The Parvalbumin Hypothesis of Autism Spectrum Disorder

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).

Congenital Hypothyroidism and Brain Development: Association With Other Psychiatric Disorders

“…Similar to observations in patients with MCT8 mutations, loss of parvalbumin expression has been observed in the brains of patients with schizophrenia and autism ( Hashimoto et al, 2003 ; Lopez-Espindola et al, 2014 ; Filice et al, 2020 ). Since these psychiatric disorders are observed in perturbation of executive functions, parvalbumin expression in the human prefrontal cortex has been preferentially analyzed accordingly.…”

“…Although there are differences in the results among studies, a decrease in parvalbumin expression in the prefrontal cortex has been confirmed in schizophrenia and autism ( Beasley and Reynolds, 1997 ; Hashemi et al, 2017 ; Ariza et al, 2018 ; Kaar et al, 2019 ) ( Table 2 ). Therefore, a parvalbumin hypothesis for developmental delay has been proposed ( Filice et al, 2020 ).…”

Interneuron Dysfunction and Inhibitory Deficits in Autism and Fragile X Syndrome

“…While it is not conclusive whether interneuron dysfunction is the primary pathological mechanism, it motivates researchers to consider these disorders to be interneuronopathies [8,76,77]. In human research, postmortem studies have consistently reported reduced cell density of PV positive fast-spiking interneurons, one of the most major classes of interneurons [67] (Figure 1), in ASD individuals [77]. In FXS individuals, however, direct evidence is limited about interneuron phenotypes.…”

“…Not only are the reductions in the number of cells, but also, the functional alterations in inhibitory interneurons, particularly in PV interneurons, are implicated in multiple studies in FXS animal models [77]. Early works demonstrated that, in the amygdala, there is a drastic reduction both in phasic and tonic inhibitory transmission in Fmr1 KO mice Alterations in this subclass of interneurons are consistently reported in ASD.…”

A functional account of stimulation-based aerobic glycolysis and its role in interpreting BOLD signal intensity increases in neuroimaging experiments.

“…Regarding (b), postmortem analyses in prefrontal cortex (Brodmann Areas: 9, 46, and 47) found a reduction in FSP+ interneurons in autistic individuals, compared to controls (Hashemi et al, 2017), although this appears to stem more from a reduction in chandelier cells (Ariza et al, 2018), as opposed to basket cells which support gamma oscillations (Buzsáki & Wang, 2012). Nonetheless, it has been hypothesized that parvalbumin expression is causally related to autism (Filice et al, 2020), and the IMF bridge can put these hypotheses into a broader metabolic context. Finally, regarding (c), autistic individuals show increased levels of circulating norepinephrine (Lam et al, 2006) and increased phasic norepinephrine activity in response to prediction errors (Palmer et al, 2017), as indexed by pupillometric measures (Laeng et al, 2012; for review, see Lawson et al, 2014;Van de Cruys et al, 2014).…”