RT Journal Article
SR Electronic
T1 Nitric Oxide Induces Pathological Synapse Loss by a Protein Kinase G-, Rho Kinase-Dependent Mechanism Preceded by Myosin Light Chain Phosphorylation
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 973
OP 984
DO 10.1523/JNEUROSCI.3911-09.2010
VO 30
IS 3
A1 Carmen R. Sunico
A1 David González-Forero
A1 Germán Domínguez
A1 José Manuel García-Verdugo
A1 Bernardo Moreno-López
YR 2010
UL http://www.jneurosci.org/content/30/3/973.abstract
AB The molecular signaling that underpins synapse loss in neuropathological conditions remains unknown. Concomitant upregulation of the neuronal nitric oxide (NO) synthase (nNOS) in neurodegenerative processes places NO at the center of attention. We found that de novo nNOS expression was sufficient to induce synapse loss from motoneurons at adult and neonatal stages. In brainstem slices obtained from neonatal animals, this effect required prolonged activation of the soluble guanylyl cyclase (sGC)/protein kinase G (PKG) pathway and RhoA/Rho kinase (ROCK) signaling. Synapse elimination involved paracrine/retrograde action of NO. Furthermore, before bouton detachment, NO increased synapse myosin light chain phosphorylation (p-MLC), which is known to trigger actomyosin contraction and neurite retraction. NO-induced MLC phosphorylation was dependent on cGMP/PKG-ROCK signaling. In adulthood, motor nerve injury induced NO/cGMP-dependent synaptic stripping, strongly affecting ROCK-expressing synapses, and increased the percentage of p-MLC-expressing inputs before synapse destabilization. We propose that this molecular cascade could trigger synapse loss underlying early cognitive/motor deficits in several neuropathological states.