Neurobiological substrates underlying corpus callosum hypoconnectivity and brain metabolic patterns in the valproic acid rat model of autism spectrum disorder

Abstract

Atypical connectivity between brain regions and altered structure of the corpus callosum (CC) in imaging studies supports the long‐distance hypoconnectivity hypothesis proposed for autism spectrum disorder (ASD). The aim of this study was to unveil the CC ultrastructural and cellular changes employing the valproic acid (VPA) rat model of ASD. Male Wistar rats were exposed to VPA (450 mg/kg i.p.) or saline (control) during gestation (embryonic day 10.5), and maturation, exploration, and social behavior were subsequently tested. Myelin content, ultrastructure, and oligodendroglial lineage were studied in the CC at post‐natal days 15 (infant) and 36 (juvenile). As a functional outcome, brain metabolic activity was determined by positron emission tomography. Concomitantly with behavioral deficits in juvenile VPA rats, the CC showed reduced myelin basic protein, conserved total number of axons, reduced percentage of myelinated axons, and aberrant and less compact arrangements of myelin sheath ultrastructure. Mature oligodendrocytes decreased and oligodendrocyte precursors increased in the absence of astrogliosis or microgliosis. In medial prefrontal and somatosensory cortices of juvenile VPA rats, myelin ultrastructure and oligodendroglial lineage were preserved. VPA animals exhibited global brain hypometabolism and local hypermetabolism in brain regions relevant for ASD. In turn, the CC of infant VPA rats showed reduced myelin content but preserved oligodendroglial lineage. Our findings indicate that CC hypomyelination is established during infancy and prior to oligodendroglial pattern alterations, which suggests that axon–oligodendroglia communication could be compromised in VPA animals. Thus, CC hypomyelination may underlie white matter alterations and contribute to atypical patterns of connectivity and metabolism found in ASD.

Prenatal valproic acid on the basis of gestational diabetes also induces autistic behavior and disrupts myelination and oligodendroglial maturation slightly in offspring

“…2E-e, f, k, l, p, r). This data rea rms the correlation delineated by Uccelli et al [45] , associating compromised myelination in the corpus callosum with the manifestations of VPA-induced autism.…”

“…The autistic phenotype observed in offspring following prenatal VPA exposure has been linked to dysmyelination in various brain regions, including the medial prefrontal cortex, pyriform cortex, basolateral amygdala, and corpus callosum [30,44,45] . Myelination in the corpus callosum in mice commences postnatally, reaching its peak between 4 and 6 weeks [46] .…”

Mapping the neuroanatomical abnormalities in a phenotype of male compulsive rats

“…Moreover, OCD-like behavior mice exhibited increased c-fos expression in the AC ([ 80 ]. In contrast, in a previous study in our laboratory we found that HD rats selected by SIP showed reduced myelin basic protein (MBP) in the CC [ 61 ], as well as in a preclinical model of ASD [ 81 , 82 ].…”

Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder

“…In contrast, a study reported a decrease in myelin content but a preserved population of OL cells in the corpus callosum at PND15. However, there was a consistent disruption observed in myelin content, number of myelinated axons, and OL population from PND15 to PND36 [ 312 ]. These stages in rats are similar to the infant and juvenile stages of human development [ 197 ].…”