The survival promoting and neuroprotective actions of brain-derived neurotrophic factor (BDNF) are well known but under certain circumstances this growth factor can also exacerbate excitotoxic insults to neurons. Prior exploration of the receptor through which BDNF exerts this action on motor neurons deflects attention away from p75. Here we investigated the possibility that BDNF acts through the receptor tyrosine kinase, TrkB, to confer on motor neurons sensitivity to excitotoxic challenge. We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody, and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons. Addition of a function blocking antibody to BDNF to mixed spinal cord neuron cultures is also neuroprotective indicating that endogenously produced BDNF participates in vulnerability to excitotoxicity. We next examined the intracellular signaling cascades that are engaged upon TrkB activation. Previously we found that inhibition of the phosphatidylinositide-3¢-kinase (PI3¢K) pathway blocks BDNF-induced excitotoxic sensitivity. Here we show that expression of a constitutively active catalytic subunit of PI3¢K, p110, confers excitotoxic sensitivity (ES) upon motor neurons not incubated with BDNF. Parallel studies with purified motor neurons confirm that these events are likely to be occuring specifically within motor neurons. The abrogation of BDNF's capacity to accentuate excitotoxic insults may make it a more attractive neuroprotective agent.

The interaction of an animal with its environment during a critical period in early postnatal life has lifelong effects on the structure and function of sensory and motor systems. To gain insight into the molecular mechanisms of experience-dependent development, we challenged young rats to adapt to a new environment that engenders novel motor behavior. Rats born in the gravitational field (1G) of the earth subsequently were reared for 2 weeks either in the absence of gravity (microgravity) or at 1G. A comparison of gene expression using microarrays led to the identification of a panel of differentially regulated transcripts. We report here that the abundance of serum-and glucocorticoid-inducible kinase (SGK) is increased in spinal cord tissue from animals reared in microgravity in comparison with 1G-reared controls. The induction of SGK expression also can be achieved by administration of glucocorticoids to animals at 1G or neurons in vitro. Expression of constitutively active SGK in neurons leads to the elaboration of neuronal dendrites and their branching. Glucocorticoids also lead to dendrite elaboration, and this effect can be abrogated by inhibiting SGK activity. Changes in the level of expression of SGK could be part of the mechanism for experience-dependent acquisition of mature neuronal properties.

These data indicate that healthy infants can digest RNA and subsequently absorb the liberated purine ribonucleotides as determined by urinary uric acid concentration.