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. 2012;7(10):e46004.
doi: 10.1371/journal.pone.0046004. Epub 2012 Oct 5.

Early life stress differentially modulates distinct forms of brain plasticity in young and adult mice

Inga Herpfer  1 , Henning Hezel, Wilfried Reichardt, Kristin Clark, Julia Geiger, Claus M Gross, Andrea Heyer, Valentin Neagu, Harsharan Bhatia, Hasan C Atas, Bernd L Fiebich, Josef Bischofberger, Carola A Haas, Klaus Lieb, Claus Normann
Affiliations

Early life stress differentially modulates distinct forms of brain plasticity in young and adult mice

Inga Herpfer et al. PLoS One. 2012.

Abstract

Background: Early life trauma is an important risk factor for many psychiatric and somatic disorders in adulthood. As a growing body of evidence suggests that brain plasticity is disturbed in affective disorders, we examined the short-term and remote effects of early life stress on different forms of brain plasticity.

Methodology/principal findings: Mice were subjected to early deprivation by individually separating pups from their dam in the first two weeks after birth. Distinct forms of brain plasticity were assessed in the hippocampus by longitudinal MR volumetry, immunohistochemistry of neurogenesis, and whole-cell patch-clamp measurements of synaptic plasticity. Depression-related behavior was assessed by the forced swimming test in adult animals. Neuropeptides and their receptors were determined by real-time PCR and immunoassay. Early maternal deprivation caused a loss of hippocampal volume, which returned to normal in adulthood. Adult neurogenesis was unaffected by early life stress. Long-term synaptic potentiation, however, was normal immediately after the end of the stress protocol but was impaired in adult animals. In the forced swimming test, adult animals that had been subjected to early life stress showed increased immobility time. Levels of substance P were increased both in young and adult animals after early deprivation.

Conclusion: Hippocampal volume was affected by early life stress but recovered in adulthood which corresponded to normal adult neurogenesis. Synaptic plasticity, however, exhibited a delayed impairment. The modulation of synaptic plasticity by early life stress might contribute to affective dysfunction in adulthood.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Reversible morphological alterations induced by early deprivation.
(A) Hippocampus (dashed line) imaged using in vivo MRI in mice. T2-weighted MRI images taken longitudinally at P15, P30, and P70 in vivo (Scale bar: 3 mm). (B) Volumetric measurements of hippocampal volumes in different experimental groups. At P15 and P30, hippocampal volumes of ED group were significantly lower than in control mice, whereas at P70, there was no significant volumetric difference (n = 12 individual animals in each group; averages ± SEM). (C) Cumulative areas of 8 consecutive whole-brain cross-sections containing the hippocampus. There was no significant difference between deprived and non-deprived animals at either time point; arguing against an unspecific brain maturation deficit in deprived mice. (D) Doublecortin immunostaining of newborn neurons in the dentate gyrus of the P70 hippocampus. Projection images are from confocal stacks with a total thickness of 30 µM from control and ED animals. (E) No significant difference in neurogenesis between control and ED mice on day P70 (control: n = 11, ED: n = 9). Error bars represent SEM.
Figure 2
Figure 2. No alteration of membrane, AP and EPSP properties by early deprivation.
Representative whole-cell measurements from single neurons in brain slices obtained from P15 (left) and P70 (right) mice after normal rearing conditions (black traces) and early deprivation (red traces). There were no significant differences in membrane, AP and EPSP properties between control animals and animals after early deprivation with the exception of a small but significant difference in the AP amplitude between the two experimental groups at P70 (A) Current response to a hyperpolarizing pulse of −5 mV from a membrane potential of −70 mV. Average of 10 consecutive traces from a single cell. (B) Train of action potentials evoked by a depolarizing current pulse. Representative single traces. (C) Representative action potentials averaged from 10 sweeps. (D) EPSPs evoked by Schaffer collateral stimulation; averaged from 10 EPSPs from one cell.
Figure 3
Figure 3. Theta-burst LTP is impaired in adult animals after early deprivation.
(A) Whole-cell patch clamp recordings were made from CA1 pyramidal neurons in hippocampal brain slices. EPSPs were induced by current stimulation of the Schaffer collateral pathway. A typical single experiment from a non-stressed mouse is shown. Dots represent maximal EPSP amplitudes (left axis). Blue squares indicate series resistance (Rs, MΩ, right axis). At the time indicated by an arrow, LTP was induced by theta-burst stimulation (TBS), with 125 EPSP-AP pairings. This resulted in stable LTP. (B) Averaged effect of TBS-LTP in different experimental groups. Effect of TBS-LTP in control animals at P15 (n = 18, C); after ED at P15 (n = 12, D); in control animals at P70 (n = 9, E); and after ED at P70 (n = 11, F). All error bars represent SEM.
Figure 4
Figure 4. Increased immobility in the forced swimming test after early deprivation.
Mice were placed in a water basin at P70 and behavior was videotaped. Immobility time represents the cumulative time spend with passive floating from minute 2 to 6 after the start of the experiment. Immobility time was significantly increased in adult mice which had been deprived after birth (n = 9 each).
Figure 5
Figure 5. Neurochemical alterations induced by early deprivation.
At P15, the content of substance P (A) and neurokinin B (B) in the frontal cortex of early deprived mice is significantly elevated compared to control animals. For substance P, this difference remains significant at P70, whereas neurokinin B levels return to normal. The differences in NK1 (C) and NK3 (D) receptor mRNA were not significant. All error bars represent SEM.
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The article processing charge was funded by the German Research Foundation (DFG) and the Albert Ludwigs University Freiburg in the funding programme Open Access Publishing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.