Postnatal handling increases the expression of cAMP-inducible transcription factors in the rat hippocampus: The effects of thyroid hormones and serotonin

Postnatal handling increases glucocorticoid receptor expression in the rat hippocampus, thus altering the regulation of hypothalamic synthesis of cort icotropin-releasing hormone and the hypothalamic-pituitary-adrenal response to stress. The effect on glucocorticoid receptor gene expression represent s one mechanism by which the early environment can exert a long-term effect on neural development. The handling effect on hippocampal glucocorticoid r eceptor expression is dependent on peripheral thyroid hormone release and t he activation of ascending serotonergic pathways. In primary hippocampal ce ll cultures, serotonin (5-HT) increases glucocorticoid receptor expression, and this effect appears to be mediated by increased cAMP levels. In the cu rrent studies we examined the in vivo effects of handling on hippocampal cA MP-protein kinase A (PKA) activity. In 7-d-old rat pups, we found that (1) postnatal handling increased adenylyl cyclase activity and hippocampal cAMP levels, (2) the effect of handling on cAMP levels was completely blocked b y treatment with either propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, or the 5-HT receptor antagonist, ketanserin, and (3) handling a lso increased hippocampal PKA activity. We then examined the effects of han dling on cAMP-inducible transcription factors. Handling rapidly increased l evels of the mRNAs for nerve growth factor-inducible factor A (NGFI-A) (zif 268, krox24) and activator protein-2 (AP-2) as well as for NGFI-A and AP-2 immunoreactivity throughout the hippocampus. Finally, we found that the eff ects of handling on NGFI-A and AP-2 expression were significantly reduced b y concurrent treatment with either PTU or ketanserin, effects that parallel ed those on cAMP formation. NGFI-A and AP-2 have been implicated in the reg ulation of glucocorticoid receptor expression during development. Thus, the se findings suggest that postnatal handling might alter glucocorticoid rece ptor gene expression via cAMP-PKA pathways involving the activation of NGFI -A and AP-2.