There is now substantial evidence to suggest that the early life environment can have a permanent effect on adult physiology. Recently we have shown that early postnatal glucocorticoid (GC) exposure produces alterations in midbrain dopaminergic cell number in the adult rat, in a gender-specific manner (McArthur et al., Brit. Neurosci. Assoc. Abstr. 2003;17:27). Since the protein annexin 1 (ANXA1) mediates some aspects of the effects of GCs within the immune system and the hypothalamo-pituitary adrenal axis (Theogaraj et al., Br. J. Pharmacol. 2002;135:225P), we aimed to determine whether ANXA1 might play a role in the aforementioned effects of neonatal GC exposure on these dopaminergic nuclei. Therefore, we evaluated the effect of ANXA1 gene deletion (Hannon et al., FASEB J 2003;17:253) on dopaminergic cell number in two midbrain nuclei: the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Hindbrains from wild-type (WT; male, n=5; female, n=6) and ANXA1 knock-out (KO; male, n=6; female, n=6) adult mice were frozen, sectioned, and immunostained for tyrosine hydroxylase (TH) using diaminobenzidine as a chromogen. Dopaminergic (TH immunopositive) cells were counted and averaged for each nucleus in each animal.
Female KO mice had significantly fewer dopaminergic cells than female WT, in both the SNc (p = 0.006) and VTA (p = 0.036). In contrast, there was no significant difference in dopaminergic cell number between male WT and male KO animals, in either nucleus. Our data therefore demonstrate a gender-specific influence of ANXA1 deletion on mesencephalic dopaminergic neurones and suggest that ANXA1 may exert important influences on the survival and/or phenotypic expression of these populations. We propose that these findings may have important implications for the aetiology of neurodevelopmental disorders such as schizophrenia, whose pathophysiology is closely linked with midbrain dopaminergic pathways, and whose environmental risk factors appear to include maternal stressors.
03 - 05 Nov 2003
Society for Endocrinology