Estradiol and luteinizing hormone reverse memory loss in phencyclidine model of schizophrenia: Evidence for hippocampal GABA action
Alexander J. Riordan, Ari W. Schaler, Jackson B. Fried, Tracie A. Paine, Janice E. Thornton
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study |
|---|---|
| Population | Ovariectomized female rats treated with phencyclidine |
| Interventions | Phencyclidine Antide Estradiol GABA-A agonist GABA-A antagonist GAD inhibitor |
| Measures | Novel object recognition task, GAD67 western blot, parvalbumin immunohistochemistry |
| Key findings | Reducing LH with Antide or increasing estradiol reversed PCP-induced memory deficits in ovariectomized rats. Antide restored hippocampal GAD67, while estradiol did not. Hippocampal GABA-A agonism rescued memory in PCP-treated rats, and blocking GABA or GABA-A receptors mimicked PCP's amnesic effect and blocked estradiol's rescue. |
Abstract
ABSTRACT The cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could rescue declarative memory in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP. To modulate E and LH, animals received hormone capsules or Antide injections. Short-term episodic memory was assessed using the novel object recognition task. Brain expression of GAD67 was analyzed via western blot, and parvalbumin-containing cells were counted using immunohistochemistry. Some rats received hippocampal infusions of a GABA A agonist, GABA A antagonist, or GAD inhibitor before behavioral testing. We found that PCP reduced hippocampal GAD67 and abolished object recognition. Antide restored hippocampal GAD67 and rescued recognition memory in PCP-treated animals. Estradiol reversed PCP’s amnesic effect but failed to restore hippocampal GAD67. PCP did not cause significant differences in number of parvalbumin-expressing cells or cortical expression of GAD67. Hippocampal infusions of a GABA A agonist restored memory in PCP-treated rats. Blocking hippocampal GAD or GABA A receptors in ovx animals reproduced memory loss similar to PCP and inhibited estradiol’s memory rescue in PCP-treated animals. In summary, decreasing LH or increasing E can reverse memory loss in a PCP model of schizophrenia. Alterations in hippocampal GABA may contribute to both PCP’s effects on declarative memory and the hormones’ ability to reverse them.