The Role of Nitric Oxide and GluR1 in Presynaptic and Postsynaptic Components of Neocortical Potentiation

Abstract

In this study, we investigated the mechanisms underlying synaptic plasticity at the layer IV to II/III pathway in barrel cortex of mice aged 6 -13 weeks. This pathway is one of the likely candidates for expression of experience-dependent plasticity in the barrel cortex and may serve as a model for other IV to II/III synapses in the neocortex. We found that postsynaptic autocamtide-2-inhibitory peptide is sufficient to block long-term potentiation (LTP) (IC 50 of 500 nM), implicating postsynaptic calcium/calmodulin-dependent kinase II in LTP induction. AMPA receptor subunit 1 (GluR1) knock-out mice also showed LTP in this pathway, but potentiation was predominantly presynaptic in origin as determined by paired-pulse analysis, coefficient of variation analysis, and quantal analysis, whereas wild types showed a mixed presynaptic and postsynaptic locus. Quantal analysis at this synapse was validated by measuring uniquantal events in the presence of strontium. The predominantly presynaptic LTP in the GluR1 knock-outs was blocked by postsynaptic antagonism of nitric oxide synthase (NOS), either with intracellular N--nitro-L-arginine methyl ester or N-nitro-L-arginine, providing the first evidence for a retrograde transmitter role for NO at this synapse. Antagonism of NOS in wild types significantly reduced but did not eliminate LTP (group average reduction of 50%). The residual LTP formed a variable proportion of the total LTP in each cell and was found to be postsynaptic in origin. We found no evidence for silent synapses in this pathway at this age. Finally, application of NO via a donor induced potentiation in layer II/III cells and caused an increase in frequency but not amplitude of miniature EPSPs, again implicating NO in presynaptic plasticity.

Constitutively active H-ras accelerates multiple forms of plasticity in developing visual cortex

“…4 A and B). Com- parably low rates of successful LTP induction are commonly seen with similar LTP protocols in this pathway (18)(19)(20). In striking contrast, LTP was enhanced in H-ras G12V mice, with 60% of neurons showing significant potentiation and a mean potentiation magnitude of 1.56 ± 0.13.…”

“…Greater short-term facilitation is likely to increase summation of postsynaptic responses and, therefore, detection of correlated activity, which is necessary for cortical plasticity. Both presynaptic and postsynaptic mechanisms are known to contribute to cortical LTP (18,19). We used changes in paired pulse ratio (PPR) to assess the contribution of presynaptic mechanisms to LTP.…”

“…Our data therefore suggest that increases in presynaptic release probability, from a low initial state, mediate enhanced plasticity in vitro in H-ras G12V mice and may do so in vivo as well. Presynaptic mechanisms of potentiation are known to occur in the cortex (18,19) but are limited if release probability is high. Therefore, by resetting the position of the synapse within its dynamic range, low initial release probability creates the "headroom" necessary for potentiation by a presynaptic mechanism.…”

An NMDA Receptor/Nitric Oxide Cascade in Presynaptic Parallel Fiber–Purkinje Neuron Long-Term Potentiation

“…6). NO contributes to the mechanisms underlying presynaptic plasticity at other synaptic pathways (Arancio et al, 1996;Hardingham and Fox, 2006). It has been proposed that NO is produced by PFs and that this production increases after tetanic PF stimulation (Kimura et al, 1998).…”

“…NMDA receptors are present on cerebellar molecular layer interneurons and can be readily activated by glutamate released from PFs, likely followed by the activation of NO synthase (NOS) (Akazawa et al, 1994;Carter and Regehr, 2000). NO, in turn, has been implicated in various forms of presynaptically expressed LTP (Arancio et al, 1996;Hardingham and Fox, 2006). To test for the possible involvement of an NMDA/NO cascade, we used an inhibitor of NOS, L-NNA (10 M) and, as shown in Figure 4 D, this efficiently prevented the induction of 4 Hz PF LTP (100.2 Ϯ 2.4% of baseline at 40 min after 4 Hz stimulation, not significantly different from baseline; p ϭ 0.885; n ϭ 18).…”