EPIGENETIC FACTORS REGULATE THE NPY EXPRESSION IN RAT CORTICAL-NEURONS

The NPY phenotype expressed in a subset of rat neocortical neurons is influenced by a variety of epigenetic factors. In the present study, w e analyzed the role of synaptically driven spontaneous bioelectric (ac tion potential) activity (SBA) and neurotrophic factors. Our model sys tems are organotypic monocultures of visual cortex which either grow a s spontaneously active cultures or as activity-blocked cultures to whi ch neurotrophic factors can be applied via the medium. NPY mRNA expres sing neurons are detected by in situ hybridization and are quantified as a percentage of all neurons. In spontaneously active cultures, abou t 7% of all neurons express NPY mRNA. This expression is regulated by SEA, because expression is reduced to about 2% by different activity b lockade paradigms. When putative NPY neurons differentiate under activ ity blockade, they are unable to restitute the NPY expression during a subsequent period of SEA. A restitution of the NPY phenotype in 6-7% of the neurons after a transient blockade of activity is only possible when neurons were initially allowed to differentiate in the presence of SEA. We then analyzed whether neurotrophic factors known to promote NPY expression can do so in the absence of SEA. Neurotrophin-4/5 and leukemia inhibitory factor, but not brain-derived neurotrophic factor and neurotrophin-3, stimulate the NPY phenotype in the absence of SEA. In situ hybridization in combination with immune-fluorescence reveals that NPY-ir neurons express the receptors trkB or LIFR beta, but not trkC. This coexpression pattern explains why neurotrophin-4/5 and leuk emia inhibitory factor are efficient regulators of the NPY-expression. Our results suggest that the NPY expression in neocortical neurons de pends on epigenetic factors: spontaneous activity and neurotrophic fac tors modulate the expression and are thus involved in shaping the neur ochemical architecture of the cerebral cortex. (C) 1998 Elsevier Scien ce B.V. All rights reserved.