience correlated with changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation and subunit composition, which could underlie changes in AMPA receptor function. Interestingly, the reversible homeostatic modification occurred in juveniles and also in adults well beyond the closure of the "classical" critical period in the superficial layers of the visual cortex. This correlates with the persistence of synapse-specific plasticity in this cortical layer, supporting the need for homeostatic synaptic plasticity in stabilizing dynamic circuits. Our investigation of the molecular mechanisms of synaptic scaling in juvenile visual cortex suggest that multiplicative scaling up of excitatory synapses by dark rearing may occur in two steps, requiring phosphorylation of the GluR1-S845 residue and anchoring of GluR1 to the postsynaptic density. Our data also suggests that GluR2-mediated mechanisms may interact with the GluR1-dependent processes to enable synaptic scaling following visual deprivation. Collectively, this study shows that the AMPA receptor regulation is a common downstream mechanism shared between Hebbian and homeostatic plasticity.