Transient Prepubertal Mifepristone Treatment Normalizes Deficits in Contextual Memory and Neuronal Activity of Adult Male Rats Exposed to Maternal Deprivation

eNeuro. 2017 Nov 2;4(5):ENEURO.0253-17.2017. doi: 10.1523/ENEURO.0253-17.2017. eCollection 2017 Sep-Oct.


Early life adversity is a well-known risk factor for behavioral dysfunction later in life, including the formation of contextual memory; it is also (transiently) accompanied by hyperactivity of the stress system. We tested whether mifepristone (MIF) treatment, which among other things blocks glucocorticoid receptors (GRs), during the prepubertal period [postnatal days (PND)26-PND28] normalizes memory deficits in adult male rats exposed to 24-h maternal deprivation (MD) at PND3. MD reduced body weight gain and increased basal corticosterone (CORT) levels during the PND26, but not in adulthood. In adulthood, contextual memory formation of MD compared to noMD (i.e., control) male rats was significantly impaired. This impairment was fully prevented by MIF treatment at PND26-PND28, whereas MIF by itself did not affect behavior. A second behavioral test, a rodent version of the Iowa Gambling Task (rIGT), revealed that flexible spatial learning rather than reward-based aspects of performance was impaired by MD; the deficit was prevented by MIF. Neuronal activity as tested by c-Fos staining in the latter task revealed changes in the right hippocampal-dorsomedial striatal pathway, but not in prefrontal areas involved in reward learning. Follow-up electrophysiological recordings measuring spontaneous glutamate transmission showed reduced frequency of miniature postsynaptic excitatory currents in adult CA1 dorsal hippocampal and enhanced frequency in dorsomedial striatal neurons from MD versus noMD rats, which was not seen in MIF-treated rats. We conclude that transient prepubertal MIF treatment normalizes hippocampus-striatal-dependent contextual memory/spatial learning deficits in male rats exposed to early life adversity, possibly by normalizing glutamatergic transmission.

Keywords: Rodent Iowa Gambling Task; early life stress; glutamate transmission; mifepristone; reward-based decision making; spatial memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / growth & development
  • Brain / physiopathology
  • Corticosterone / metabolism
  • Excitatory Postsynaptic Potentials / drug effects
  • Glutamic Acid / metabolism
  • Male
  • Maternal Deprivation*
  • Memory / drug effects
  • Memory / physiology
  • Memory Disorders / drug therapy*
  • Memory Disorders / etiology
  • Memory Disorders / physiopathology
  • Mifepristone / administration & dosage*
  • Miniature Postsynaptic Potentials / drug effects
  • Neurons / drug effects*
  • Neurons / physiology
  • Nootropic Agents / administration & dosage*
  • Random Allocation
  • Rats, Wistar
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Receptors, Glucocorticoid / metabolism
  • Spatial Learning / drug effects
  • Spatial Learning / physiology
  • Stress, Psychological / complications
  • Stress, Psychological / drug therapy
  • Stress, Psychological / physiopathology
  • Tissue Culture Techniques
  • Weight Gain / drug effects


  • Nootropic Agents
  • Receptors, Glucocorticoid
  • Mifepristone
  • Glutamic Acid
  • Corticosterone