Abstract
Due to the complex and heterogeneous etiology of autism spectrum disorder (ASD), identification of convergent pathways and/or common molecular endpoints in the pathophysiological processes of ASD development are highly needed in order to facilitate treatment approaches targeted at the core symptoms. We recently reported on decreased expression of the Ca2+-binding protein parvalbumin (PV) in three well-characterized ASD mouse models, Shank1−/−, Shank3B−/− and in utero VPA-exposed mice. Moreover, PV-deficient mice (PV+/− and PV−/−) were found to show behavioral impairments and neuroanatomical changes closely resembling those frequently found in human ASD individuals. Here, we combined a stereology-based approach with molecular biology methods to assess changes in the subpopulation of PV-expressing (Pvalb) interneurons in the recently characterized contactin-associated protein-like 2 (Cntnap2−/−) knockout mouse model of ASD. The CNTNAP2 gene codes for a synaptic cell adhesion molecule involved in neurodevelopmental processes; mutations affecting the human CNTNAP2 locus are associated with human ASD core symptoms, in particular speech and language problems. We demonstrate that in Cntnap2−/− mice, no loss of Pvalb neurons is evident in ASD-associated brain regions including the striatum, somatosensory cortex (SSC) and medial prefrontal cortex (mPFC), shown by the unaltered number of Pvalb neurons ensheathed by VVA-positive perineuronal nets. However, the number of PV-immunoreactive (PV+) neurons and also PV protein levels were decreased in the striatum of Cntnap2−/− mice indicating that PV expression levels in some striatal Pvalb neurons dropped below the detection limit, yet without a loss of Pvalb neurons. No changes in PV+ neuron numbers were detected in the cortical regions investigated and also cortical PV expression levels were unaltered. Considering that Cntnap2 shows high expression levels in the striatum during human and mouse embryonic development and that the cortico-striato-thalamic circuitry is important for speech and language development, alterations in striatal PV expression and associated (homeostatic) adaptations are likely to play an important role in Cntnap2−/− mice and, assumingly, in human ASD patients with known Cntnap2 mutations.
Highlights
The etiology of autism spectrum disorder (ASD) is highly complex and diverse
We show that the number of Pvalb neurons, identified by Vicia Villosa Agglutinin-positive (VVA+) perineuronal nets (PNN), is unchanged in contactinassociated protein-like 2 (Cntnap2)−/− compared to WT mice in the somatosensory cortex, medial prefrontal cortex and striatum, three brain regions often implicated in ASD pathophysiology
The optical fractionator method and the Cavalieri estimator were used to quantify cell numbers and volumes in the striatum, somatosensory cortex (SSC) and medial prefrontal cortex, three brain regions frequently implicated in ASD pathology
Summary
The etiology of autism spectrum disorder (ASD) is highly complex and diverse. A combination of genetic, epigenetic and environmental factors is assumed to lead to the ASD phenotype characterized by impairments in social interaction and language/communication, and the presence of restricted or stereotyped patterns of behavior (Kleijer et al, 2014). Rare, and de novo mutations are known to contribute to the genetic risk of ASD and the number of risk genes is steadily increasing (Bourgeron, 2015). Several studies identified CNVs, common and rare SNPs and/or polymorphisms in the CNTNAP2 locus associated with syndromic neurodevelopmental disorders such as cortical dysplasia-focal epilepsy (CDFE) syndrome (Strauss et al, 2006), Pitt-Hopkins syndrome (Zweier et al, 2009), Gilles de la Tourette syndrome (Belloso et al, 2007), intellectual disability (ID) (Mikhail et al, 2011), obsessive compulsive disorder (Verkerk et al, 2003), attention deficit hyperactivity disorder (ADHD) (Elia et al, 2010), schizophrenia (Friedman et al, 2008) and autism (Alarcon et al, 2008; Arking et al, 2008). Cntnap2−/− mice show impairments in social behavior and reduced vocalizations (Penagarikano et al, 2011; Brunner et al, 2015; Liska et al, 2017), deficits in learning and memory (Rendall et al, 2016) and epileptiform activity (Penagarikano et al, 2011; Thomas et al, 2016)
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