Long-term potentiation in the visual cortex requires both nitric oxide receptor guanylyl cyclases.

The role of nitric oxide (NO)/cGMP signaling in long-term potentiation (LTP) has been a lingering matter of debate. Within the cascade, the NO receptor guanylyl cyclase (GC), the cGMP-forming enzyme that is stimulated by NO, plays a key role. Two isoforms of GC (alpha2-GC, alpha1-GC) exist. To evaluate their contribution to synaptic plasticity, we analyzed knock-out mice lacking either one of the GC isoforms. We found that LTP induced in the visual cortex is NO dependent in the wild-type mice, absent in either of the GC isoform-deficient mice, and restored with application of a cGMP analog in both strains. The requirement of both NO receptor GCs for LTP indicates the existence of two distinct NO/cGMP-mediated pathways, which have to work in concert for expression of LTP.