Interaction of nNOS with PSD-95 Negatively Controls Regenerative Repair after Stroke

• DOI: 10.1523/jneurosci.1305-14.2014
• Publication Date: 2014-10-01T16:52:49Z
• Authors: Chun-Xia Luo; Yu-Hui Lin; Xiao-Dan Qian; Ying Tang; Hai-Hui Zhou; Xing Jin; Huan-Yu Ni; Feng-Yun Zhang; Cheng Qin; Fei Li; Yu Zhang; Hai-Yin Wu; Lei Chang; Dong-Ya Zhu
• Keywords: Cerebral Cortex; Male; 0301 basic medicine; 0303 health sciences; Intracellular Signaling Peptides and Proteins; Brain; Histone Deacetylase 2; Membrane Proteins; Cell Differentiation; Infarction, Middle Cerebral Artery; Mice, Transgenic; Embryo, Mammalian; Coculture Techniques; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Glucose; Neural Stem Cells; Animals; Hypoxia; Disks Large Homolog 4 Protein; Cells, Cultured

Stroke is a major public health concern. The lack of effective therapies heightens the need for new therapeutic targets. Mammalian brain has the ability to rewire itself to restore lost functionalities. Promoting regenerative repair, including neurogenesis and dendritic remodeling, may offer a new therapeutic strategy for the treatment of stroke. Here, we report that interaction of neuronal nitric oxide synthase (nNOS) with the protein postsynaptic density-95 (PSD-95) negatively controls regenerative repair after stroke in rats. Dissociating nNOS–PSD-95 coupling in neurons promotes neuronal differentiation of neural stem cells (NSCs), facilitates the migration of newborn cells into the injured area, and enhances neurite growth of newborn neurons and dendritic spine formation of mature neurons in the ischemic brain of rats. More importantly, blocking nNOS–PSD-95 binding during the recovery stage improves stroke outcome via the promotion of regenerative repair in rats. Histone deacetylase 2 in NSCs may mediate the role of nNOS–PSD-95 association. Thus, nNOS–PSD-95 can serve as a target for regenerative repair after stroke.