Article ; Online: Endoplasmic Reticulum Stress Contributes to the Loss of Newborn Hippocampal Neurons after Traumatic Brain Injury.
The Journal of neuroscience : the official journal of the Society for Neuroscience
2018 Volume 38, Issue 9, Page(s) 2372–2384
Abstract: Adult hippocampal neurogenesis has been shown to be required for certain types of cognitive function. For example, studies have shown that these neurons are critical for pattern separation, the ability to store similar experiences as distinct memories. ... ...
| Abstract | Adult hippocampal neurogenesis has been shown to be required for certain types of cognitive function. For example, studies have shown that these neurons are critical for pattern separation, the ability to store similar experiences as distinct memories. Although traumatic brain injury (TBI) has been shown to cause the loss of newborn hippocampal neurons, the signaling pathway(s) that triggers their death is unknown. Endoplasmic reticulum (ER) stress activates the PERK-eIF2α pathway that acts to restore ER function and improve cell survival. However, unresolved/intense ER stress activates C/EBP homologous protein (CHOP), leading to cell death. We show that TBI causes the death of hippocampal newborn neurons via CHOP. Using CHOP KO mice, we show that loss of CHOP markedly reduces newborn neuron loss after TBI. Injured CHOP mice performed significantly better in a context fear discrimination task compared with injured wild-type mice. In contrast, the PERK inhibitor GSK2606414 exacerbated doublecortin cell loss and worsened contextual discrimination. Administration of guanabenz (which reduces ER stress) to injured male rats reduced the loss of newborn neurons and improved one-trial contextual fear memory. Interestingly, we also found that the surviving newborn neurons in brain-injured animals had dendritic loss, which was not observed in injured CHOP KO mice or in animals treated with guanabenz. These results indicate that ER stress plays a key role in the death of newborn neurons after TBI. Further, these findings indicate that ER stress can alter dendritic arbors, suggesting a role for ER stress in neuroplasticity and dendritic pathologies. |
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| MeSH term(s) | Animals ; Brain Injuries, Traumatic/metabolism ; Brain Injuries, Traumatic/physiopathology ; Cell Death/physiology ; Endoplasmic Reticulum Stress/physiology ; Hippocampus/metabolism ; Hippocampus/physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurogenesis/physiology ; Neurons/metabolism ; Neurons/pathology ; Rats ; Rats, Sprague-Dawley ; Transcription Factor CHOP/metabolism |
| Chemical Substances | Transcription Factor CHOP (147336-12-7) |
| Language | English |
| Publishing date | 2018-01-31 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 604637-x |
| ISSN | 1529-2401 ; 0270-6474 |
| ISSN (online) | 1529-2401 |
| ISSN | 0270-6474 |
| DOI | 10.1523/JNEUROSCI.1756-17.2018 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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