Ongoing in Vivo experience triggers synaptic metaplasticity in the neocortex

In vivo experience can occlude subsequent induction of long-term potentiation and enhance long-term depression of synaptic responses. Although a reduced capacity for synaptic strengthening may function to prevent excessive excitation, such an effect paradoxically implies that continued experience or training should not improve and may even degrade neural representations. In mice, we examined the effect of ongoing whisker stimulation on synaptic strengthening at layer 4-2/3 synapses in the barrel cortex. Although N-methyl-D-aspartate receptors were required to initiate strengthening, they subsequently suppressed further potentiation at these synapses in vitro and in vivo. Despite this transition, synaptic strengthening continued with additional sensory activity but instead required the activation of metabotropic glutamate receptors, suggesting a mechanism by which continued experience can result in increasing synaptic strength over time. N-methyl-D-aspartate receptor–dependentsynaptic strengthening is the most com-mon and best-understood form of plas-ticity in the central nervous system, found in brain areas ranging from the hypothalamus to the cerebral cortex and in species including amphibians, birds, and mammals. Because NMDARs are required for both learning in vivo and synaptic potentiatio