256 Fig. 3 Effects of MD on water maze acquisition. Travel distance to the hidden platform was similar in both CON and MD animals (both groups n=10; p=0.16) MD 42.5 ± 12.8 s, p = 0.70), frequency (CON 6.7 ± 1.4 times; MD 6.6 ± 1.2 times, p = 0.70) and/or percentage of time spent in the open arms of the maze (CON 38.4 ± 6.0%; MD 48.7 ± 7.0%; p = 0.37). Fear conditioning did not reveal any effects of MD on baseline freezing behaviour nor on freezing behaviour during training (data not shown), supporting the notion that MD does not affect overall anxiety in female rats later in life. Twenty-four hours later—during the contextual test —both groups showed comparable freezing behaviour (F1,35 = 0.92, p = 0.35; Fig. 4a). While contextual fear conditioning was not affected by MD, exposure to a novel environment 24 h after the cue-shock training did result in elevated levels of freezing in MD compared to CON animals (p = 0.002; Fig. 4b). Subsequent exposure to the earlier cue in this novel environment caused extensive Fig. 4 Effects of MD on fear conditioning. a MD does not affect the amount of freezing behaviour in response to the context (p=0.35). b During cued fear conditioning, MD animals (n=10) show increased freezing in response to the novel environment (p=0.002) and an increased freezing behaviour in response to the tone when compared to controls (both groups, n=10, p<0.05) Psychopharmacology (2011) 214:249–260 freezing behaviour, which also differed significantly between MD and CON animals (p < 0.05; Fig. 4b). Discussion In the present study, we show that a history of early maternal deprivation exerts irreversible effects on hippocampal struc- ture and function in adult female offspring. Adult female rats exposed to MD early in life showed a lower cell number and cell density in the GCL and significant dendritic re-arrangement of DG neurons. No effects of MD at PND 3 were found on hippocampal neurogenesis in adult female rats, indicating that the decreased neurogenesis after MD reported earlier at PND 21 (Oomen et al. 2009) does not last into adulthood. We also observed surprisingly little effect of MD on synaptic plasticity in the DG and on hippocampal- dependent learning tasks. While we have no indication that MD alters general anxiety in adult female rats, amygdala- dependent fear memory after MD was improved. Effects of maternal deprivation on structural parameters of the dentate gyrus In our current MD model of early life stress, rat pups experienced elevated levels of corticosterone (Oomen et al. 2009) during a period that is normally characterised by low corticosterone levels (Levine 2001). This coincides with a crucial period in DG development (Altman and Bayer 1990a, b) as around this time, extensive migration of the secondary matrix takes place that gives rise to the inner two thirds of the GCL. Previously, we have shown that 24 h of MD on PND 3 decreases the number of doublecortin- positive cells, i.e. immature neurons, in 3-week-old females (Oomen et al. 2009). Others have shown that MD increases cell death in the infant rat hippocampus, independent of sex (Llorente et al. 2009; Zhang et al. 2002). In addition, on PND 12, a modest increase in DG glia cell number was found after MD on PND 9 (Llorente et al. 2009). Interestingly, neuroprotective effects of calcium-binding proteins in infant rats subjected to MD were only found in male but not female offspring (Lephart and Watson 1999). These cellular effects of MD on the infant female hippocampus during a crucial phase in DG development, in combination with the apparent lack of protective mecha- nisms in females, may explain the irreversible decrease in GCL number after MD in this study. Another prominent finding, in addition to the reduction in GCL number and density, is the altered dendritic morphology of the individual DG neuron after early life stress. Females subjected to MD in infancy showed an increased number of primary dendrites extending from the soma, without effects on the total dendritic length. Other