There is accumulating evidence that NO-sensitive Guanylyl Cyclase (GC) and the formed second messenger cGMP are involved in synaptic plasticity in various regions of the brain, in particular in hippocampus. However, its implication for neocortical long-term plasticity has rarely been evaluated. In the present study we investigated the functional properties of NO-sensitive GC with regard to long-term potentiation (LTP) in the visual cortex. Two isoforms of NO-sensitive GC exist a1 b1, a2 b1), and we studied two mice lines deficient in either one of the isoforms generated by deletion of the a1 or a2 subunit, respectively. The expression of LTP was significantly (p<0.05) reduced in slices of the visual cortex from both knock-out animal models (n=7, n=9; respectively) as compared to wild type (WT) controls (n=9). A similar effect was observed after exposure of WT slices to the GC inhibitor (ODQ). The failure of LTP expression in slices of both transgenic mice could be reversed by application of the cGMP analog 8-pCPT-cGMP (n=7, n=7; respectively). However, treatment of WT slices with 8-pCPT-cGMP had no effect on the level of LTP (n=8). These results support the view of a contribution of cGMP to the induction of LTP in the visual cortex and, in addition suggest a role for both GC isoforms within the cGMP-mediated component of LTP. Supported by the DFG (GRK 736 and by SFB 509, C4).