Nitric oxide is required for expression of LTP that is induced by stimulation phase-locked with theta rhythm

Long-term potentiation (LTP) can be induced by giving only one burst (five stimuli at 200 Hz) on the positive phase of sensory-induced theta rhythm in awake or anaesthetized rats, a stimulation protocol that mimics naturally occurring neuronal activity. Nitric oxide has been discussed as an important neuronal messenger in the induction of LTP. However, experiments testing inhibitors of nitric oxide synthase (NOS) in vitro produced contradictory results. The non-specific NOS inhibitor Nitro-L-arginine (L-NARG) impaired LTP induced by high-frequency stimulation (HFS) [from 155 +/- 7% to 122 +/- 8%), but completely blocked theta-dependent LTP induction (161 +/- 8% to 102 +/- 5%). NOS inhibitors, e.g. 7-nitro indazole (7-NI) or 1-(2-trifluoromethylphenyl) imidazole (TRIM) that are more selective for neuronal NOS and affect blood pressure less also impaired HFS-induced LTP (186 +/- 11% to 135 +/- 9% for TRIM) but completely blocked theta-dependent LTP (154 +/- 7 to 91 +/- 8). L-Arginine reversed the effects of the NOS inhibitors tested. Therefore, NO appears to be a modulator that is important for synaptic plasticity in this more physiological stimulation technique in vivo. NO is not released in slice preparations in sufficient quantities or at the right timing. Instead, the unphysiologically strong HFS protocol appears to induce an NO-independent type of LTP in some cases.