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Our previous studies have shown that prenatal caffeine exposure (PCE) can induce programmed hypersensitivity of the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis in offspring rats, which is involved in developing many chronic adult diseases. The present study further examined the potential molecular mechanism and toxicity targets of hippocampal dysfunction, which might mediate the programmed hypersensitivity of the HPA axis in offspring. Pregnant rats were intragastrically administered with 0, 30, and 120\u2009mg\/kg\/day caffeine from gestational days (GD) 9\u201320, and the fetal rats were extracted at GD20. Rat fetal hippocampal H19\u20107\/IGF1R cell line was treated with caffeine, adenosine A2A receptor (A2AR) agonist (CGS\u201021680) or adenylate cyclase agonist (forskolin) plus caffeine. Compared with the control group, hippocampal neurons of male fetal rats by PCE displayed increased apoptosis and reduced synaptic plasticity, whereas glutamate decarboxylase 67 (GAD67) expression was increased. Moreover, the expression of A2AR was down\u2010regulated, PCE inhibited the cAMP\/PKA\/CREB\/BDNF\/TrkB pathway. Furthermore, the results in vitro were consistent with the in vivo study. Both CGS21680 and forskolin could reverse the above alteration caused by caffeine. These results indicated that PCE inhibits the BDNF pathway and mediates the hippocampus's glutamate (Glu) excitotoxicity. The compensatory up\u2010regulation of GAD67 unbalanced the Glu\/gamma\u2010aminobutyric acid (GABA)ergic output, leading to the impaired negative feedback to the hypothalamus and hypersensitivity of the HPA axis.<\/jats:p>","DOI":"10.1002\/tox.23630","type":"journal-article","created":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T19:57:03Z","timestamp":1659470223000},"page":"2703-2717","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The upregulation of glutamate decarboxylase 67 against hippocampal excitability damage in male fetal rats by prenatal caffeine exposure"],"prefix":"10.1002","volume":"37","author":[{"given":"Mengxi","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Pharmaceutical Sciences, Wuhan University  Wuhan 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