Abstract
Nitric oxide (NO) has long been implicated in the generation of long-term potentiation (LTP) and other types of synaptic plasticity, a role for which the intimate coupling between NMDA receptors (NMDARs) and the neuronal isoform of NO synthase (nNOS) is likely to be instrumental in many instances. While several types of synaptic plasticity depend on NMDARs, others do not, an example of which is LTP triggered by opening of L-type voltage-gated Ca2+ channels (L-VGCCs) in postsynaptic neurons. In CA3-CA1 synapses in the hippocampus, NMDAR-dependent LTP (LTPNMDAR) appears to be primarily expressed postsynaptically whereas L-VGCC-dependent LTP (LTPL−VGCC), which often coexists with LTPNMDAR, appears mainly to reflect enhanced presynaptic transmitter release. Since NO is an excellent candidate as a retrograde messenger mediating post-to-presynaptic signaling, we sought to determine if NO functions in LTPL−VGCC in mouse CA3-CA1 synapses. When elicited by a burst type of stimulation with NMDARs and the associated NO release blocked, LTPL−VGCC was curtailed by inhibition of NO synthase or of the NO-receptor guanylyl cyclase to the same extent as occurred with inhibition of L-VGCCs. Unlike LTPNMDAR at these synapses, LTPL−VGCC was unaffected in mice lacking endothelial NO synthase, implying that the major source of the NO is neuronal. Transient delivery of exogenous NO paired with tetanic synaptic stimulation under conditions of NMDAR blockade resulted in a long-lasting potentiation that was sensitive to inhibition of NO-receptor guanylyl cyclase but was unaffected by inhibition of L-VGCCs. The results indicate that NO, acting through its second messenger cGMP, plays an unexpectedly important role in L-VGCC-dependent, NMDAR-independent LTP, possibly as a retrograde messenger generated in response to opening of postsynaptic L-VGCCs and/or as a signal acting postsynaptically, perhaps to facilitate changes in gene expression.
Highlights
Long-term potentiation (LTP) of CA3-CA1 glutamatergic transmission in the hippocampus is a widely studied example of synaptic plasticity considered to underlie certain aspects of learning and memory formation
The clearest distinction is between LTP that is initiated by influx of Ca2+ through NMDA receptor (NMDAR) channels (Park et al, 2014) and LTP that can be elicited when NMDA receptors (NMDARs) are blocked and which relies on the activation of L-type voltagegated Ca2+ channels (L-VGCCs) in the postsynaptic neuron (Grover and Teyler, 1990). ‘‘Pure’’ NMDAR-dependent LTP (LTPNMDAR) generally displays the lowest induction threshold, develops within a few minutes and at least to begin with, involves post-translational alterations to postsynaptic proteins, including AMPA receptors
It had been assumed that the participation of Nitric oxide (NO) in hippocampal CA3-CA1 LTP, which is traditionally regarded as NMDAR-dependent (Collingridge et al, 1983), reflects the functional and molecular coupling between NMDARs and neuronal isoform of NO synthase (nNOS) activity, together with a background input from endothelial NO synthase (eNOS) in the microcirculation and to our knowledge, the possibility that NO could participate in LTPL−VGCC had not been considered
Summary
Long-term potentiation (LTP) of CA3-CA1 glutamatergic transmission in the hippocampus is a widely studied example of synaptic plasticity considered to underlie certain aspects of learning and memory formation. Under NMDAR blockade, eliciting L-VGCC-dependent LTP (LTPL−VGCC) needs patterns of stimuli that are relatively strong in terms of amplitude and/or frequency and/or duration, presumably reflecting the strong depolarization needed to activate the channels. It has a relatively slow onset (peaking generally 10–30 min post-tetanus) and appears to be largely maintained by presynaptic changes. Without NMDAR blockade, many types of stimulation commonly delivered to afferent fibers can elicit a composite LTP in which LTPNMDAR and LTPL−VGCC coexist in varying proportions (Cavus and Teyler, 1996; Morgan and Teyler, 2001; Bayazitov et al, 2007; Grover et al, 2009), separable as early postsynaptic and late-onset presynaptic components (Zakharenko et al, 2001; Bayazitov et al, 2007). By virtue of their depolarizing effect, activated NMDARs can contribute importantly to LTPL−VGCC so that, without specific tests, the resulting LTP can masquerade as being LTPNMDAR despite, in reality, being mixed (Blundon and Zakharenko, 2008; Padamsey and Emptage, 2014)
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