Cypin: A novel target for traumatic brain injury

• Published in: Neurobiology of disease 2018-11, Vol.119, p.13-25
• Main Authors: Swiatkowski, Przemyslaw, Sewell, Emily, Sweet, Eric S., Dickson, Samantha, Swanson, Rachel A., McEwan, Sara A., Cuccolo, Nicholas, McDonnell, Mark E., Patel, Mihir V., Varghese, Nevin, Morrison, Barclay, Reitz, Allen B., Meaney, David F., Firestein, Bonnie L.
• Format: Article
• Language: English
• Subjects: Animals; Brain Injuries, Traumatic - metabolism; Brain Injuries, Traumatic - physiopathology; Brain Injuries, Traumatic - prevention & control; Cells, Cultured; Chlorocebus aethiops; Controlled cortical impact; COS Cells; Cypin; Dimethyl Sulfoxide - pharmacology; Electrophysiology; Fear - drug effects; Fear - physiology; Glutamate-induced toxicity; Guanine Deaminase - antagonists & inhibitors; Guanine Deaminase - metabolism; Guanine deaminase activity; Heterocyclic Compounds, 3-Ring - pharmacology; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiopathology; Male; Mice; Mice, Inbred C57BL; N-Methylaspartate - pharmacology; Neuroprotection; Organ Culture Techniques; Rats; Traumatic brain injury
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2018.07.019

Cytosolic PSD-95 interactor (cypin), the primary guanine deaminase in the brain, plays key roles in shaping neuronal circuits and regulating neuronal survival. Despite this pervasive role in neuronal function, the ability for cypin activity to affect recovery from acute brain injury is unknown. A key barrier in identifying the role of cypin in neurological recovery is the absence of pharmacological tools to manipulate cypin activity in vivo. Here, we use a small molecule screen to identify two activators and one inhibitor of cypin's guanine deaminase activity. The primary screen identified compounds that change the initial rate of guanine deamination using a colorimetric assay, and secondary screens included the ability of the compounds to protect neurons from NMDA-induced injury and NMDA-induced decreases in frequency and amplitude of miniature excitatory postsynaptic currents. Hippocampal neurons pretreated with activators preserved electrophysiological function and survival after NMDA-induced injury in vitro, while pretreatment with the inhibitor did not. The effects of the activators were abolished when cypin was knocked down. Administering either cypin activator directly into the brain one hour after traumatic brain injury significantly reduced fear conditioning deficits 5 days after injury, while delivering the cypin inhibitor did not improve outcome after TBI. Together, these data demonstrate that cypin activation is a novel approach for improving outcome after TBI and may provide a new pathway for reducing the deficits associated with TBI in patients. •Cypin induces changes in synaptic electrophysiology that restore neuronal function after injury.•We identified activators of cypin that promote neuroprotection in vitro and cognitive recovery in mice post-TBI.•Cypin is a new target for TBI research and therapies.