Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) initiates a complex cascade of secondary neurodegenerative mechanisms contributing to cell dysfunction and necrotic and apoptotic cell death. The injured brain responds by activating endogenous reparative processes to counter the neurodegeneration or remodel the brain to enhance functional recovery. A vast array of genetically altered mice provide a unique opportunity to target single genes or proteins to better understand their role in cell death and endogenous repair after TBI. Among the earliest targets for transgenic and knockout studies in TBI have been programmed cell death mediators, such as the Bcl-2 family of proteins, caspases, and caspaseindependent pathways. In addition, the role of cell cycle regulatory elements in the posttraumatic cell death pathway has been explored in mouse models. As interest grows in neuroplasticity in TBI, the use of transgenic and knockout mice in studies focused on gliogenesis, neurogenesis, and the balance of growth-promoting and growth-inhibiting molecules has increased in recent years. With proper consideration of potential effects of constitutive gene alteration, traditional transgenic and knockout models can provide valuable insights into TBI pathobiology. Through increasing sophistication of conditional and cell-type specific genetic manipulations, TBI studies in genetically altered mice will be increasingly useful for identification and validation of novel therapeutic targets.

Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment

“…Since activitydependent regulation of gene expression is critical for inhibitory network remodeling through life experiences [29,30], it is possible that beneficial effects of an enriched environment might be related to its ability to enhance neuronal viability or possibly by providing sufficient compensatory inhibition to the overexcited hippocampal circuitry. Finally, our results revealed that there was no colocalization of caspase-3 and PV interneurons, suggesting that caspase-independent pathways may be involved in mediation of the decreased PV expression induced by sevoflurane [35]. Also, there was no colocalization of BrdU and PV interneuron, indicating the abnormalities of PV interneurons were not due to the effect of sevoflurane on the proliferating cells.…”

Function and Mechanisms of Autophagy in Brain and Spinal Cord Trauma

“…Recent studies also demonstrate a potential second peak of inflammation till 2 months after injury as well as chronic neuroinflammatory changes ( 6 , 71 ). Additional damage can occur at a distance over days and months after injury via Wallerian degeneration and/or demyelination, reflecting CNS connectivity ( 54 , 65 ).…”

Hyperphosphorylated Tau is Implicated in Acquired Epilepsy and Neuropsychiatric Comorbidities

“…Given this delayed onset, it is possible that secondary injuries may be prevented and are considered to be potential pharmaceutical targets to improve TBI outcomes [24]. These secondary mechanisms represent complex, parallel, interacting and interdependent injury processes that remain poorly understood, with no pharmacological treatment known to effectively limit their progression and improve TBI patient outcome.…”