Early life stress facilitates synapse premature unsilencing to enhance AMPA receptor function in the developing hippocampus

Abstract

Chronic early life stress (ELS) increases vulnerability to psychopathologies and cognitive deficits in adulthood by disrupting the function of related neural circuits. However, whether this disruption emerges early in the developing brain remains largely unexplored. In the current study, using an established limited-bedding and nesting model of ELS in P2-10 mice, we provide direct evidence that ELS caused early modification of hippocampal glutamatergic synapses in the developing brain. We demonstrated that ELS induced rapid enhancement of AMPA receptor function in hippocampal CA1 pyramidal neurons through a postsynaptic mechanism, and importantly, this was associated with premature unsilencing of NMDA receptor-only silent hippocampal synapses. These results suggest that potentiation of AMPAR function may represent an early mediator of ELS-induced alterations of neural networks in the developing brain and may potentially contribute to subsequent cognitive impairments later in life.

Early life stress lastingly alters the function and AMPA‐receptor composition of glutamatergic synapses in the hippocampus of male mice

“…19 Although the experiments in this study are performed in male mice only, accelerated synaptic maturation following ELS exposure is suggested to be independent of sex. 31 Together with our current findings, dynamic and enduring developmental effects of ELS on hippocampal synapses emerge, which are initially characterized by accelerated synaptic maturation of DG granular cells, observed as an increase in mEPSC frequency and amplitude, and altered synaptosomal AMPAR and NMDAR content. With age, enhanced synaptic activity sustains and synaptic GluA3 content increases.…”

“…A previous study reported similar effects of ELS on synapses in the hippocampal CA1 area at P11 following the LBN paradigm, demonstrating that ELS prematurely "unsilences" CA1 synapses by enhancing the recruitment of AMPARs at silent synapses. 31 ELS may similarly induce premature synapse unsilencing at DG synapses. Interestingly, we found an overall decrease in synaptic protein levels in synaptosomal fractions of P9 pups that were exposed to ELS with a significant decrease for PSD-95, GluA3 and GluN2B.…”

“…45 In line with other studies, this suggests that the hippocampus is particularly sensitive to enduring effects of ELS. 13,30,31,66 In fact, previous studies have shown even longer-lasting effects of ELS on CA1 synaptic plasticity at 6 months of age. 19 Although the experiments in this study are performed in male mice only, accelerated synaptic maturation following ELS exposure is suggested to be independent of sex.…”

“…So far, the DG has been reported to be lastingly affected by a variety of models for ELS, 6,17,24–29 but the effects of LBN on synaptic function in early development and adulthood are not fully understood. ELS is suggested to accelerate synaptic development by altering NMDA receptor (NMDAR) composition 26,30 and enhancing α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor (AMPAR) function early in life, 31 thereby prematurely “unsilencing” otherwise silent synapses. While this is well‐characterized in the CA1 area of the hippocampus using the LBN model, 31 the developmental effects of LBN on synaptic function in the DG remain to be investigated.…”

“…So far, the DG has been reported to be lastingly affected by a variety of models for ELS, 6,17,[24][25][26][27][28][29] but the effects of LBN on synaptic function in early development and adulthood are not fully understood. ELS is suggested to accelerate synaptic development by altering NMDA receptor (NMDAR) composition 26,30 and enhancing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) function early in life, 31 thereby prematurely "unsilencing" otherwise silent synapses. While this is well-characterized in the CA1 area of the hippocampus using the LBN model, 31 the developmental effects of LBN on synaptic function in the DG remain to be investigated.…”