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 utero exposure 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 in in utero VPA-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 for Pvalb, Gad67, Kcnc1, Kcnc2, Kcns3, Hcn1, Hcn2, and Hcn4 were performed. We found a ∼15% reduction in the number of PV+ cells and decreased Pvalb mRNA 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 of Kcnc1, 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 including Pvalb, Kcnc1, and Hcn1 possibly linked to homeostatic mechanisms. Striatal PV down-regulation appears as a common feature in a subset of genetic (Shank3B-/-) and environmental ASD models.
Highlights
Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders that share core behavioral symptoms in the domains of social interaction, language/communication and repetitive, or stereotyped patterns of behavior (American Psychiatric Association, 2013)
Since results with respect to Pvalb neurons in Valproic acid (VPA) mice showed a high similarity with what we had observed before in Shank3B−/− mice, i.e., a significant decrease in striatal PV levels (Filice et al, 2016) and the recent findings that Shank3 mutations resulted in a decrease in hyperpolarization-activated cation (Ih) currents likely being the result of decreased HCN3 and HCN4 levels (Yi et al, 2016), we investigated transcript levels of the various hyperpolarization-activated cyclic nucleotidegated (HCN) channels in VPA mice including transcript levels of Hcn1, Hcn2, and Hcn4, the predominant forms expressed in the brain
Altered synaptic transmission in VPA mice or rats is of particular interest, since ASD are broadly characterized by synaptic deficits leading to an E/I imbalance in the brain (Rubenstein and Merzenich, 2003)
Summary
Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders that share core behavioral symptoms in the domains of social interaction, language/communication and repetitive, or stereotyped patterns of behavior (American Psychiatric Association, 2013). VPA monotherapy during pregnancy results in about seven-fold greater incidence of ASD or ASD key symptoms including language impairment, reduced attention, social deficits and restricted interests (Vinten et al, 2009). VPA exposure during pregnancy has been extensively studied in rodents and has evolved as the well-established “VPA mouse or rat model” for the study of ASD. Behavioral phenotypes related to all human core symptoms of ASD including impaired social behavior, repetitive or stereotyped patterns of behavior and impaired communication exist in juvenile VPA rats and mice and persist into adulthood (reviewed in Roullet et al, 2013; Ergaz et al, 2016). The striking and robust ASD phenotype, together with the given construct validity, has made it attractive for further studying the pathophysiology of ASD
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