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Abstract
Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by alterations in social functioning, communicative abilities, and engagement in repetitive or restrictive behaviors. The process of aging in individuals with autism and related neurodevelopmental disorders is not well understood, despite the fact that the number of individuals with ASD aged 65 and older is projected to increase by over half a million individuals in the next 20 years. To elucidate the effects of aging in the context of a modified central nervous system, we investigated the effects of age on the BTBR T + tf/j mouse, a well characterized and widely used mouse model that displays an ASD-like phenotype. We found that a reduction in social behavior persists into old age in male BTBR T + tf/j mice. We employed quantitative proteomics to discover potential alterations in signaling systems that could regulate aging in the BTBR mice. Unbiased proteomic analysis of hippocampal and cortical tissue of BTBR mice compared to age-matched wild-type controls revealed a significant decrease in brain derived neurotrophic factor and significant increases in multiple synaptic markers (spinophilin, Synapsin I, PSD 95, NeuN), as well as distinct changes in functional pathways related to these proteins, including “Neural synaptic plasticity regulation” and “Neurotransmitter secretion regulation.” Taken together, these results contribute to our understanding of the effects of aging on an ASD-like mouse model in regards to both behavior and protein alterations, though additional studies are needed to fully understand the complex interplay underlying aging in mouse models displaying an ASD-like phenotype.
Highlights
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by varying degrees of altered social functioning and engagement in repetitive, stereotyped behaviors accompanied by display of narrowed interests (American Psychiatric Association, DSM-V 2012)
In light-dark exploration tests black and tan (BTBR) mice spent significantly more time in the dark chamber compared to the lighted chamber, while WT control mice show no statistical difference in preference for either chamber (Figure 1I)
In the present study we evaluated the behavior, synaptic protein alterations and targeted proteomic signatures in the hippocampus and cortex of 15 month old BTBR and WT mice to determine whether the ASD-like phenotype of BTBR mice was resistant to neuronal aging
Summary
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by varying degrees of altered social functioning and engagement in repetitive, stereotyped behaviors accompanied by display of narrowed interests (American Psychiatric Association, DSM-V 2012). A limited number of human studies have investigated the persistence of the ASD core deficits into adulthood (Ballaban-Gil et al, 1996; Seltzer et al, 2003; Shattuck et al, 2007), childhood factors that are associated with prognosis (Rumsey et al, 1985), and outcome studies (Rutter et al, 1967; Howlin et al, 2004; Renty and Roeyers, 2006) Major findings from these studies suggest that language development (Kanner et al, 1972) and Intelligence Quotient (IQ) predicts outcome (Lotter, 1974; Rumsey et al, 1985; Szatmari et al, 1989). The ASD diagnosis persists with inconsistent findings about which, if any, core deficits change
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