A novel nitric oxide (NO)-dependent 'molecular switch' mediates LTP in the Octopus vulgaris brain through persistent activation of nitric oxide synthase (NOS)

Cephalopods are a renowned example of the independent evolution of complex behavior in invertebrates. The octopuss outstanding learning capability is a prominent feature that depends on the vertical lobe (VL). Previously, we found that the synaptic input into the VL exhibits robust activity-dependent long-term potentiation (LTP) mediated by molecular processes that are only partially understood. Here, we reveal that the VL LTP is mediated by nitric oxide (NO). In contrast to the prevailing dogma, in the octopus VL, NO does not mediate LTP induction, as tetanization-induced LTP occurs even in the presence of NO-synthase (NOS) inhibitors. Remarkably, however, NOS inhibitors block the long-term presynaptic expression of LTP, and high doses of NO donor induce short-term synaptic potentiation, suggesting that a persistent elevation of NO concentration mediates LTP expression. Moreover, in a distinct group of synapses, NOS inhibitors also disrupted LTP maintenance, as following drug washout, a high-frequency stimulation reinstated full LTP, suggesting that NO is also involved in maintaining LTP. We propose a novel molecular-switch mechanism whereby a positive feedback loop of NO-dependent NOS reactivation mediates persistent NOS activation, thus providing an LTP maintenance mechanism. Subsequently, retrograde NO diffusion facilitates presynaptic transmitter release, driving LTP expression. These findings demonstrate how evolutionary adaptation of molluscan molecular mechanisms has contributed to the emergence of the advanced cognitive abilities observed in octopuses.