NO Orchestrates the Loss of Synaptic Boutons from Adult “Sick” Motoneurons: Modeling a Molecular Mechanism

Abstract

Synapse elimination is the main factor responsible for the cognitive decline accompanying many of the neuropathological conditions affecting humans. Synaptic stripping of motoneurons is also a common hallmark of several motor pathologies. Therefore, knowledge of the molecular basis underlying this plastic process is of central interest for the development of new therapeutic tools. Recent advances from our group highlight the role of nitric oxide (NO) as a key molecule triggering synapse loss in two models of motor pathologies. De novo expression of the neuronal isoform of NO synthase (nNOS) in motoneurons commonly occurs in response to the physical injury of a motor nerve and in the course of amyotrophic lateral sclerosis. In both conditions, this event precedes synaptic withdrawal from motoneurons. Strikingly, nNOS-synthesized NO is "necessary" and "sufficient" to induce synaptic detachment from motoneurons. The mechanism involves a paracrine/retrograde action of NO on pre-synaptic structures, initiating a downstream signaling cascade that includes sequential activation of (1) soluble guanylyl cyclase, (2) cyclic guanosine monophosphate-dependent protein kinase, and (3) RhoA/Rho kinase (ROCK) signaling. Finally, ROCK activation promotes phosphorylation of regulatory myosin light chain, which leads to myosin activation and actomyosin contraction. This latter event presumably contributes to the contractile force to produce ending axon retraction. Several findings support that this mechanism may operate in the most prevalent neurodegenerative diseases.

Endogenous Rho-Kinase Signaling Maintains Synaptic Strength by Stabilizing the Size of the Readily Releasable Pool of Synaptic Vesicles

“…Through its regulatory role in actin cytoskeletal rearrangements, ROCK controls smooth-muscle contraction as well as cell migration, neurite outgrowth, and synapse retraction (Riento and Ridley, 2003;Mueller et al, 2005;Sunico et al, 2010;Moreno-Ló pez et al, 2011). Two isoforms of ROCK, I (or ␤) and II (or ␣) have been described so far (Nakagawa et al, 1996).…”

Viral Vectors as Tools to Investigate the Role of Dysregulated Proteins in Nervous System Pathologies: the Case of Acquired Motor Neuropathies

“…Thus, nNOS transfection mimicked the effect of axonal injury on the synaptic coverage of HMNs. In this way, it seems clear that NO, synthesized by up-regulated nNOS in adult axotomized motoneurons, is not only necessary but also sufficient to trigger the molecular cascade leading to synapse withdrawal from HMN perikarya Moreno-López et al, 2011). This indicates that NO synthesized by transduced HMN interacts with the NO-sensitive dye DAA.…”

“…Alteration in the expression level of nitric oxide (NO) synthase (NOS) is a hallmark of Alzheimer (AD), Parkinson (PD), and Huntington diseases (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and HIV dementia in humans and/or in animal models, as well as after peripheral and central traumatic lesions of the nervous system (Montero et al, 2010;Moreno-López et al, 2011). Subsequently, dysregulation of protein expression and/or function is a key event in a broad spectrum of neuropathological states.…”

“…Axotomy provokes changes in axonal, synaptic and www.intechopen.com intrinsic membrane properties, including enhanced somato-dendritic excitability, decreased axonal conduction speed, considerable loss of afferent synaptic contacts, and disorders in the firing properties and recruitment order of motor units (González-Forero et al, 2004;. Synapse loss is the major feature underlying cognitive impairment in patients and/or animal models of AD, PD, MS, HD, and HIV-related dementia Moreno-López et al, 2011). Interestingly, synaptic alteration, rather than neuronal death, is the main factor responsible for the age-related downturn in neuronal function.…”

Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis

“…Acting through the GSK3 regulator of KIF-5, 5HT is observed to increase transport, while DA decreases it (Chen et al, 2007. Other neuromodulators, such as nitric oxide, GABA B , and adenosine, could also be worth investigating as modulators of motoneuron synaptic strength, reduction of the Ca 2+ PIC, and modulation of both high-voltage-activated Ca 2+ channels and input conductance, respectively (Marks et al, 1993, Mynlieff and Beam, 1994, Li et al, 2004, Moreno-Lopez et al, 2011. Another useful target of neuromodulators that modify Ca 2+ influx is protein clearance; inhibition of L-type Ca 2+ channels has been found to increase autophagy (Williams et al, 2008).…”