Experience-Dependent Plasticity Acts via GluR1 and a Novel Neuronal Nitric Oxide Synthase-Dependent Synaptic Mechanism in Adult Cortex

Abstract

Synaptic plasticity directs development of the nervous system and is thought to underlie memory storage in adult animals. A great deal of our current understanding of the role of AMPA receptors in synaptic plasticity comes from studies on developing cortex and cell cultures. In the present study we instead focus on plasticity in mature neurons in the neocortex of adult animals. We find that the GluR1 subunit of the AMPA receptor is involved in experience-dependent plasticity in adult cortex in vivo and that it acts in addition to αNOS1 (neuronal nitric oxide synthase), an enzyme that produces the rapid synaptic signaling molecule nitric oxide (NO). Potentiation of the spared whisker response, following single whisker experience, is approximately 33% less in GluR1 null mutants than in wild-types. We found that the remaining plasticity depended upon αNOS1. Potentiation was reduced by over 42% in the single αNOS1 null mutants and completely abolished in GluR1/αNOS1 double knockout mice. However, potentiation in GluR1/NOS3 double knockouts occurred at similar levels to that seen in GluR1 single knockouts. Synaptic plasticity in the layer IV to II/III pathway in vitro mirrored the results in vivo, in that LTP was present in GluR1/NOS3 double knockout mice but not in the GluR1/αNOS1 animals. While basal levels of NO in cortical slices depended on both αNOS1 and NOS3, NMDA receptor-dependent NO release only depended on αNOS1 and not on NOS3. These findings demonstrate that αNOS1 acts in concert with GluR1 to produce experience-dependent plasticity in the neocortex.

The Role of GluA1 in Ocular Dominance Plasticity in the Mouse Visual Cortex

“…A feasible candidate for a second homeostatic mechanism is one that operates via GluA2 rather than GluA1 (Gainey et al, 2009;Altimimi and Stellwagen, 2013;Lambo and Turrigiano, 2013). The main evidence comes from experiments in which TTX is applied to cultured cortical neurons leading to up-scaling of mEPSPs.…”

“…The main evidence comes from experiments in which TTX is applied to cultured cortical neurons leading to up-scaling of mEPSPs. If shRNA for GluA2 is applied to the cell cultures, it blocks the TTX-driven up-scaling, as does a peptide designed to interfere with the C-terminal tail of GluA2 (Gainey et al, 2009). In contrast, a peptide designed to interfere with GluA1 does not affect TTX-induced scaling (Gainey et al, 2009).…”

“…If shRNA for GluA2 is applied to the cell cultures, it blocks the TTX-driven up-scaling, as does a peptide designed to interfere with the C-terminal tail of GluA2 (Gainey et al, 2009). In contrast, a peptide designed to interfere with GluA1 does not affect TTX-induced scaling (Gainey et al, 2009). This suggests that the GluA2-dependent scaling mechanism could be the second homeostatic mechanism responsible for the difference in response levels in the cortex of GluA1 Ϫ/Ϫ 6J versus GluA1 Ϫ/ ϪOlaHsd mice.…”

α4* Nicotinic Acetylcholine Receptors Modulate Experience-Based Cortical Depression in the Adult Mouse Somatosensory Cortex

“…Although it is certain that cortical depression takes place, the molecular mechanisms that mediate this form of plasticity are not well understood, especially for adult animals that are less well studied. Thus far, mechanistic studies conducted primarily in young animals have implicated glutamate (Rema et al, 1998;Takahashi et al, 2003;Clem et al, 2008;Wright et al, 2008;Dachtler et al, 2011) and cannabinoid (L. ) receptor signaling in experience-based cortical depression. This leaves open the possibility that other modulators of synaptic signaling, perhaps acting through inhibitory circuits which have recently been implicated in visual (Yazaki-Sugiyama et al, 2009) and barrel cortex plasticity (Jiao et al, 2006;Sun, 2009) may be involved.…”

The intercalated nuclear complex of the primate amygdala

“…NO is involved in activity-dependent synaptic plasticity in several brain regions that play key roles in cognition and flexible, adaptive behavior (Prast and Philippu, 2001, Dachtler et al, 2011, Walton et al, 2013). In the amygdala, NO is additionally linked with modulation of anxiety levels and other emotional processes (Shindou et al, 1993, Yao et al, 2007).…”