Cortical interneurons upregulate neurotrophins in vivo in response to targeted apoptotic degeneration of neighboring pyramidal neurons

Intercellular signals provided by growth and neurotrophic factors play a cr itical role during neurogenesis and as part of cellular repopulation strate gies directed toward reconstruction of complex CNS circuitry. Local signals influence the differentiation of transplanted and endogenous neurons and n eural precursors, but the cellular sources and control over expression of t hese molecules remain unclear. We have previously examined microenvironment al control in neocortex over neuron and neural precursor migration and diff erentiation following transplantation, using an approach of targeted apopto tic neuronal degeneration to specific neuronal populations in vivo. Prior r esults suggested the hypothesis that upregulated or reexpressed development al signal molecules, produced by degenerating pyramidal neurons and/or by n eighboring neurons or nonneuronal cells, may be responsible for observed ev ents of directed migration, differentiation, and connectivity by transplant ed immature neurons and precursors. To directly investigate this hypothesis , we analyzed the gene expression of candidate and control neurotrophins, g rowth factors, and receptors within regions of targeted neuronal cell death , first by quantitative Northern blot analysis and then by in situ hybridiz ation combined with immunocytochemical analysis. The genes for BDNF, NT-4/5 , trkB receptors, and to a lesser extent NT-3 were upregulated specifically within the regions of neocortex undergoing targeted neuronal degeneration and specifically during the period of ongoing pyramidal neuron apoptosis. U pregulation occurred during the same 3-week period as the previously invest igated cellular events of directed migration, differentiation, and integrat ion. No upregulation was seen in panels of control neurotrophins, growth fa ctors, and receptors that are not as developmentally regulated in cortex or that are thought to have primary actions in other CNS regions. In situ hyb ridization and immunocytochemistry revealed that BDNF mRNA expression was u pregulated specifically by local interneurons adjacent to degenerating pyra midal neurons. These findings suggest specific effects of targeted apoptosi s on neurotrophin and other gene expression via mechanisms, including inter cellular signaling between degenerating pyramidal neurons and surrounding i nterneurons. Further understanding of these and other controls over neocort ical projection neuron differentiation may provide insight regarding normal neocortical development, intercellular signaling induced by apoptosis, and toward reconstruction and cellular repopulation of complex neocortical and other CNS circuitry. (C) 1998 Academic Press.