The NO/cGMP signaling cascade is known to modulate synaptic transmission and long-term synaptic plasticity. Here, NO activates the NO-sensitive cGMP-generating guanylyl cyclases (NO-GCs) that exist in 2 different isoforms with indistinguishable regulatory properties. We have recently shown that LTP is missing in KO mice deficient in either one of the NO-GC isoforms (NO-GC1, NO-GC2) indicating a contribution of both isoforms to synaptic plasticity. We also showed a presynaptic modulatory function of NO-GC1 in glutamatergic neurons, where it increased glutamate release via hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in area CA1 of the hippocampus. The present study evaluated the role of the NO-GC2 isoform on postsynaptic function in CA1 pyramidal neurons after stimulation of Schaffer collaterals in vitro. Electrophysiological whole-cell recordings from hippocampal slices of NO-GC2 KOs revealed a reduction of HCN currents and a hyperpolarizing-shift of the activation curve associated with a reduced resting membrane potential. This could be mimicked in WT neurons with an NO-GC inhibitor. Analysis of glutamate receptors revealed a cGMP-dependent reduction of NMDA receptor currents in NO-GC2 KO mice, and which was mimicked in WT by HCN channel inhibition. These data indicate that postsynaptic cGMP modulates HCN channels and increases NMDA receptor currents, thereby supporting LTP like processes of long-term synaptic plasticity.