Premium
Altered cerebellar development in mice lacking pituitary adenylate cyclase‐activating polypeptide
Author(s) -
Allais Aurélie,
Burel Delphine,
Isaac Emma R.,
Gray Sarah L.,
Basille Magali,
Ravni Aurélia,
Sherwood Nancy M.,
Vaudry Hubert,
Gonzalez Bruno J.
Publication year - 2007
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2007.05535.x
Subject(s) - granule cell , synaptophysin , biology , medicine , cerebellum , endocrinology , pituitary adenylate cyclase activating peptide , nestin , receptor , microbiology and biotechnology , dentate gyrus , central nervous system , neuropeptide , immunohistochemistry , vasoactive intestinal peptide , neural stem cell , stem cell , biochemistry , immunology
Previous studies have demonstrated that pituitary adenylate cyclase‐activating polypeptide (PACAP) exerts trophic effects during neurodevelopment. In particular, the occurrence of PACAP and its receptors in the cerebellum during pre‐ and postnatal periods suggests that it could play a crucial role in ontogenesis of this structure. To test this hypothesis, we compared the histogenesis of cerebellar cortex in wild‐type and PACAP‐knockout (PACAP –/– ) mice at postnatal days (P)4 and 7. Morphometric analysis of PACAP –/– mice revealed a significant reduction in the thickness of the external granule cell layer at P4 and of the internal granule cell layer at P7. Expression of nestin, a neural precursor marker, and synaptophysin, a mature neuronal marker, was quantified by real‐time PCR and Western blot. No modification of nestin expression was noticed between wild‐type and PACAP –/– mice, but a substantial decrease in synaptophysin expression was observed in PACAP –/– mice at P4 and P7. Immunohistochemistry revealed a reduction in synaptophysin labelling in the molecular and internal granule cell layers of PACAP –/– mice at P7. Caspase‐3 activation was significantly increased in PACAP –/– mice at P4 and P7. Autoradiographic studies revealed no difference in PACAP binding site distributions and PACAP was effective at stimulating cAMP production in both wild‐type and PACAP –/– cultured granule cells. This study demonstrates that disruption of the PACAP gene induces alteration of the immature cerebellum. Neuronal differentiation of granule cells was delayed whereas cell death that naturally occurs during ontogeny was increased in PACAP –/– mice. These data provide the first evidence of a physiological role for PACAP during cerebellar development.