Dissociation of nNOS from PSD‐95 promotes functional recovery after cerebral ischaemia in mice through reducing excessive tonic GABA release from reactive astrocytes

• DOI: 10.1002/path.4999
• Publication Date: 2017-10-20T13:30:12Z
• Authors: Yu‐Hui Lin; Hai‐Ying Liang; Ke Xu; Huan‐Yu Ni; Jian Dong; Hui Xiao; Lei Chang; Hai‐Yin Wu; Fei Li; Dong‐Ya Zhu; Chun‐Xia Luo
• Keywords: 0301 basic medicine; 0303 health sciences; Benzylamines; GABA Plasma Membrane Transport Proteins; Neuronal Plasticity; Behavior, Animal; Glutamate Decarboxylase; Motor Cortex; Nipecotic Acids; Neural Inhibition; Nitric Oxide Synthase Type I; Anisoles; Motor Activity; Nitric Oxide; Brain Ischemia; Aminosalicylic Acids; Disease Models, Animal; 03 medical and health sciences; Neuroprotective Agents; 0302 clinical medicine; Astrocytes; Animals; Disks Large Homolog 4 Protein; Monoamine Oxidase

Abstract Mechanisms underlying functional recovery after stroke are little known, and effective drug intervention during the delayed stage is desirable. One potential target, protein–protein interaction between neuronal nitric oxide synthase (nNOS) postsynaptic density protein 95 (PSD‐95), critical to acute ischaemic damage neurogenesis. We show that nNOS–PSD‐95 dissociation induced by microinjection of a recombinant fusion protein, Tat‐nNOS‐N 1–133 , or systemic administration small‐molecule, ZL006, from day 4 10 photothrombotic ischaemia in mice reduced excessive tonic inhibition peri‐infarct cortex ameliorated motor outcome. also demonstrated improved neuroplasticity including increased dendrite spine synaptogenesis reducing dissociation. Levels gamma‐aminobutyric acid (GABA) GABA transporter‐3/4 (GAT‐3/4) reactive astrocytes cortex. The GAT‐3/4‐selective antagonist SNAP‐5114 promoted function recovery, suggesting was due release reversed GAT‐3/4 astrocytes. Treatments with ZL006 inhibited astrocyte activation production, prevented reversal GAT‐3/4, consequently decreased molecular mechanisms were associated epigenetic glutamic decarboxylase 67 monoamine oxidase B expression through NO production. thus target for restoration small molecule inhibitor this interaction, promising pharmacological lead compound. Copyright © 2017 Pathological Society Great Britain Ireland. Published John Wiley & Sons, Ltd.