Most of the effects of the signalling molecule nitric oxide (NO) are mediated by the NO-receptor guanylyl cyclase (GC) whose cGMP forming activity is stimulation upon NO binding to its heme moiety. The subsequent cGMP increase changes the activity of the cGMP effector molecule (kinases, phosphodiesterase, ion-channels) NO/cGMP signalling plays an important role in the vascular system and has been proposed to participate in synaptic plasticity in brain. The NO-receptor GC consist of two subunit (αβ) and exists in two isoforms that share regulatory properties but differ in the subcellular localization; the more ubiquitously expressed NO-GC1 (α₁β₁) and NO-GC2 (α₂β₁) mainly expressed in brain. Genetic deletion of either one the α subunit causes a loss of the respective NO-receptor isoform. As the remaining non-deleted NO-receptor isoform was not up regulated, the respective KOs can provide information about the functional role of the NO receptors isoforms and of NO in general. Long term potentiation (LTP) was measured in slices of the visual cortex. NO-dependent LTP was absent in either one of NO-receptor-deficient mice but was reconstituted with a cGMP analogue in both strains. The results suggest that the NO-receptor isoforms cannot substitute for each other and play distinct roles in LTP. LTP measurements in the CA1 region of hippocampus will show whether both NO-receptor isoforms are also required in this best studied form of LTP.