Corticosterone effects on postnatal cerebellar development in mice.

ABSTRACT

Glucocorticoids administered early in infancy can affect the architectonic organization of brain structures, particularly those with a postnatal development and resulting in long-term deficits of neuromotor function and cognition. The present study was undertaken to study the effects of daily corticosterone (CORT) injections at a pharmacological dose from postnatal days 8-15 on cerebellar and hippocampal development in mouse pups. Gene expression status for trophic factors involved in synaptic development and function as well as measures of layer thickness associated with cytochrome oxidase labelling were analyzed in the hippocampus, hypothalamus, and specific cerebellar lobules involved in motor control. Repeated CORT injections dysregulated the HPA axis with increased Crh and Nr3c1 mRNA levels in the hypothalamus and a resulting higher serum corticosterone level. The CORT treatment altered the morphology of the hippocampus and down-regulated gene transcription for corticotropin-releasing hormone (Crh) and its type-1 receptor (Crhr1), glucocorticoid receptor (Nr3c1), and brain-derived neurotrophic factor Bdnf and its receptor Ntrk2 (neurotrophic receptor tyrosine kinase 2). Similar mRNA expression decreases were found in the cerebellum for Crhr1, Crhr2, Nr3c1, and Grid2 (glutamatergic δ2 receptor). Morphological alterations and metabolic activity variations were observed in specific cerebellar lobules involved in motor control. The paramedian lobule, normally characterized by mitotic activity in the external germinative layer during the second postnatal week, was atrophic but metabolically hyperactive in its granule cell and molecular layers. On the contrary, lobules with an earlier cell proliferation displayed neurogenesis but a hypoactivated granule cell layer, suggesting a developmental delay in synaptogenesis. The results indicate that glucocorticoid, administered daily during the second postnatal week modulated the developmental programming of the hippocampus and cerebellum. These growth and metabolic alterations may lead possibly to morphological and functional changes later in life.