Inhibiting PTEN Protects Hippocampal Neurons against Stretch Injury by Decreasing Membrane Translocation of AMPA Receptor GluR2 Subunit

Yuan Liu,Ya-Min Wu,Jian-Xin Jiang,Qi Wan,Li Wang,Zai-Yun Long,Zheng-Guo Wang,Simone Di Giovanni

doi:10.1371/journal.pone.0065431

Yuan Liu, Ya-Min Wu + Show 6 more

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https://doi.org/10.1371/journal.pone.0065431

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Abstract

The AMPA type of glutamate receptors (AMPARs)-mediated excitotoxicity is involved in the secondary neuronal death following traumatic brain injury (TBI). But the underlying cellular and molecular mechanisms remain unclear. In this study, the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in GluR2-lacking AMPARs mediated neuronal death was investigated through an in vitro stretch injury model of neurons. It was indicated that both the mRNA and protein levels of PTEN were increased in cultured hippocampal neurons after stretch injury, which was associated with the decreasing expression of GluR2 subunits on the surface of neuronal membrane. Inhibition of PTEN activity by its inhibitor can promote the survival of neurons through preventing reduction of GluR2 on membrane. Moreover, the effect of inhibiting GluR2-lacking AMPARs was similar to PTEN suppression-mediated neuroprotective effect in stretch injury-induced neuronal death. Further evidence identified that the total GluR2 protein of neurons was not changed in all groups. So inhibition of PTEN or blockage of GluR2-lacking AMPARs may attenuate the death of hippocampal neurons post injury through decreasing the translocation of GluR2 subunit on the membrane effectively.

Highlights

Traumatic brain injury (TBI) is one of the major cause of death and permanent disability in traumatic patients [1,2]
Increasement of extracellular glutamate following brain injury will lead to over-stimulation the function of glutamate receptors, such as AMPA, NMDA receptor, that may result in secondary injury and causing the death of neuronal cells [5]
AMPA receptors (AMPARs) mediate fast synaptic transmission at excitatory synapses of neurons in the central nervous system(CNS) and are assemblies of GluR1-4 subunits, which are differentially expressed throughout the CNS [6].The GluR2 subunit governs a number of characteristics of AMPARs, among which AMPARs containing GluR2 subunit are impermeable to divalent cations and protect neurons against injury caused by influx of Ca2+ and Zn2+

Summary

Introduction

Traumatic brain injury (TBI) is one of the major cause of death and permanent disability in traumatic patients [1,2]. Neuronal degeneration following TBI is believed to involve in primary mechanical injury and progressive secondary injury [1]. The underlying mechanism of secondary injury in TBI is not clear entirely. Alteration in excitatory amino and its receptor is regarded as a critical cause for the progressive neuronal death following TBI [3,4].Glutamate is the most abundant excitatory neurotransmitter in the brain. Increasement of extracellular glutamate following brain injury will lead to over-stimulation the function of glutamate receptors, such as AMPA, NMDA receptor, that may result in secondary injury and causing the death of neuronal cells [5]. AMPARs lacking GluR2 subunit are permeable to Ca2+ and Zn2+ [7]

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