This is an exploratory R21application in response to PA number PAS-99-080. Traumatic brain injury (TBI) is the leading cause of death and disability in traumatically injured children. Additionally, children suffer diffuse TBI more often than adults and we have developed a reproducible and clinically relevant model of diffuse pediatric TBI in the rat. This model produces cognitive deficits in spatial memory, as assessed by the Morris Water Maze (MWM) task, which is uncomplicated by acute or delayed forebrain neuronal death either related to injury or developmental apoptosis. Cognitive dysfunction is the most persistent consequence of pediatric TBI and the hippocampus plays crucial roles in experimental and clinical TBI cognitive impairment. Recent studies have implicated hippocampal protein synthesis after brain injury in neuronal survival or active death programs; however, protein synthesis is also critical for hippocampal dependent learning and memory. The neural cell adhesion molecule (NCAM) has been associated with hippocampal synaptic plasticity both during development in the immature and learning in the adult rat. The consolidation phase of spatial memory acquisition is prevented by inhibiting the synthesis of new proteins such as NCAM during learning of the MWM task. Impaired translation of new proteins may contribute to enduring learning deficits after pediatric TBI. Specifically, pathological changes in two key protein synthesis initiation pathways mediated by dysfunction of eIF2 and eIF4 initiation factor proteins may contribute to cognitive deficits after pediatric TBI. Critical roles for protein kinase C (PKC) and protein tyrosine kinase (PTK) activity in the initiation and fidelity of protein synthesis and in modulating injury related stress responses have been documented. Changes in PKC and PTK levels persist for days after adult TBI but have not been evaluated in pediatric TBI. Protein kinase activity can be modulated by exogenously administered insulin growth factor-I (IGF-1) which has also been shown to improve outcome in adult clinical and experimental TBI. We propose: 1) that pediatric TBI also produces persistent changes in PKC and PTK function impairing the initiation phase of protein synthesis and reducing the translation of key proteins such as NCAM necessary for spatial memory learning in the MWM paradigm. 2) that therapeutic modulation of PKC and PTK activity (at 2 wk after injury) with insulin growth factor-I will improve spatial memory after TBI and will help normalize protein synthesis and the expression of NCAM during MWM learning.
