Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission efficacy and is considered the base for some forms of learning and memory. Hyperammonemia impairs LTP in hippocampus. Proper LTP induction in hippocampal slices requires activation of the soluble guanylate cyclase (sGC)-protein kinase G (PKG)-cyclic guanosine monophosphate (cGMP)-degrading phosphodiesterase pathway. Hyperammonemia impairs LTP by impairing the tetanus-induced activation of this pathway. The tetanus induces a rapid cGMP rise, reaching a maximum at 10 s, both in the absence or in the presence of ammonia. The increase in cGMP is followed, in control slices, by a sustained decrease in cGMP because of PKG-mediated activation of cGMP-degrading phosphodiesterase, which is required for maintenance of LTP. Hyperammonemia prevents completely tetanus-induced decrease in cGMP by impairing PKG-mediated activation of cGMP-degrading phosphodiesterase. Addition of 8 Br-cGMP to slices treated with ammonia restores both phosphodiesterase activation and maintenance of LTP. Impairment of LTP in hyperammonemia may be involved in the impairment of the cognitive function in patients with hepatic encephalopathy.