Gestational chronodisruption impairs hippocampal expression of NMDA receptor subunits Grin1b/Grin3a and spatial memory in the adult offspring

PLoS One. 2014 Mar 24;9(3):e91313. doi: 10.1371/journal.pone.0091313. eCollection 2014.


Epidemiological and experimental evidence correlates adverse intrauterine conditions with the onset of disease later in life. For a fetus to achieve a successful transition to extrauterine life, a myriad of temporally integrated humoral/biophysical signals must be accurately provided by the mother. We and others have shown the existence of daily rhythms in the fetus, with peripheral clocks being entrained by maternal cues, such as transplacental melatonin signaling. Among developing tissues, the fetal hippocampus is a key structure for learning and memory processing that may be anticipated as a sensitive target of gestational chronodisruption. Here, we used pregnant rats exposed to constant light treated with or without melatonin as a model of gestational chronodisruption, to investigate effects on the putative fetal hippocampus clock, as well as on adult offspring's rhythms, endocrine and spatial memory outcomes. The hippocampus of fetuses gestated under light:dark photoperiod (12:12 LD) displayed daily oscillatory expression of the clock genes Bmal1 and Per2, clock-controlled genes Mtnr1b, Slc2a4, Nr3c1 and NMDA receptor subunits 1B-3A-3B. In contrast, in the hippocampus of fetuses gestated under constant light (LL), these oscillations were suppressed. In the adult LL offspring (reared in LD during postpartum), we observed complete lack of day/night differences in plasma melatonin and decreased day/night differences in plasma corticosterone. In the adult LL offspring, overall hippocampal day/night difference of gene expression was decreased, which was accompanied by a significant deficit of spatial memory. Notably, maternal melatonin replacement to dams subjected to gestational chronodisruption prevented the effects observed in both, LL fetuses and adult LL offspring. Collectively, the present data point to adverse effects of gestational chronodisruption on long-term cognitive function; raising challenging questions about the consequences of shift work during pregnancy. The present study also supports that developmental plasticity in response to photoperiodic cues may be modulated by maternal melatonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circadian Clocks / drug effects
  • Circadian Clocks / genetics
  • Circadian Clocks / radiation effects
  • Female
  • Gene Expression Regulation* / drug effects
  • Gene Expression Regulation* / radiation effects
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Hippocampus / physiopathology
  • Hippocampus / radiation effects
  • Light
  • Maternal Exposure / adverse effects
  • Melatonin / pharmacology
  • Membrane Glycoproteins / genetics*
  • Photoperiod
  • Pregnancy
  • Prenatal Exposure Delayed Effects / genetics*
  • Prenatal Exposure Delayed Effects / physiopathology*
  • Prenatal Exposure Delayed Effects / prevention & control
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / genetics*
  • Spatial Memory* / drug effects
  • Spatial Memory* / radiation effects


  • Grin3a protein, rat
  • Membrane Glycoproteins
  • NMDA receptor A1
  • Receptors, N-Methyl-D-Aspartate
  • Melatonin

Grant support

This work was supported by Grants 1120938 (CTF) from Fondo Nacional de Desarrollo Científico y Tecnológico, Chile (FONDECYT) and ANILLO ACT-1116. LAC was supported by a Ph.D. fellowship from Comisión Nacional de Ciencia y Tecnología (CONICYT), Chile. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.