Mechanisms of hippocampal dysfunction following pediatric brain trauma

Dana Lengel

doi:10.17918/00000861

Traumatic brain injury (TBI) is the leading cause of long-term disability in children below the age of four. Survivors of childhood TBI face life-long cognitive, psychosocial, and behavioral impairments, which can emerge or worsen as they age into adolescence and adulthood. This susceptibility may be due in part to the vulnerability of neural stress circuits to TBI during early postnatal development. Moderate closed-head injury in male and female 11-day-old rats (equivalent to late infancy) resulted in a range of cognitive and behavioral deficits at 4 weeks post-injury (adolescence), including spatial learning and memory deficits, impairments in hippocampal long-term potentiation (LTP), and an increase in open arm exploration in the elevated plus maze (EPM). The expression of glucocorticoid receptors (GR) within the hippocampus has been linked to both hippocampal-dependent cognitive behaviors and emotional regulation, suggesting that a disruption of GR expression or activity within the hippocampus may underlie these post-traumatic deficits. Follow-up studies confirmed that pediatric TBI impaired the transcriptional activity of hippocampal GRs, as demonstrated by a reduction in the expression of the glucocorticoid-inducible gene, serum- and glucocorticoid-inducible kinase 1 (sgk1) mRNA following both water maze training and exposure to the EPM. The viral transfection of human GR (hGR) into the DH attenuated spatial learning and LTP deficits following pediatric TBI, increased hippocampal sgk1 mRNA following water maze training, and increased the expression of the glutamatergic AMPA and NMDA receptor subunits GluA1 and GluN1. Viral transfection of hGR into the ventral, but not the DH reversed the increase in open arm exploration following pediatric TBI, which was associated with an increase in hippocampal corticotropin releasing hormone (CRH) mRNA following EPM testing. These results support a significant role of neural stress response systems (glucocorticoids, CRH) in the chronic sequelae of pediatric TBI, and suggest that the targeting the glucocorticoid system may be an effective strategy for mitigating cognitive and behavioral symptoms following childhood brain trauma.

Mechanisms of hippocampal dysfunction following pediatric brain trauma

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Mechanisms of hippocampal dysfunction following pediatric brain trauma

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