Abstract
The prevalence of autism spectrum disorder (ASD)—a type of neurodevelopmental disorder—is increasing and is around 2% in North America, Asia, and Europe. Besides the known genetic link, environmental, epigenetic, and metabolic factors have been implicated in ASD etiology. Although highly heterogeneous at the behavioral level, ASD comprises a set of core symptoms including impaired communication and social interaction skills as well as stereotyped and repetitive behaviors. This has led to the suggestion that a large part of the ASD phenotype is caused by changes in a few and common set of signaling pathways, the identification of which is a fundamental aim of autism research. Using advanced bioinformatics tools and the abundantly available genetic data, it is possible to classify the large number of ASD-associated genes according to cellular function and pathways. Cellular processes known to be impaired in ASD include gene regulation, synaptic transmission affecting the excitation/inhibition balance, neuronal Ca2+ signaling, development of short-/long-range connectivity (circuits and networks), and mitochondrial function. Such alterations often occur during early postnatal neurodevelopment. Among the neurons most affected in ASD as well as in schizophrenia are those expressing the Ca2+-binding protein parvalbumin (PV). These mainly inhibitory interneurons present in many different brain regions in humans and rodents are characterized by rapid, non-adaptive firing and have a high energy requirement. PV expression is often reduced at both messenger RNA (mRNA) and protein levels in human ASD brain samples and mouse ASD (and schizophrenia) models. Although the human PVALB gene is not a high-ranking susceptibility/risk gene for either disorder and is currently only listed in the SFARI Gene Archive, we propose and present supporting evidence for the Parvalbumin Hypothesis, which posits that decreased PV level is causally related to the etiology of ASD (and possibly schizophrenia).
Highlights
Complex mechanisms underlie neurodevelopmental disorders (NDDs) and neuropsychiatric conditions
We focus on NDD models affecting Pvalb neurons in terms of neuron number and function and PV expression level, irrespective whether they are currently classified as models of validated autism spectrum disorder (ASD) risk genes
Based on findings from ASD patients and ASD animal models discussed in Decreased Number of PV+ Neurons in Human ASD Postmortem Brains: Pvalb Neuron Loss vs. PV and Downregulation and Animal NDD Models of ASD With Reduced PV Expression and/or Decreased Number/Altered Distribution of PV+ Neurons, respectively, as well as our own in vitro studies, we investigated the role of PV in the development of an ASD-like behavioral phenotype using genetically modified mice
Summary
Complex mechanisms underlie neurodevelopmental disorders (NDDs) and neuropsychiatric conditions. Reduced layer 4 stimulation-evoked feedforward inhibition (i.e., eIPSC) and a smaller decrease in feedforward excitation (i.e., evoked EPSC) onto layer 2/3 SSC pyramidal cells results in a higher E/I ratio in several ASD mouse models including Cntnap2−/− and Fmr1y/− mice (Antoine et al, 2019) This only weakly affects spontaneous (basal) spiking in layer 2/3 pyramidal cells in vitro; the whisker-evoked firing rate of FSI (likely Pvalb neurons) is reduced in these two ASD models (Antoine et al, 2019). Based on findings from ASD patients and ASD animal models discussed in Decreased Number of PV+ Neurons in Human ASD Postmortem Brains: Pvalb Neuron Loss vs PV and Downregulation and Animal NDD Models of ASD With Reduced PV Expression and/or Decreased Number/Altered Distribution of PV+ Neurons, respectively, as well as our own in vitro studies (reviewed in Schwaller, 2020), we investigated the role of PV in the development of an ASD-like behavioral phenotype using genetically modified mice. Additional studies are required to determine whether NAC can reduce ASD core symptoms
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