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Late onset deficits in synaptic plasticity in the valproic acid rat model of autism

Valproic acid (VPA) is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes ne...

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Autores principales: Martin, Henry G. S., Manzoni, Olivier J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907704/
https://www.ncbi.nlm.nih.gov/pubmed/24550781
http://dx.doi.org/10.3389/fncel.2014.00023
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author Martin, Henry G. S.
Manzoni, Olivier J.
author_facet Martin, Henry G. S.
Manzoni, Olivier J.
author_sort Martin, Henry G. S.
collection PubMed
description Valproic acid (VPA) is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC) physiology and synaptic connectivity. Specifically, principal neurons show decreased excitability but increased local connectivity, coupled with an increase in long-term potentiation (LTP) due to an up-regulation of NMDA receptor (NMDAR) expression. However recent evidence suggests compensatory homeostatic mechanisms lead to normalization of synaptic NMDARs during later postnatal development. Here we have extended study of mPFC synaptic physiology into adulthood to better understand the longitudinal consequences of early developmental abnormalities in VPA exposed rats. Surprisingly in contrast to early postnatal life and adolescence, we find that adult VPA exposed rats show reduced synaptic function. Both NMDAR mediated currents and LTP are lower in adult VPA rats, although spontaneous activity and endocannabinoid dependent long-term depression are normal. We conclude that rather than correcting, synaptic abnormalities persist into adulthood in VPA exposed rats, although a quite different synaptic phenotype is present. This switch from hyper to hypo function in mPFC may be linked to some of the neurodevelopmental defects found in prenatal VPA exposure and autism spectrum disorders in general.
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spelling pubmed-39077042014-02-18 Late onset deficits in synaptic plasticity in the valproic acid rat model of autism Martin, Henry G. S. Manzoni, Olivier J. Front Cell Neurosci Neuroscience Valproic acid (VPA) is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC) physiology and synaptic connectivity. Specifically, principal neurons show decreased excitability but increased local connectivity, coupled with an increase in long-term potentiation (LTP) due to an up-regulation of NMDA receptor (NMDAR) expression. However recent evidence suggests compensatory homeostatic mechanisms lead to normalization of synaptic NMDARs during later postnatal development. Here we have extended study of mPFC synaptic physiology into adulthood to better understand the longitudinal consequences of early developmental abnormalities in VPA exposed rats. Surprisingly in contrast to early postnatal life and adolescence, we find that adult VPA exposed rats show reduced synaptic function. Both NMDAR mediated currents and LTP are lower in adult VPA rats, although spontaneous activity and endocannabinoid dependent long-term depression are normal. We conclude that rather than correcting, synaptic abnormalities persist into adulthood in VPA exposed rats, although a quite different synaptic phenotype is present. This switch from hyper to hypo function in mPFC may be linked to some of the neurodevelopmental defects found in prenatal VPA exposure and autism spectrum disorders in general. Frontiers Media S.A. 2014-01-31 /pmc/articles/PMC3907704/ /pubmed/24550781 http://dx.doi.org/10.3389/fncel.2014.00023 Text en Copyright © 2014 Martin and Manzoni. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Martin, Henry G. S.
Manzoni, Olivier J.
Late onset deficits in synaptic plasticity in the valproic acid rat model of autism
title Late onset deficits in synaptic plasticity in the valproic acid rat model of autism
title_full Late onset deficits in synaptic plasticity in the valproic acid rat model of autism
title_fullStr Late onset deficits in synaptic plasticity in the valproic acid rat model of autism
title_full_unstemmed Late onset deficits in synaptic plasticity in the valproic acid rat model of autism
title_short Late onset deficits in synaptic plasticity in the valproic acid rat model of autism
title_sort late onset deficits in synaptic plasticity in the valproic acid rat model of autism
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907704/
https://www.ncbi.nlm.nih.gov/pubmed/24550781
http://dx.doi.org/10.3389/fncel.2014.00023
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