Prenatal blockade of vasoactive intestinal peptide alters cell death and synaptic equipment in the murine neocortex

Vasoactive intestinal peptide (VIP) is a potent growth factor that stimulat es murine neocortical astrocyte genesis during the period of ontogenesis co rresponding to premature delivery in humans. In rodents, part of the VIP su pplied to the fetal brain is maternal VIP that crosses the placenta. If the se data also apply to human brain development, premature newborns may be pa rtly VIP-deficient because of loss of the maternal supply, and this may adv ersely affect their brain development. The goal of the present study was to determine the effects of VIP blockade during mouse neocortical astrocyte g enesis on neuritic survival and maturation. VIP blockade by a specific VIP antagonist on embryonic d 17 and 18 induced transient, postnatal depletion of astrocytes in the upper neocortical layers. Combined use of in situ DNA fragmentation analysis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method, a marker of cell death); immunohistochemical det ection of synaptophysin, microtubule-associated proteins, and neurofilament s; and quantification of mRNA for synaptophysin and N-methyl-D-aspartate R1 receptor subunit revealed that early VIP blockade significantly altered pr ogrammed neuritic death and impaired neuritic differentiation. VIP inhibiti on induced 1) exaggerated postnatal terminal deoxynucleotidyl transferase-m ediated dUTP nick-end labeling of cortical neurons, 2) long-term overexpres sion of synaptophysin and N-methyl-D-aspartate R1 receptor subunit, and 3) long-term overexpression of microtubule-associated protein-5 and neurofilam ent 160 kD. Although the functional consequences of this deviant pattern of murine neocortical development remain to be determined, these data open up new avenues for investigating some of the cognitive deficits observed in h uman premature infants.