title: Late onset deficits in synaptic plasticity in the valproic acid rat model of autism.
abstract: 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.
authors.affiliation: INSERM U901 Pathophysiology of Synaptic Plasticity Group Marseille, France ; Institut de Neurobiologie de la Méditerranée (INMED) Marseille, France ; Université de Aix-Marseille Marseille, France.
authors.forename: Henry G S
authors.initials: HG
authors.lastname: Martin
authors.affiliation: INSERM U901 Pathophysiology of Synaptic Plasticity Group Marseille, France ; Institut de Neurobiologie de la Méditerranée (INMED) Marseille, France ; Université de Aix-Marseille Marseille, France.
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Manzoni
keywords: NMDA receptor; age; autism; prefrontal cortex; synaptic plasticity; valproic acid