Moderate Traumatic Brain Injury Triggers Rapid Necrotic Death of Immature Neurons in the Hippocampus

Abstract

Traumatic brain injury (TBI) causes cell death predominantly in the cerebral cortex but there is additional secondary cell death in the hippocampus. We previously found that the majority of the dying cells in the mouse hippocampus are newborn immature granular neurons in a mouse model of lateral controlled cortical impact (CCI) injury with a moderate level of impact. It is not known how long this selective cell death in the hippocampal dentate gyrus lasts, and how it is induced. Using Fluoro-Jade B and immunohistochemistry, we show that most of the neuron death in the hippocampus occurs within 24 hours post-TBI and that cell death continues at low level for at least another 2 wks in this lateral CCI model. The majority of the dying immature granular neurons did not exhibit morphological characteristics of apoptosis and only a small subpopulation of the dying cells was positive for apoptotic markers. In contrast, most of the dying cells co-expressed the receptor-interacting protein-1, a marker of necrosis, suggesting that immature neurons mainly died of necrosis. These results indicate that moderate TBI mainly triggers rapid necrotic death of immature neurons in the hippocampus in a mouse CCI model.

Beneficial Effects of Early mTORC1 Inhibition after Traumatic Brain Injury

“…21,22 FJB staining is specific for damaged neurons and has been used as a reliable method to quantify post-CCI damage in the L-side of the brain. 23 Indeed, we detected extensive FJB signal in the L-side and no detectable signal in the C-side hippocampus of vehicle-treated CCI-exposed mice in low magnification images (Fig.…”

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“…19 About 50% of immature neurons in the hippocampus die within 24 h after TBI with a moderate CCI injury. 19,21 Recent studies further show that TBI promotes NSPC proliferation in the adult, 20,[51][52][53][54][55][56][57][58][59] leading to increased generation of immature neurons. Thus, it is assumed that more immature neurons will be generated trying to compensate for TBI-induced immature neuron death.…”

“…19,21 The number of immature neurons in the epicenter reduced about 50% at 24 h after moderate TBI. 19 Our recent study found that pretreatment of DHF increased the number of immature neurons in the hippocampus following moderate TBI.…”

“…18 Further study found that the adult-born immature neuron in the hippocampus is the cell type most vulnerable to TBI insult. [19][20][21] Most immature neuron death occurs within 24 h of the initial insult. 21 Disturbances in hippocampal neurogenesis may play a significant role in TBI-related pathologies, as the hippocampus is implicated in higher cognitive function 22 and is frequently associated with post-traumatic seizure generation.…”

“…[19][20][21] Most immature neuron death occurs within 24 h of the initial insult. 21 Disturbances in hippocampal neurogenesis may play a significant role in TBI-related pathologies, as the hippocampus is implicated in higher cognitive function 22 and is frequently associated with post-traumatic seizure generation. 23 Thus, in addition to other neuroprotection strategies, it is important to explore approaches preventing immature neuron death after TBI.…”