Role of neuronal nitric oxide in neuroplasticity-associated protein expression.

摘要

Experience-induced alterations in neural activity can elicit long-lasting modifications in synaptic structure and transmission. By allowing neurons to respond and adapt to a changing environment, certain forms of neuroplasticity may underlie various important brain processes, including learning and memory. Because aging and aging-related disorders are characterized by a decline in cognitive function linked to early impairments in synaptic plasticity, it is imperative to elucidate the underlying mechanisms. Nitric oxide (NO) synthesized by neuronal NO synthase (nNOS) in response to N-methyl-D-aspartate (NMDA) receptor activation has long been implicated in brain plasticity. However, it is unclear how this short-lived mediator contributes to the long-term molecular changes underlying neuroplasticity, which typically require activation of the MAPK/ERK signaling pathway and gene expression. To address this issue we used a neuroplasticity model based on treatment of neuronal cultures with bicuculline and a model of experience-dependent plasticity in the barrel cortex. In neuronal cultures, NOS inhibition attenuated the bicuculline-induced activation of ERK and the expression of c-Fos, Egr-1, Arc and brain derived neurotrophic factor (BDNF), proteins essential for neuroplasticity. Furthermore, inhibition of the NO target soluble guanylyl cyclase or of the cGMP effector kinase PKG reduced both ERK activation and plasticity-related protein expression. NOS inhibition did not affect phosphorylation of CREB, a well-established ERK nuclear target, but it attenuated the nuclear accumulation of the CREB coactivator TORC1 and suppressed the activation of Elk-1, another transcription factor target of ERK. Consistent with these in vitro observations, induction of c-Fos, Egr-1, and BDNF was attenuated in the D1 cortical barrel of nNOS4-/- mice subjected to single whisker experience. These results establish nNOS-derived NO as a key factor in the expression of proteins involved in neuroplasticity, an effect involving cGMP, PKG, and ERK signaling. These actions of NO do not depend on CREB phosphorylation, but may involve TORC1 and Elk-1. Our data unveil a previously unrecognized link between neuronal NO and the molecular machinery responsible for the sustained synaptic changes underlying neuroplasticity, while providing new insight on different targets of potential therapeutic value for neurological conditions characterized by alterations in neuroplasticity mechanisms.