title: Involvement of aberrant cyclin-dependent kinase 5/p25 activity in experimental traumatic brain injury.
abstract: Traumatic brain injury (TBI) is associated with adverse effects on brain functions, including sensation, language, emotions and/or cognition. Therapies for improving outcomes following TBI are limited. A better understanding of the pathophysiological mechanisms of TBI may suggest novel treatment strategies to facilitate recovery and improve treatment outcome. Aberrant activation of cyclin-dependent kinase 5 (Cdk5) has been implicated in neuronal injury and neurodegeneration. Cdk5 is a neuronal protein kinase activated via interaction with its cofactor p35 that regulates numerous neuronal functions, including synaptic remodeling and cognition. However, conversion of p35 to p25 via Ca(2+) -dependent activation of calpain results in an aberrantly active Cdk5/p25 complex that is associated with neuronal damage and cell death. Here, we show that mice subjected to controlled cortical impact (CCI), a well-established experimental TBI model, exhibit increased p25 levels and consistently elevated Cdk5-dependent phosphorylation of microtubule-associated protein tau and retinoblastoma (Rb) protein in hippocampal lysates. Moreover, CCI-induced neuroinflammation as indicated by increased astrocytic activation and number of reactive microglia. Brain-wide conditional Cdk5 knockout mice (Cdk5 cKO) subjected to CCI exhibited significantly reduced edema, ventricular dilation, and injury area. Finally, neurophysiological recordings revealed that CCI attenuated excitatory post-synaptic potential field responses in the hippocampal CA3-CA1 pathway 24 h after injury. This neurophysiological deficit was attenuated in Cdk5 cKO mice. Thus, TBI induces increased levels of p25 generation and aberrant Cdk5 activity, which contributes to pathophysiological processes underlying TBI progression. Hence, selectively preventing aberrant Cdk5 activity may be an effective acute strategy to improve recovery from TBI. Traumatic brain injury (TBI) increases astrogliosis and microglial activation. Moreover, TBI deregulates Ca(2+) -homeostasis triggering p25 production. The protein kinase Cdk5 is aberrantly activated by p25 leading to phosphorylation of substrates including tau and Rb protein. Loss of Cdk5 attenuates TBI lesion size, indicating that Cdk5 is a critical player in TBI pathogenesis and thus may be a suitable therapeutic target for TBI.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Yousuf
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Tan
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Melissa I
authors.initials: MI
authors.lastname: Torres-Altoro
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Fang-Min
authors.initials: FM
authors.lastname: Lu
authors.affiliation: Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Plautz
authors.affiliation: Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Shanrong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Adan
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: Department of Pediatrics and Pathology & Cell Biology, Columbia University, New York, New York, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kernie
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Plattner
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D000070642:Brain Injuries, Traumatic / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D002154:Calpain
keywords: cyclin-dependent kinase 5; microtubule-associated protein tau; neuroinflammation; p25; retinoblastoma protein; traumatic brain injury