Protein Synthesis, Memory and Pediatric Brain Injury
Larry W. Jenkins, P.I.

Through a grant from the NIH we have begun to examine the potential role of impaired protein synthesis in memory deficits after experimental pediatric traumatic brain injury (TBI). As our grant funding will begin in April 2000 our results are preliminary but promising. The diagram below outlines some of the pathways that will be examined after TBI and during memory consolidation in the immature rodent (Figure 1). Our long-term goals are to characterize some of the most important changes in neuronal signaling known to influence cognitive dysfunction after injury and determine if these changes can be normalized by delayed treatment with trophic factors. Our initial data suggests that the important phosphoinositide 3-kinase (PI3K) - protein kinase B (PKB) pathway coupled to trophic factor-protein tyrosine kinase receptors (PTK) is up regulated during the first 24 hours after mild pediatric TBI (Figure 2). This is an injury level where cognitive function is preserved. We expect an opposite response in this important signaling pathway with more severe pediatric TBI that results in cognitive dysfunction.

Figure 1 - ACUTE PATHOLOGICAL INTERACTIONS BETWEEN EXCITATORY NEUROTRANSMITTERS AND NEUROTROPHINS AT TRAUMATIC IMPACT AND CHRONIC EFFECTS ON KEY PROTEIN SYNTHESIS INITIATION CONTROL FACTORS - Neurotransmitter and neuromodulator storms at TBI impact over-activate many signal transduction systems. Hydrolysis of inositol phospholipids by PLC_ß1 or PLC_g1 is initiated by either G protein coupled receptor stimulation, tyrosine kinase phosphorylation or can be activated by increases in intracellular calcium coupled to receptor operated calcium channels such as the NMDA ionotropic receptor. However, it is also apparent that agonist induced hydrolysis of other phospholipid pools by PLD or PLA2 can produce greater and more sustained levels of PKC activators (DAG and AA) which may increase, prolong and subsequently downregulate PKC activity.

Furthermore, PKC has been shown to negative modulate G protein receptor coupled PLC activation while providing positive modulation of ionotropic receptors such as NMDA and AMPA receptors and voltage sensitive calcium channels. At the same time, tyrosine kinases can also produce PKC activators either directly or indirectly via the activation of PLC_g1 PLA2 and PLD. Acute pathological activation of these receptorcascades such as occur during traumatic impact produces persistent downregulation of protein kinases due to over-activation that may alter:

1) the efficacy of ionotropic and metabotropic receptor coupling resulting in chronic intracellular release; 2) gene expression and protein translation that may modulate cell death pathways and /or learning and memory consolidation; and 3) the efficacy of subsequent growth factor treatment after TBI. Acutely, second messenger storms produce a stress response that inhibits both eIF2 and eIF4 protein synthesis initiation pathways with only cap-independent mRNAs (HSPs) being translated.

Also, calpain activation by increased calcium may partially degrade critical members of the eIF4 binding proteins and PKCs. Chronically, diminished PKC and PKB signaling reduce eIF4 pathway activity impairing the rate of protein synthesis but more importantly the selection of mRNAs that are translated for days and weeks after TBI.

Exogenous stimulation at this time with growth factors and insulin may help increase the activity of the PKB - eIF4 pathway restoring, in part, proper mRNA processing. The GSK 3 pathway can be activated by insulin either via ribosomal S6 protein or a MAP kinase cascade. (IP3 - inositol (1,4,5) trisphosphate, 1,2DAG - 1,2 diacylglycerol, IP4 - inositol (1,3,4,5) tetrakisphosphate, AA - arachidonic acid, P13K - phosphoinositide-3 kinase, PTK - protein tyrosine kinase, PKB - protein kinase B, PKC - protein kinase C, PKA protein kinase A, cAMP - cyclic adenosine monophosphate, (PLC, PLD, PLA2- phospholipase C, D, A2), HSPs - heat shock proteins, ER endoplasmic reticulum, eIF-2a/2B - eukaryotic initiation factor 2a and eIF-2B (guanine exchange factor), eIF4E - eukaryotic initiation factor 4E (cap binding protein), eEF2 - eukaryotic elongation factor 2, IP3R - inositol trisphosphate receptor, RyR - ryanodine receptor, p70s6k - ribosomal protein S6, pp99rsk -ribosomal protein kinase S6 kinase, GSK-3 - glycogen synthase kinase -3, MAP KK - mitogen activated protein kinase kinase, MAP K - mitogen activated kinase).

Figure 2. PKB immunohistochemistry reveals increased PKB protein expression in hippocampal pyramidal neurons 24 hours after a mild sublethal controlled cortical impact (CCI) on the ipsilateral side under the contusion but not on the non-contused contralateral side. PKB is not only a pro-survival downstream trophic signal but influences protein synthesis that may be important in cognitive function.

Collaborators (alphabetical order):

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