Involvement of Pituitary Adenylate Cyclase-Activating Polypeptide II Vasoactive Intestinal Peptide 2 Receptor in Mouse Neocortical Astrocytogenesis


Address correspondence and reprint requests to Dr. P. Gressens at Service de Neuropédiatrie, Hôpital Robert-Debré, 48 Boulevard Sérurier, F-75019 Paris, France.


Abstract: At the end of neuronal migration, the neopallial germinative zone produces glial cells destined to colonize the upper layers of neocortex. High densities of binding sites for vasoactive intestinal peptide (VIP) have been found in the rodent germinative zone just after completion of neuronal migration, suggesting a possible role of VIP in neocortical astrocytogenesis. In the present study, administration of a VIP antagonist at embryonic days 17 and 18 to pregnant mice was followed by a dramatic depletion of astrocytes in the upper cortical layer of the offspring. The depletion of astrocytes was dose-dependent, with a 42% reduction in the density of astrocytes observed with 50 µg of antagonist. The antagonist effect was reversed by cotreatment with VIP or pituitary adenylate cyclase-activating polypeptide (PACAP), suggesting the involvement of a receptor common to these two neuropeptides. VIP antagonist-induced inhibition of astrocytogenesis was also blocked by Ro 25-1553, a long-acting cyclic VIP analogue selective for the PACAP II VIP2 receptor subclass. Our results demonstrate that VIP and/or PACAP play a crucial physiological role in neocortical astrocytogenesis, possibly through interaction with PACAP II VIP2 receptors.

Abbreviations used: ADNF, activity-dependent neurotrophic factor; BRDU, 5-bromo-2′-deoxyuridine; E, embryonic day; GFAP, glial fibrillary acidic protein; HSP-70, heat shock protein of 70 kDa; MAP, microtubule-associated protein; NF-160, neurofilament of 160 kDa; P, postnatal day; PACAP, pituitary adenylate cyclase-activating polypeptide; PBS, phosphate-buffered saline; SNV, stearyl norleucine vasoactive intestinal peptide; VA, vasoactive intestinal peptide antagonist (neurotensin 1–6 vasoactive intestinal peptide 7–28 hybrid); VIP, vasoactive intestinal peptide.