期刊
JOURNAL OF NEUROSCIENCE
卷 30, 期 3, 页码 973-984出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3911-09.2010
关键词
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资金
- Ministerio de Ciencia e Innovacion (Spain) [SAF2008-01415]
- Consejer a de Innovacion, Ciencia y Empresa of the Junta de Andalucia [PAI2005-CTS-844, PAI2007-CTS-02606]
- Mutua Madrilena Foundation
- Ministerio de Ciencia e Innovacion [SAF2008-01274]
- Instituto de Salud Carlos III [RD06/0010/0022]
- Conselleria de Sanitat-Centro de Investigacion Principe Felipe
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.
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