Impact of Traumatic Brain Injury on Neurogenesis

Abstract

New neurons are generated in the hippocampal dentate gyrus from early development through adulthood. Progenitor cells and immature granule cells in the subgranular zone are responsive to changes in their environment; and indeed, a large body of research indicates that neuronal interactions and the dentate gyrus milieu regulates granule cell proliferation, maturation, and integration. Following traumatic brain injury (TBI), these interactions are dramatically altered. In addition to cell losses from injury and neurotransmitter dysfunction, patients often show electroencephalographic evidence of cortical spreading depolarizations and seizure activity after TBI. Furthermore, treatment for TBI often involves interventions that alter hippocampal function such as sedative medications, neuromodulating agents, and anti-epileptic drugs. Here, we review hippocampal changes after TBI and how they impact the coordinated process of granule cell adult neurogenesis. We also discuss clinical TBI treatments that have the potential to alter neurogenesis. A thorough understanding of the impact that TBI has on neurogenesis will ultimately be needed to begin to design novel therapeutics to promote recovery.

Keywords: adult neurogeneses; anesthetic neurotoxicity; dentate gyrus; epilepsy; granule cell; spreading depolarization (SD); traumatic brain injury.

FIGURE 1

Generation and integration of adult-born granule cells is a coordinated process that is impacted by TBI. At each stage of adult neurogenesis, the normal process (blue) has potential to be altered by TBI (orange). (1) Quiescent radial neural stem cells (NSCs) in the subgranular zone (SGZ) can be depleted by frequent activation early in life, such as by TBI-induced seizures, leading to deficiencies with age. (2) TBI and its effects, including spreading depolarizations and seizures, cause an increase in proliferation of progenitor cells. (3) Newly-generated neurons migrate from the SGZ to the granule cell layer (GCL), and after TBI abnormal hilar migration is apparent. (4) Parvalbumin interneurons and (5) mossy hilar neurons are susceptible to cell death after TBI. Reduction in their numbers results in decreased GABAergic and glutamatergic (respectively) input to the newly-generated neurons. Newly-generated neurons show additional signs of aberrant neurogenesis such as abnormal connectivity (6), hyperexcitability (7) and inappropriate integration and dendritic maturity (8) which can be caused by changes in the environmental milieu.