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Impaired Bidirectional Synaptic Plasticity in Juvenile Offspring Following Prenatal Ethanol Exposure.

ABSTRACT: BACKGROUND:The hippocampus is particularly vulnerable to the teratogenic effects of prenatal ethanol exposure (PNEE), and hippocampal structural and functional deficits are thought to contribute to the learning and memory deficits that are a hallmark feature of fetal alcohol spectrum disorders. METHODS:Sprague Dawley dams were exposed to a liquid diet that contained EtOH (35.5% EtOH-derived calories) throughout gestation, and then, PNEE juvenile (P21-28) male and female offspring were used for in vitro electrophysiological recordings. We examined long-term potentiation (LTP), long-term depression (LTD), and depotentiation in the medial perforant path input to the dentate gyrus (DG) to determine the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in both sexes. RESULTS:PNEE reduced the responsiveness of the DGs of male but not in female offspring, and this effect was no longer apparent when GABAergic signaling was inhibited. There was also a sex-specific LTD impairment in males, but increasing the duration of the conditioning stimulus could overcome this deficit. The magnitude of LTP was also reduced, but in both sexes following PNEE. This appears to be an increase in the threshold for induction, not in capacity, as the level of LTP induced in PNEE animals was increased to control levels when additional conditioning stimuli were administered. CONCLUSIONS:These data are the first to describe, in a single study, the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in the juvenile DG in both males and in females. The data suggest that PNEE increases the threshold for LTP in the DG in both sexes, but produces a sex-specific increase in the threshold for LTD in males These alterations reduce the dynamic range for synaptic plasticity in both sexes.

SUBMITTER: Fontaine CJ

PROVIDER: S-EPMC6779507 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Impaired Bidirectional Synaptic Plasticity in Juvenile Offspring Following Prenatal Ethanol Exposure.

Fontaine Christine J CJ Pinar Cristina C Yang Waisley W Pang Angela F AF Suesser Konrad E KE Choi James S J JSJ Christie Brian R BR

Alcoholism, clinical and experimental research 20190826 10

<h4>Background</h4>The hippocampus is particularly vulnerable to the teratogenic effects of prenatal ethanol exposure (PNEE), and hippocampal structural and functional deficits are thought to contribute to the learning and memory deficits that are a hallmark feature of fetal alcohol spectrum disorders.<h4>Methods</h4>Sprague Dawley dams were exposed to a liquid diet that contained EtOH (35.5% EtOH-derived calories) throughout gestation, and then, PNEE juvenile (P21-28) male and female offspring ...[more]

PMID: 31386206

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Project description:Prenatal exposure to anesthetics has raised increasing attention about the neuronal development in offspring. Animal models are usually used for investigation. As a new drug, esketamine is the s-isoform of ketamine and is twice as potent as the racemic ketamine with less reported adverse effects. Esketamine is currently being used and become more favorable in clinical anesthesia work, including surgeries during pregnancy, yet the effect on the offspring is unknown. The present study aimed to elucidate the effects of gestational administration of esketamine on neuronal development in offspring, using a rat model. Gestational day 14.5 pregnant rats received intravenous injections of esketamine. The postnatal day 0 (P0) hippocampus was digested and cultured in vitro to display the neuronal growth morphology. On Day 4 the in vitro experiments revealed a shorter axon length and fewer dendrite branches in the esketamine group. The results from the EdU- imaging kit showed decreased proliferative capacity in the subventricular zone (SVZ) and dentate gyrus (DG) in both P0 and P30 offspring brains in the esketamine group. Moreover, neurogenesis, neuron maturity and spine density were impaired, resulting in attenuated long-term potentiation (LTP). Compromised hippocampal function accounted for the deficits in neuronal cognition, memory and emotion. The evidence obtained suggests that the neurobehavioral deficit due to prenatal exposure to esketamine may be related to the decrease phosphorylation of CREB and abnormalities in N-methyl-D-aspartic acid receptor subunits. Taken together, these results demonstrate the negative effect of prenatal esketamine exposure on neuronal development in offspring rats. G14.5 esketamine administration influenced the neurobehavior of the offspring in adolescence. Poorer neuronal growth and reduced brain proliferative capacity in late gestation and juvenile pups resulted in impaired P30 neuronal plasticity and synaptic spines as well as abnormalities in NMDAR subunits. Attenuated LTP reflected compromised hippocampal function, as confirmed by behavioral tests of cognition, memory and emotions. This figure was completed on the website of Figdraw.

Project description:We show that a 2-step phospho/dephosphorylation cycle for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor (AMPAR), as used in in vivo learning experiments to assess long-term potentiation (LTP) induction and establishment, exhibits bistability for a wide range of parameters, consistent with values derived from biological literature. The AMPAR model we propose, hence, is a candidate for memory storage and switching behavior at a molecular-microscopic level. Furthermore, the stochastic formulation of the deterministic model leads to a mesoscopic interpretation by considering the effect of enzymatic fluctuations on the Michelis-Menten average dynamics. Under suitable hypotheses, this leads to a stochastic dynamical system with multiplicative noise whose probability density evolves according to a Fokker-Planck equation in the Stratonovich sense. In this approach, the probability density associated with each AMPAR phosphorylation state allows one to compute the probability of any concentration value, whereas the Michaelis-Menten equations consider the average concentration dynamics. We show that bistable dynamics are robust for multiplicative stochastic perturbations and that the presence of both noise and bistability simulates LTP and long-term depression (LTD) behavior. Interestingly, the LTP part of this model has been experimentally verified as a result of in vivo, one-trial inhibitory avoidance learning protocol in rats, that produced the same changes in hippocampal AMPARs phosphorylation state as observed with in vitro induction of LTP with high-frequency stimulation (HFS). A consequence of this model is the possibility of characterizing a molecular switch with a defined biochemical set of reactions showing bistability and bidirectionality. Thus, this 3-enzymes-based biophysical model can predict LTP as well as LTD and their transition rates. The theoretical results can be, in principle, validated by in vitro and in vivo experiments, such as fluorescence measurements and electrophysiological recordings at multiple scales, from molecules to neurons. A further consequence is that the bistable regime occurs only within certain parametric windows, which may simulate a "history-dependent threshold". This effect might be related to the Bienenstock-Cooper-Munro theory of synaptic plasticity.

Dataset Information

Impaired Bidirectional Synaptic Plasticity in Juvenile Offspring Following Prenatal Ethanol Exposure.

Publications

Impaired Bidirectional Synaptic Plasticity in Juvenile Offspring Following Prenatal Ethanol Exposure.

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