Involvement of NO in NMDA receptor-independent long-term potentiation

Abstract

Long-term potentiation (LTP) is a persistent increase in synaptic efficacy and, throughout the brain, a putative model of processes underlying learning and memory. Multiple forms of LTP exist with different dependences on NMDA receptor activation. Since nNOS is thought to be preferentially activated by NMDA receptor channel-opening, the role of NO in NMDA receptor-dependent LTP has attracted much attention. In contrast, less is known about the contribution of NO to NMDA receptor-independent LTP. At hippocampal CA3–CA1 synapses, a component of 200 Hz stimulation-induced LTP is resistant to NMDA receptor antagonism but reduced by L-type voltage-gated Ca 2+ channel (L-VGCC) inhibition. Since this component (called here L-VGCC-dependent LTP) shares properties with NO-dependent LTP, we tested the involvement of NO in it. Using field potential recording in hippocampal slices pre-incubated with the NMDA antagonist, D-AP5 (100 μM), we found that the L-VGCC-dependent LTP could be inhibited by NOS antagonism (100 μM L-NNA). The time-course of the inhibition was similar to the reduction caused by the L-VGCC inhibitor, nifedipine (30 μM), and could be mimicked by the NO-targeted guanylyl cyclase antagonist, ODQ (10 μM), suggesting that the NO signal involved was transduced by cGMP. The results of experiments on slices from eNOS-deficient mice, together with the lack of iNOS in hippocampal slices, suggested that nNOS was the sole source of the NO required. These data extend an essential role for neuron-derived NO from NMDA receptor-dependent to NMDA receptor-independent LTP and suggest that some forms of LTP necessitate a currently unknown mechanism for nNOS activation.