Effects of Early Life Stress on Synaptic Plasticity in the Developing Hippocampus of Male and Female Rats

Abstract

Introduction: Early life stress (ELS) increases the risk for developing psychopathology in adulthood. When these effects occur is largely unknown. We here studied at which time during development ELS affects hippocampal synaptic plasticity, from early life to adulthood, in a rodent ELS model. Moreover, we investigated whether the sensitivity of synaptic plasticity to the stress-hormone corticosterone is altered by exposure to ELS.

Materials & methods: Male and female Wistar rats were exposed to maternal deprivation (MD) for 24h on postnatal day (P)3 or left undisturbed with their mother (control). On P8-9, 22-24 and P85-95, plasma corticosterone (CORT) levels, body weight, and thymus and adrenal weights were determined to validate the neuroendocrine effects of MD. Field potentials in the CA1 hippocampus were recorded in vitro before and after high frequency stimulation. Brain slices were incubated for 20 min with 100nM CORT or vehicle 1-4h prior to high frequency stimulation, to mimic high-stress conditions in vitro.

Results & discussion: Body weight was decreased by MD only at P4 (p = 0.02). There were minimal effects on P8-9, 22-24 or 85-95 thymus and adrenal weight and basal CORT levels. Glutamate transmission underwent strong developmental changes: half-maximal signal size strongly increased (p<0.0001) while the required half-maximal stimulation intensity concomitantly decreased with age (p = 0.04). Synaptic plasticity developed from long-term depression at P8-9 to increasing levels of long-term potentiation at later ages (p = 0.0001). MD caused a significant increase in long-term potentiation of P22-24 males (p = 0.03) and P85-95 females (p = 0.04). Bayesian modeling strongly supported the age-dependent development, with some evidence for accelerated maturation after MD in males (Bayes factor 1.23). CORT suppressed LTP in adult males; synaptic plasticity at other ages and in females remained unaffected. Thus, MD affects the development of synaptic plasticity in the CA1 hippocampus in a sex-dependent manner, with some support for the notion that maturation is accelerated in MD males.

Fig 1. Experimental design.

Half of the litters were maternally deprived for 24h at postnatal day (P)3. At P8-9, 22–24 and 85–95, animals were used for field potential recordings in the CA1 hippocampus.

Fig 2. Basal field potential properties and LTP strongly increase during development.

With age, the baseline halfmaximum signal amplitude strongly increased (A, p<0.0001), the required stimulation intensity decreased (B, p = 0.04) and the response to high-frequency stimulation developed from long-term depression at P8-9 to increasing levels of long-term potentiation with age (C, mean 60 min post-HFS, p = 0.0001). Data are on based on data obtained in the control male group, except for P8-9 where data from males and females were pooled.

Fig 3. Influences of MD and CORT on the development of synaptic plasticity in the CA1 hippocampus in males and females.

The response to high-frequency stimulation (HFS) is shown as the mean signal amplitude (P8-9) or slope (other ages) during the last 10 minutes of the 60 min post-HFS recording (± SEM). Male and female data on P8-9 was pooled after being tested for sex effects on fEPSP baseline characteristics and synaptic plasticity. (A) In males, control animals showed an increase in response to HFS which continued up into adulthood, while MD animals reached adult levels of long-term potentiation already at P22-24. (B) In females, controls showed a plateau effect in the development of synaptic strength. MD did not accelerate maturation in this case, but instead showed an even further increased magnitude of LTP induction.