Abstract
SummaryHow changes in brain scaling relate to altered behavior is an important question in neurodevelopmental disorder research. Mice with germline Pten haploinsufficiency (Pten+/-) closely mirror the abnormal brain scaling and behavioral deficits seen in humans with macrocephaly/autism syndrome, which is caused by PTEN mutations. We explored whether deviation from normal patterns of growth can predict behavioral abnormalities. Brain regions associated with sensory processing (e.g., pons and inferior colliculus) had the biggest deviations from expected volume. While Pten+/- mice showed little or no abnormal behavior on most assays, both sexes showed sensory deficits, including impaired sensorimotor gating and hyporeactivity to high-intensity stimuli. Developmental analysis of this phenotype showed sexual dimorphism for hyporeactivity. Mapping behavioral phenotypes of Pten+/- mice onto relevant brain regions suggested abnormal behavior is likely when associated with relatively enlarged brain regions, while unchanged or relatively decreased brain regions have little predictive value.
Highlights
Autism spectrum disorder (ASD), a neurodevelopmental disorder present in 1:39 children in the USA (Baio et al, 2018), is diagnosed based on behavioral symptoms: deficits in social behavior and communication; restricted, repetitive behavior and interests; and sensory abnormalities (APA, 2013)
Rate of brain growth in Pten+/- mice deviates from controls To gain a high-level overview of altered developmental brain scaling in Pten+/- mice, we extended our analysis of our MRI dataset (Clipperton-Allen et al, 2019) to calculate growth indices
To explore this potential desynchrony, and to determine if specific Pten+/- brain regions developed at a different rate than in Pten+/+ littermates, we further examined the deviation of Pten+/- from a typical (Pten+/+) growth trajectory
Summary
Autism spectrum disorder (ASD), a neurodevelopmental disorder present in 1:39 children in the USA (Baio et al, 2018), is diagnosed based on behavioral symptoms: deficits in social behavior and communication; restricted, repetitive behavior and interests; and sensory abnormalities (APA, 2013). These sensory abnormalities include hypo- or hyper-responsiveness and sensory processing deficits (Marco et al, 2011). As it is a very heterogeneous disorder that presents with a wide range of symptoms and comorbidities, biomarkers that can classify ASD into subgroups are important. Similar analyses of brain scaling in ASD are routinely performed (e.g., Bigler et al, 2010; Brun et al, 2009; Cleavinger et al, 2008; Herbert et al, 2003; Sears et al, 1999; Sparks et al, 2002), but the behavioral consequences of these alterations in brain scaling are poorly understood
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