Abstract
Autism spectrum disorder (hereafter referred to as “ASD”) is a heterogeneous neurodevelopmental condition characterized by impaired social communication and interactions, and restricted, repetitive activities or interests. Alterations in network connectivity and memory function are frequently observed in autism patients, often involving the hippocampus. However, specific changes during early brain development leading to disrupted functioning remain largely unclear. Here, we investigated the development of dendritic arbor of hippocampal CA1 pyramidal neurons in the BTBR T+tf/J (BTBR) mouse model of autism. BTBR mice display the defining behavioural features of autism, and also exhibit impaired learning and memory. We found that compared to control C57BL/6J (B6) animals, the lengths of both apical and basal dendrites were significantly greater in neonatal BTBR animals. Further, basal dendrites in the BTBR mice had higher branching complexity. In contrast, cross-sectional area of the soma was unchanged. In addition, we observed a similar density of CA1 pyramidal neurons and thickness of the neuronal layer between the two strains. Thus, there was a specific, compartmentalized overgrowth of dendrites during early development in the BTBR animals. Biochemical analysis further showed that the extracellular signal-regulated kinases (ERK) pathway was up-regulated in the hippocampus of neonatal BTBR animals. Since dendritic structure is critical for information integration and relay, our data suggest that altered development of dendrites could potentially contribute to impaired hippocampal function and behavior observed in the BTBR model, and that this might be related to increased activation of the ERK pathway.
Highlights
Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder, characterized by deficits in socio-emotional functions and language development, as well as repetitive and/or restrictive behaviours [1,2,3,4]
We found that the lengths of both apical and basal dendrites, and the total length of the dendritic arbor, were significantly increased in the BTBR T+tf/J strain (BTBR) animals compared with C57BL/6J strain (B6) mice (Fig 2A–2C, P = 0.006 for apical dendrites, P = 0.041 for basal dendrites, and P = 0.008 for total dendritic length)
Our results showed that the relative expression levels of both phosphorylated mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK) kinase (MEK) and ERK were increased in the hippocampal lysate from postnatal day 8 (P8) BTBR animals compared to control B6 animals (Fig 4)
Summary
Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder, characterized by deficits in socio-emotional functions and language development, as well as repetitive and/or restrictive behaviours [1,2,3,4]. ASD has broad and heterogeneous clinical manifestations, which has been associated with many potential etiological factors including both genetic and environmental ones, making it challenging to investigate its neurobiological basis and find interventions for affected individuals. Large amount of data point to age-dependent changes in structural and functional connectivity [12, 13], which may underlie the heterogeneous symptomatology seen in ASD. Together, these findings suggest that alterations in early neurodevelopment may contribute to disease pathogenesis, and that these early changes may be very dynamic
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