title: Nitric oxide and synaptic dynamics in the adult brain: physiopathological aspects.
abstract: The adult brain retains the capacity to rewire mature neural circuits in response to environmental changes, brain damage or sensory and motor experiences. Two plastic processes, synaptic remodeling and neurogenesis, have been the subject of numerous studies due to their involvement in the maturation of the nervous system, their prevalence and re-activation in adulthood, and therapeutic relevance. However, most of the research looking for the mechanistic and molecular events underlying synaptogenic phenomena has been focused on the extensive synaptic reorganization occurring in the developing brain. In this stage, a vast number of synapses are initially established, which subsequently undergo a process of activity-dependent refinement guided by target-derived signals that act as synaptotoxins or synaptotrophins, promoting either loss or consolidation of pre-existing synaptic contacts, respectively. Nitric oxide (NO), an autocrine and/or paracrine-acting gaseous molecule synthesized in an activity-dependent manner, has ambivalent actions. It can act by mediating synapse formation, segregation of afferent inputs, or growth cone collapse and retraction in immature neural systems. Nevertheless, little information exists about the role of this ambiguous molecule in synaptic plasticity processes occurring in the adult brain. Suitable conditions for elucidating the role of NO in adult synaptic rearrangement include physiopathological conditions, such as peripheral nerve injury. We have recently developed a crush lesion model of the XIIth nerve that induces a pronounced stripping of excitatory synaptic boutons from the cell bodies of hypoglossal motoneurons. The decline in synaptic coverage was concomitant with de novo expression of the neuronal isoform of NO synthase in motoneurons. We have demonstrated a synaptotoxic action of NO mediating synaptic withdrawal and preventing synapse formation by cyclic GMP (cGMP)-dependent and, probably, S-nitrosylation-mediated mechanisms, respectively. This action possibly involves the participation of other signaling molecules working together with NO. Brain-derived neurotrophic factor (BDNF), a target-derived synaptotrophin synthesized and released postsynaptically in an activity-dependent form, is a potential candidate for effecting such a concerted action. Several items of evidence support an interrelationship between NO and BDNF in the regulation of synaptic remodeling processes in adulthood: i) BDNF and its receptor TrkB are expressed by motoneurons and upregulated by axonal injury; ii) they promote axon arborization and synaptic formation, and modulate the structural dynamics of excitatory synapses; iii) NO and BDNF each control the production and activity of the other at the level of individual synapses; iv) the NO/cGMP pathway inhibits BDNF secretion; and finally, v) BDNF protects F-actin from depolymerization by NO, thus preventing the collapsing and retracting effects of NO on growth cones. Therefore, we propose a mechanism of action in which the NO/BDNF ratio regulates synapse dynamics after peripheral nerve lesion. This hypothesis also raises the possibility that variations in this NO/BDNF balance constitute a common hallmark leading to synapse loss in the progression of diverse neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases.
authors.affiliation: Area de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain. bernardo.moreno@uca.es
authors.forename: Bernardo
authors.initials: B
authors.lastname: Moreno-López
authors.forename: David
authors.initials: D
authors.lastname: González-Forero
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism*; D017711:Nonlinear Dynamics; D013569:Synapses / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins; D009569:Nitric Oxide