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Neurotrophic activity of pituitary adenylate cyclase-activating polypeptide on rat cerebellar cortex during
D Vaudry1, B J Gonzalez, M Basille
1European Institute for Peptide Research (Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23), Laboratory of Cellular and Molecular Neuroendocrinology, Institut National de la Santé etde la Recherche Médicale (U-413), France.
Insights
Pituitary adenylate cyclase-activating polypeptide (PACAP) acts as a trophic factor in developing rat brains. PACAP promotes cerebellar granule cell proliferation and migration, enhancing cerebellar cortex development.
Area of Science:
- Neuroscience
- Developmental Biology
- Neuroendocrinology
Background:
- Pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are abundant in the developing rat cerebellum.
- In vitro studies suggest PACAP supports cerebellar granule cell survival and neurite outgrowth.
Purpose of the Study:
- To investigate the in vivo effects of PACAP on cerebellar cortex development in 8-day-old rats.
- To determine if PACAP influences cerebellar granule cell proliferation, migration, and overall cerebellar growth.
Main Methods:
- In vitro incubation of cerebellar granule cells with PACAP to assess proliferation via [(3)H]thymidine incorporation.
- In vivo administration of PACAP to rats, followed by analysis of cerebellar cell counts and cortical volume.
- Utilized PACAP receptor antagonist PACAP(6-38) to confirm receptor-mediated effects.
Main Results:
- PACAP significantly increased [(3)H]thymidine incorporation in cultured granule cells, indicating stimulated proliferation.
- In vivo PACAP administration led to a transient increase in granule cell numbers in the molecular and internal granule cell layers.
- PACAP treatment increased cerebellar cortex volume and this effect was blocked by PACAP(6-38).
- No significant effect of PACAP on Purkinje cell numbers was observed.
Conclusions:
- PACAP functions as a trophic factor in vivo during rat cerebellar development.
- PACAP enhances cerebellar granule cell proliferation and/or inhibits apoptosis.
- PACAP promotes neuronal migration from the external to the internal granule cell layer, contributing to cerebellar growth.
Abstract:
High concentrations of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are present in the external granule cell layer of the rat cerebellum during postnatal development. In vitro studies have shown that PACAP promotes cell survival and neurite outgrowth on immature cerebellar granule cells in primary culture. In the present study, we have investigated the effect of PACAP on the development of the cerebellar cortex of 8-day-old rats. Incubation of cultured granule cells for 12 or 18 h with PACAP provoked a significant increase in the rate of incorporation of [(3)H]thymidine in cultured granule cells, suggesting that PACAP could stimulate the proliferation of granule cells. After 96 h of treatment, in vivo administration of PACAP provoked a transient increase in the number of granule cells in the molecular layer and in the internal granule cell layer. In contrast, PACAP did not affect the number of Purkinje cells. The augmentation of the number of granule cells evoked by PACAP was significantly inhibited by the PACAP receptor antagonist PACAP(6-38). Administration of PACAP also caused a significant increase in the volume of the cerebellar cortex. The present study provides evidence that PACAP can act in vivo as a trophic factor during rat brain development. Our data indicate that PACAP increases proliferation and/or inhibits programmed cell death of granule cells, as well as stimulating neuronal migration from the external granule cell layer toward the internal granule cell layer.