Disruption of NMDAR Function Prevents Normal Experience-Dependent Homeostatic Synaptic Plasticity in Mouse Primary Visual Cortex.

Homeostatic regulation of synaptic strength allows for maintenance of neural activity within a dynamic range for proper circuit function. There are largely two distinct modes of synaptic plasticity that allow for homeostatic adaptation of cortical circuits: synaptic scaling and sliding threshold (BCM theory). Previous findings suggest that the induction of synaptic scaling is not prevented by blocking NMDARs, whereas the sliding threshold model posits that the synaptic modification threshold of LTP and LTD readjusts with activity and thus the outcome of synaptic plasticity is NMDAR dependent. Although synaptic scaling and sliding threshold have been considered two distinct mechanisms, there are indications from recent studies that these two modes of homeostatic plasticity may interact or that they may operate under two distinct activity regimes. Here, we report using both sexes of mouse that acute genetic knock-out of the obligatory subunit of NMDAR or acute pharmacological block of NMDAR prevents experience-dependent homeostatic regulation of AMPAR-mediated miniature EPSCs in layer 2/3 of visual cortex. This was not due to gross changes in postsynaptic neuronal activity with inhibiting NMDAR function as determine by c-Fos expression and two-photon Ca2+ imaging in awake mice. Our results suggest that experience-dependent homeostatic regulation of intact cortical circuits is mediated by NMDAR-dependent plasticity mechanisms, which supports a sliding threshold model of homeostatic adaptation.SIGNIFICANCE STATEMENT Prolonged changes in sensory experience lead to homeostatic adaptation of excitatory synaptic strength in sensory cortices. Both sliding threshold and synaptic scaling models can account for the observed homeostatic synaptic plasticity. Here we report that visual experience-dependent homeostatic plasticity of excitatory synapses observed in superficial layers of visual cortex is dependent on NMDAR function. In particular, both strengthening of synapses induced by visual deprivation and the subsequent weakening by reinstatement of visual experience were prevented in the absence of functional NMDARs. Our results suggest that sensory experience-dependent homeostatic adaptation depends on NMDARs, which supports the sliding threshold model of plasticity and input-specific homeostatic control observed in vivo.