Acute Physiology and Neurologic Outcomes after Brain Injury in SCOP/PHLPP1 KO Mice

Travis C Jackson,Vincent Vagni,Shawn E Kotermanski,Keri Janesko-Feldman,Patrick M Kochanek,Edwin K Jackson,C Edward Dixon

doi:10.1038/s41598-018-25371-2

Travis C Jackson, Vincent Vagni + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-25371-2

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Abstract

Suprachiasmatic nucleus circadian oscillatory protein (SCOP) (a.k.a. PHLPP1) regulates long-term memory consolidation in the brain. Using a mouse model of controlled cortical impact (CCI) we tested if (1) brain tissue levels of SCOP/PHLPP1 increase after a traumatic brain injury (TBI), and (2) if SCOP/PHLPP1 gene knockout (KO) mice have improved (or worse) neurologic outcomes. Blood chemistry (pH, pCO2, pO2, pSO2, base excess, sodium bicarbonate, and osmolarity) and arterial pressure (MAP) differed in isoflurane anesthetized WT vs. KOs at baseline and up to 1 h post-injury. CCI injury increased cortical/hippocampal SCOP/PHLPP1 levels in WTs 7d and 14d post-injury. Injured KOs had higher brain tissue levels of phosphorylated AKT (pAKT) in cortex (14d post-injury), and higher levels of phosphorylated MEK (pMEK) in hippocampus (7d and 14d post-injury) and in cortex (7d post-injury). Consistent with an important role of SCOP/PHLPP1 on memory function, injured-KOs had near normal performance on the probe trial of the Morris water maze, whereas injured-WTs were impaired. CA1/CA3 hippocampal survival was lower in KOs vs. WTs 24 h post-injury but equivalent by 7d. No difference in 21d cortical lesion volume was detected. SCOP/PHLPP1 overexpression in cultured rat cortical neurons had no effect on 24 h cell death after a mechanical stretch-injury.

Highlights

Neuronal Suprachiasmatic nucleus circadian oscillatory protein (SCOP)/PHLPP1 blocks membrane localized K-Ras, which in turn inhibits the downstream kinase, mitogen activated protein kinase (MEK)[3]
To the best of our knowledge it has not been tested if (1) SCOP/PHLPP1 levels are disturbed after a traumatic brain injury (TBI), (2) if memory deficits induced by acute brain injury are improved or exacerbated in SCOP/PHLPP1 KOs, and (3) if naïve KOs have normal or altered memory function as assessed by the MWM learning and memory paradigm
In this study we report several novel findings: (1) we identified differences in baseline and post-injury physiology in isoflurane anesthetized KOs vs. WTs, (2) baseline MWM performance is similar in naïve KOs vs. WTs, (3) after a cortical impact (CCI), hippocampal/cortical phosphorylated MEK (pMEK) is increased in injured KOs vs. WTs and is associated with improved performance on the probe trial of the MWM, and (4) after a CCI, long-term histological outcomes are equivalent in KOs vs. WTs

Summary

Introduction

Neuronal SCOP/PHLPP1 blocks membrane localized K-Ras (a small GTPase), which in turn inhibits the downstream kinase, mitogen activated protein kinase (MEK)[3]. Transgenic mice overexpressing SCOP/PHLPP1 in the forebrain had impaired long-term memory consolidation on a novel object recognition task (i.e. impaired recall to identify the novel object 24 h post-training) but normal acquisition (i.e. overexpression did not affect learning)[5]. In this study we report several novel findings: (1) we identified differences in baseline and post-injury physiology in isoflurane anesthetized KOs vs WTs, (2) baseline MWM performance is similar in naïve KOs vs WTs, (3) after a CCI, hippocampal/cortical pMEK is increased in injured KOs vs WTs and is associated with improved performance on the probe trial (memory component) of the MWM, and (4) after a CCI, long-term histological outcomes are equivalent in KOs vs WTs. Our findings add to a growing body of evidence which supports SCOP/ PHLPP1 targeting as a novel therapeutic strategy to improve neurological recovery after brain injury

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