Induction of Neuronal PI3Kγ Contributes to Endoplasmic Reticulum Stress and Long-Term Functional Impairment in a Murine Model of Traumatic Brain Injury

Shan Liu, Rong Jin, Adam Y. Xiao, Rui Chen, Jarvis Li, Wei Zhong, Xiaozhou Feng, Guohong Li

Research output: Contribution to journalArticle

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Abstract

Phosphoinositide 3-kinase γ (PI3Kγ) expressed in immune cells is linked to neuroinflammation in several neurological diseases. However, the expression and role of PI3Kγ in preclinical traumatic brain injury (TBI) have not been investigated. In WT mice, we found that TBI induced rapid and extensive expression of PI3Kγ in neurons within the perilesional cortex and the ipsilateral hippocampal subfields (CA1, CA3), which peaked between 1 and 3 days and declined significantly 7 days after TBI. Intriguingly, the induction of neuronal PI3Kγ in these subregions of the brain spatiotemporally coincided with both the TBI-induced activation of the neuronal ER stress pathway (p-eIF2α, ATF4, and CHOP) and neuronal cell death (marked by TUNEL-positive neurons) 3 days after TBI. Further, we show that the absence of PI3Kγ in knockout mice profoundly reduced the TBI-induced activation of the ER stress pathway and neuronal cell death. White matter disruption is a better predictor of long-term clinical outcomes than focal lesion size. We show that PI3Kγ deficiency not only reduced brain tissue loss but also alleviated white matter injury (determined by axonal injury and demyelination) up to 28 days after TBI. Importantly, PI3Kγ-knockout mice exhibited greater functional recovery including forepaw use, sensorimotor balance and coordination, and spatial learning and memory up to 28 days after TBI. These results unveil a previously unappreciated role for neuronal PI3Kγ in the regulation of ER stress associated with neuronal cell death, white matter damage, and long-term functional impairment after TBI.

Original languageEnglish (US)
JournalNeurotherapeutics
DOIs
StatePublished - Jan 1 2019

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Endoplasmic Reticulum Stress
1-Phosphatidylinositol 4-Kinase
Cell Death
Knockout Mice
Traumatic Brain Injury
Neurons
In Situ Nick-End Labeling
Wounds and Injuries
Brain
Demyelinating Diseases

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

Cite this

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title = "Induction of Neuronal PI3Kγ Contributes to Endoplasmic Reticulum Stress and Long-Term Functional Impairment in a Murine Model of Traumatic Brain Injury",
abstract = "Phosphoinositide 3-kinase γ (PI3Kγ) expressed in immune cells is linked to neuroinflammation in several neurological diseases. However, the expression and role of PI3Kγ in preclinical traumatic brain injury (TBI) have not been investigated. In WT mice, we found that TBI induced rapid and extensive expression of PI3Kγ in neurons within the perilesional cortex and the ipsilateral hippocampal subfields (CA1, CA3), which peaked between 1 and 3 days and declined significantly 7 days after TBI. Intriguingly, the induction of neuronal PI3Kγ in these subregions of the brain spatiotemporally coincided with both the TBI-induced activation of the neuronal ER stress pathway (p-eIF2α, ATF4, and CHOP) and neuronal cell death (marked by TUNEL-positive neurons) 3 days after TBI. Further, we show that the absence of PI3Kγ in knockout mice profoundly reduced the TBI-induced activation of the ER stress pathway and neuronal cell death. White matter disruption is a better predictor of long-term clinical outcomes than focal lesion size. We show that PI3Kγ deficiency not only reduced brain tissue loss but also alleviated white matter injury (determined by axonal injury and demyelination) up to 28 days after TBI. Importantly, PI3Kγ-knockout mice exhibited greater functional recovery including forepaw use, sensorimotor balance and coordination, and spatial learning and memory up to 28 days after TBI. These results unveil a previously unappreciated role for neuronal PI3Kγ in the regulation of ER stress associated with neuronal cell death, white matter damage, and long-term functional impairment after TBI.",
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Induction of Neuronal PI3Kγ Contributes to Endoplasmic Reticulum Stress and Long-Term Functional Impairment in a Murine Model of Traumatic Brain Injury. / Liu, Shan; Jin, Rong; Xiao, Adam Y.; Chen, Rui; Li, Jarvis; Zhong, Wei; Feng, Xiaozhou; Li, Guohong.

In: Neurotherapeutics, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Induction of Neuronal PI3Kγ Contributes to Endoplasmic Reticulum Stress and Long-Term Functional Impairment in a Murine Model of Traumatic Brain Injury

AU - Liu, Shan

AU - Jin, Rong

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AU - Chen, Rui

AU - Li, Jarvis

AU - Zhong, Wei

AU - Feng, Xiaozhou

AU - Li, Guohong

PY - 2019/1/1

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N2 - Phosphoinositide 3-kinase γ (PI3Kγ) expressed in immune cells is linked to neuroinflammation in several neurological diseases. However, the expression and role of PI3Kγ in preclinical traumatic brain injury (TBI) have not been investigated. In WT mice, we found that TBI induced rapid and extensive expression of PI3Kγ in neurons within the perilesional cortex and the ipsilateral hippocampal subfields (CA1, CA3), which peaked between 1 and 3 days and declined significantly 7 days after TBI. Intriguingly, the induction of neuronal PI3Kγ in these subregions of the brain spatiotemporally coincided with both the TBI-induced activation of the neuronal ER stress pathway (p-eIF2α, ATF4, and CHOP) and neuronal cell death (marked by TUNEL-positive neurons) 3 days after TBI. Further, we show that the absence of PI3Kγ in knockout mice profoundly reduced the TBI-induced activation of the ER stress pathway and neuronal cell death. White matter disruption is a better predictor of long-term clinical outcomes than focal lesion size. We show that PI3Kγ deficiency not only reduced brain tissue loss but also alleviated white matter injury (determined by axonal injury and demyelination) up to 28 days after TBI. Importantly, PI3Kγ-knockout mice exhibited greater functional recovery including forepaw use, sensorimotor balance and coordination, and spatial learning and memory up to 28 days after TBI. These results unveil a previously unappreciated role for neuronal PI3Kγ in the regulation of ER stress associated with neuronal cell death, white matter damage, and long-term functional impairment after TBI.

AB - Phosphoinositide 3-kinase γ (PI3Kγ) expressed in immune cells is linked to neuroinflammation in several neurological diseases. However, the expression and role of PI3Kγ in preclinical traumatic brain injury (TBI) have not been investigated. In WT mice, we found that TBI induced rapid and extensive expression of PI3Kγ in neurons within the perilesional cortex and the ipsilateral hippocampal subfields (CA1, CA3), which peaked between 1 and 3 days and declined significantly 7 days after TBI. Intriguingly, the induction of neuronal PI3Kγ in these subregions of the brain spatiotemporally coincided with both the TBI-induced activation of the neuronal ER stress pathway (p-eIF2α, ATF4, and CHOP) and neuronal cell death (marked by TUNEL-positive neurons) 3 days after TBI. Further, we show that the absence of PI3Kγ in knockout mice profoundly reduced the TBI-induced activation of the ER stress pathway and neuronal cell death. White matter disruption is a better predictor of long-term clinical outcomes than focal lesion size. We show that PI3Kγ deficiency not only reduced brain tissue loss but also alleviated white matter injury (determined by axonal injury and demyelination) up to 28 days after TBI. Importantly, PI3Kγ-knockout mice exhibited greater functional recovery including forepaw use, sensorimotor balance and coordination, and spatial learning and memory up to 28 days after TBI. These results unveil a previously unappreciated role for neuronal PI3Kγ in the regulation of ER stress associated with neuronal cell death, white matter damage, and long-term functional impairment after TBI.

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