Neuronal survival mechanisms - Activity regulation of neuronal survival and circuit activation in the mammalian central nervous system: In the early post-natal brain, approximately half of neurons are eliminated during a restricted period. Recently, we reported that neurotrophins induced survival of neonatal rat hippocampal neurons by promoting neural activity. We have recently shown that the survival of neurons in the hippocampus is regulated by the transient activation of neurotrophin receptors. This signal leads to a sustained phosphorylation of the Ser/Thr kinase Akt at Ser-473 that is maintained for several hours by calcium flux through L-type channels and integrin signaling. In this project, we have now shown that the levels of the matrix metalloproteinases (MMP2 and MMP9) decrease and the level of the extracellular matrix (ECM) protein laminin increases in the newborn hippocampus during the period of neuronal death. In vitro, the MMP inhibitor FN-439 promoted survival of neurons in a laminin-integrin beta1-dependent manner. Blocking laminin signaling attenuated induction of phosphorylation of Akt at Ser-473 by depolarization. In vivo, injecting FN-439 into the neonatal hippocampus increased the level of laminin, and promoted neuronal survival. These results show that extracellular matrix signals are not simply permissive as they actively control the number of hippocampal neurons. Our current work focuses on the signaling mechanisms downstream of the extracellular matrix that control neuronal survival at a later step in development. The prospect that these signals establish and maintain circuit specificity in the brain is a particularly exciting aspect of this work
