Nitric Oxide Induces Pathological Synapse Loss by a Protein Kinase G-, Rho Kinase-Dependent Mechanism Preceded by Myosin Light Chain Phosphorylation

Sunico, Carmen R.; González-Forero, David; Domínguez, Germán; García‐Verdugo, José Manuel; Moreno‐López, Bernardo

doi:10.1523/jneurosci.3911-09.2010

Cited by 61 publications

(82 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, this could go a step further because an increase in neuronal-nitric oxide synthase has been shown to be directly associated with neuronal injury and loss of synapses. 48 In contrast to progressive deterioration of the mitochondrial ultrastructure in neuronal population, we generally did not observe any similar changes in other cell types. Specifically, within astrocytic processes that are frequently observed in degenerating hippocampal neuropil, the sparsely distributed mitochondria appeared to be normal.…”

Section: Discussioncontrasting

confidence: 67%

Morphological and Functional Abnormalities in Mitochondria Associated with Synaptic Degeneration in Prion Disease

Šišková

Mahad

Pudney

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

Synaptic and dendritic pathology is a well-documented component of prion disease. In common with other neurodegenerative diseases that contain an element of protein misfolding, little is known about the underlying mechanisms of synaptic degeneration. In particular, in prion disease the relationship between synaptic malfunction, degeneration, and mitochondria has been neglected. We investigated a wide range of mitochondrial parameters, including changes in mitochondrial density, inner membrane ultrastructure, functional properties and nature of mitochondrial DNA from hippocampal tissue of mice with prion disease, which have ongoing synaptic pathology. Our results indicate that despite a lack of detectable changes in either mitochondrial density or expression of the mitochondrial proteins, mitochondrial function was impaired when compared with age-matched control animals. We observed changes in mitochondrial inner membrane morphology and a reduction in the cytochrome c oxidase activity relative to a sustained level of mitochondrial proteins such as porin and individual, functionally important subunits of complex II and complex IV. These data support the idea that mitochondrial dysfunction appears to occur due to inhibition or modification of respiratory complex rather than deletions of mitochondrial DNA. Indeed , these changes were seen in the stratum radiatum where synaptic pathology is readily detected , indicating that mitochondrial function is impaired and could potentially contribute to or even initiate the synaptic pathology in prion disease. Mitochondria are vital organelles in all eukaryotic cells and are responsible for the efficient generation of highenergy compounds such as ATP produced by oxidativephosphorylation system, also called the respiratory chain. The mitochondrial respiratory chain is located in the inner mitochondrial membrane and consists of five complexes (complexes I-V), each consisting of multiple subunits encoded by both nuclear and mitochondrial DNA (mtDNA), except complex II or succinate dehydrogenase (SDH) that is entirely encoded by nuclear DNA.

show abstract

Section: Discussioncontrasting

confidence: 67%

Morphological and Functional Abnormalities in Mitochondria Associated with Synaptic Degeneration in Prion Disease

Šišková

Mahad

Pudney

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Whole-cell patch-clamp experiments were performed on HMNs from transverse brainstem slices of 6-to 9-d-old Wistar rats as previously described (González-Forero et al, 2007;Sunico et al, 2010). Recordings were performed at 31°C on slices superfused (rate ϳ3-4 ml/min) with aCSF solution equilibrated with 95% O 2 and 5% CO 2 .…”

Section: Whole-cell Patch-clamp Recordings From Hmns In Brainstem Slicesmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

González-Forero¹,

Montero²,

García‐Morales³

et al. 2012

J. Neurosci.

Self Cite

View full text Add to dashboard Cite

Rho-associated kinase (ROCK) regulates neural cell migration, proliferation and survival, dendritic spine morphology, and axon guidance and regeneration. There is, however, little information about whether ROCK modulates the electrical activity and information processing of neuronal circuits. At neonatal stage, ROCK␣ is expressed in hypoglossal motoneurons (HMNs) and in their afferent inputs, whereas ROCK␤ is found in synaptic terminals on HMNs, but not in their somata. Inhibition of endogenous ROCK activity in neonatal rat brainstem slices failed to modulate intrinsic excitability of HMNs, but strongly attenuated the strength of their glutamatergic and GABAergic synaptic inputs. The mechanism acts presynaptically to reduce evoked neurotransmitter release. ROCK inhibition increased myosin light chain (MLC) phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. Functional and ultrastructural changes induced by ROCK inhibition were fully prevented/reverted by MLC kinase (MLCK) inhibition. Furthermore, ROCK inhibition drastically reduced the phosphorylated form of p21-associated kinase (PAK), which directly inhibits MLCK. We conclude that endogenous ROCK activity is necessary for the normal performance of motor output commands, because it maintains afferent synaptic strength, by stabilizing the size of the readily releasable pool of synaptic vesicles. The mechanism of action involves a tonic inhibition of MLCK, presumably through PAK phosphorylation. This mechanism might be present in adults since unilateral microinjection of ROCK or MLCK inhibitors into the hypoglossal nucleus reduced or increased, respectively, whole XIIth nerve activity.

show abstract

“…The impact of PARP-1 on intracellular concentration of its nicotinamideadenine dinucleotide substrate (NAD), creates a bioenergetic imbalance that culminates with ATP depletion, thereby triggering necrotic neuronal death [62,63]. In addition, NO can drive the retraction of the synaptic button via the activation of small GTPase RhoA/ROCK signaling through a paracrine/retrograde-signaling pathway [64]. Taken together, these events could contribute to neuronal dysfunction and death associated with cognitive decline.…”

Section: Nmda-nnos Pathway and Excitotoxicity Developmentmentioning

confidence: 99%

Role of Nitric Oxide Synthase in the Function of the Central Nervous System under Normal and Infectious Conditions

Reis¹,

Gonçalves-de-Albuquerque²,

Maron‐Gutierrez³

et al. 2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

View full text Add to dashboard Cite

Nitric oxide (NO) was discovered as an endothelium-derived relaxing factor more than two decades ago. Since then, it has been shown to participate in many pathways. NO has been described as a key mediator of different pathways in the central nervous system (CNS) in both healthy and diseased processes. The three isoforms of nitric oxide synthase differ in their activity patterns and expression in different cells. Neuronal nitric oxide synthase (nNOS) is localized in synaptic spines, astrocytes, and the loose connective tissue surrounding blood vessels in the brain; eNOS is present in both cerebral vascular endothelial cells and motor neurons; and iNOS is induced in astrocytes and microglia under pathological conditions. During physiological processes, NO produced by eNOS/nNOS, respectively, controls blood flow activation, and act as a messenger during long-term potentiation (LTP). However, under pathological conditions, eNOS appears to be impaired, leading to a reduction in blood flow and, consequently, low oxygen/metabolites delivery, efflux of toxicological agents from the brain tissue and disturbance in the blood-brain barrier. The NO produced by iNOS in glial cells and nNOS, which triggers the NMDA-excitotoxic pathway, combines with superoxide anion and results in peroxynitrite synthesis, a potent free radical that contributes to tissue damage in the brain. Here, we intend to show the controversial role of the nitric oxide delivered by the three isoforms of the nitric oxide synthase in the CNS, assess its impact under healthy/pathological conditions and speculate on its possible sequela, particularly in long-term cognitive decline.

show abstract

Nitric Oxide Induces Pathological Synapse Loss by a Protein Kinase G-, Rho Kinase-Dependent Mechanism Preceded by Myosin Light Chain Phosphorylation

Cited by 61 publications

References 65 publications

Morphological and Functional Abnormalities in Mitochondria Associated with Synaptic Degeneration in Prion Disease

Morphological and Functional Abnormalities in Mitochondria Associated with Synaptic Degeneration in Prion Disease

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

Role of Nitric Oxide Synthase in the Function of the Central Nervous System under Normal and Infectious Conditions

Contact Info

Product

Resources

About