Experience-Dependent Plasticity Acts via GluR1 and a Novel Neuronal Nitric Oxide Synthase-Dependent Synaptic Mechanism in Adult Cortex

Synaptic plasticity directs development of the nervous system and is thought to underlie memory storage in adult animals. A great deal of our current understanding of the role of AMPA receptors in synaptic plasticity comes from studies on developing cortex and cell cultures. In the present study, we instead focus on plasticity in mature neurons in the neocortex of adult animals. We find that the glutamate receptor 1 (GluR1) subunit of the AMPA receptor is involved in experience-dependent plasticity in adult cortex in vivo and that it acts in addition to neuronal nitric oxide synthase (alpha NOS1), an enzyme that produces the rapid synaptic signaling molecule nitric oxide (NO). Potentiation of the spared whisker response, following single whisker experience, is similar to 33% less in GluR1-null mutants than in wild types. We found that the remaining plasticity depended on alpha NOS1. Potentiation was reduced by >42% in the single alpha NOS1-null mutants and completely abolished in GluR1/alpha NOS1 double-knock-out mice. However, potentiation in GluR1/NOS3 double knock-outs occurred at similar levels to that seen in GluR1 single knock-outs. Synaptic plasticity in the layer IV to II/III pathway in vitro mirrored the results in vivo, in that LTP was present in GluR1/NOS3 double-knock-out mice but not in the GluR1/alpha NOS1 animals. While basal levels of NO in cortical slices depended on both alpha NOS1 and NOS3, NMDA receptor-dependent NO release only depended on alpha NOS1 and not on NOS3. These findings demonstrate that alpha NOS1 acts in concert with GluR1 to produce experience-dependent plasticity in the neocortex.