title: Prenatal Valproate Exposure Differentially Affects Parvalbumin-Expressing Neurons and Related Circuits in the Cortex and Striatum of Mice.
abstract: Autism spectrum disorders (ASD) comprise a number of heterogeneous neurodevelopmental diseases characterized by core behavioral symptoms in the domains of social interaction, language/communication and repetitive or stereotyped patterns of behavior.In uteroexposure to valproic acid (VPA) has evolved as a highly recognized rodent ASD model due to the robust behavioral phenotype observed in the offspring and the proven construct-, face- and predictive validity of the model. The number of parvalbumin-immunoreactive (PV+) GABAergic interneurons has been consistently reported to be decreased in human ASD subjects and in ASD animal models. The presumed loss of this neuron subpopulation hereafter termed Pvalb neurons and/or PV deficits were proposed to result in an excitation/inhibition imbalance often observed in ASD. Importantly, loss of Pvalb neurons and decreased/absent PV protein levels have two fundamentally different consequences. Thus, Pvalb neurons were investigated inin uteroVPA-exposed male ("VPA") mice in the striatum, medial prefrontal cortex (mPFC) and somatosensory cortex (SSC), three ASD-associated brain regions. Unbiased stereology of PV+neurons and Vicia Villosa Agglutinin-positive (VVA+) perineuronal nets, which specifically enwrap Pvalb neurons, was carried out. Analyses of PV protein expression and mRNA levels forPvalb, Gad67, Kcnc1, Kcnc2, Kcns3, Hcn1, Hcn2, and Hcn4were performed. We found a ∼15% reduction in the number of PV+cells and decreasedPvalbmRNA and PV protein levels in the striatum of VPA mice compared to controls, while the number of VVA+cells was unchanged, indicating that Pvalb neurons were affected at the level of the transcriptome. In selected cortical regions (mPFC, SSC) of VPA mice, no quantitative loss/decrease of PV+cells was observed. However, expression ofKcnc1, coding for the voltage-gated potassium channel Kv3.1 specifically expressed in Pvalb neurons, was decreased by ∼40% in forebrain lysates of VPA mice. Moreover, hyperpolarization-activated cyclic nucleotide-gated channel (HCN) 1 expression was increased by ∼40% in the same samples from VPA mice. We conclude that VPA leads to alterations that are brain region- and gene-specific includingPvalb, Kcnc1, andHcn1possibly linked to homeostatic mechanisms. Striatal PV down-regulation appears as a common feature in a subset of genetic (Shank3B-/-) and environmental ASD models.
authors.affiliation: Anatomy, Department of Medicine, University of Fribourg Fribourg, Switzerland.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Lauber
authors.affiliation: Anatomy, Department of Medicine, University of Fribourg Fribourg, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Filice
authors.affiliation: Anatomy, Department of Medicine, University of Fribourg Fribourg, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Schwaller
keywords: ASD; HCN; Kv3; VPA; excitation/inhibition balance; parvalbumin