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The effects of aging on the BTBR mouse model of autism spectrum disorder.

Jasien JM, Daimon CM, Wang R, Shapiro BK, Martin B, Maudsley S - Front Aging Neurosci (2014)

Bottom Line: 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.We found that a reduction in social behavior persists into old age in male BTBR T + tf/j 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.

View Article: PubMed Central - PubMed

Affiliation: Metabolism Unit, Laboratory of Clinical Investigation, National Institutes of Health, National Institute on Aging Baltimore, MD, USA ; Department of Neurology, Johns Hopkins University School of Medicine, Kennedy Krieger Institute Baltimore, MD, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Signaling pathway analysis of cortical and hippocampal proteins differentially regulated BTBR and WT. Cortical and hippocampal proteins exhibiting differential regulation between BTBR and control mice were analyzed for potential functional pathway interactions using KEGG (A-cortex, B-hippocampus) and Ingenuity Canonical Signaling pathway analysis (C-cortex, D-hippocampus). For (A,B), the top 10 most significantly-populated (calculated with Hybrid scores: enrichment factor (R) * (−log10 enrichment probability, P) neuronally-specific KEGG or Canonical signaling pathways are shown.
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Figure 5: Signaling pathway analysis of cortical and hippocampal proteins differentially regulated BTBR and WT. Cortical and hippocampal proteins exhibiting differential regulation between BTBR and control mice were analyzed for potential functional pathway interactions using KEGG (A-cortex, B-hippocampus) and Ingenuity Canonical Signaling pathway analysis (C-cortex, D-hippocampus). For (A,B), the top 10 most significantly-populated (calculated with Hybrid scores: enrichment factor (R) * (−log10 enrichment probability, P) neuronally-specific KEGG or Canonical signaling pathways are shown.

Mentions: While GO annotation indicates some degree of functional commonality between groups of proteins, associating multiple proteins with classically-identified molecular signaling paradigms provides additional functional information regarding the potential physiological ramifications of specific group of differentially-regulated factors. We therefore performed both KEGG and Ingenuity-base pathway analysis upon our cortical and hippocampal BTBR protein sets. Inspecting the top ten highest scoring KEGG pathways from cortical proteins (Figure 5A: Table 3) a strong population of metabolic (Glutathione metabolism, Insulin signaling pathway, Metabolic pathways), neurotransmission/degenerative (Neurotrophic signaling pathway, Alzheimer's disease) and ultrastructural (Gap junction, Tight junction, Spliceosome) signaling pathways was evident. Applying the same analysis to the hippocampus an intense population of signaling systems linked to oxidative metabolism [Oxidative phosphorylation, Pyruvate metabolism, Citrate cycle (TCA cycle)] and central neurodegeneration (Alzheimer's disease, Huntington's disease, Parkinson's disease, Long-term potentiation) was clear (Figure 5B: Table 4). Extraction of potential physiological meaning from complex data sets is best performed using multiple informatics tools. Therefore, we also sought interpretation of the potential signaling pathways enriched in the BTBR tissues using canonical signaling pathway analysis (Ingenuity). Canonical signaling analysis of the cortex revealed a strong bias toward cytokine signaling (Leptin signaling in obesity, JAK family kinases in IL-6-type signaling), neurodegenerative disease related activity (Amyloid processing, CDK5 signaling, CNTF signaling) and energy metabolism (IGF-1 signaling) (Figure 5C: Table 5). Similar pathway processing of hippocampal data again revealed a strong prediction of metabolism-related activity (Oxidative phosphorylation, Mitochondrial dysfunction, G protein signaling mediated by Tubby), neurodegenerative activity (Huntington's disease signaling) and interestingly, given the strong presentation of, Melanocyte development and pigmentation signaling' in the cortex (Figure 5C), melatonin-related activity (Melatonin signaling) (Figure 5D: Table 6).


The effects of aging on the BTBR mouse model of autism spectrum disorder.

Jasien JM, Daimon CM, Wang R, Shapiro BK, Martin B, Maudsley S - Front Aging Neurosci (2014)

Signaling pathway analysis of cortical and hippocampal proteins differentially regulated BTBR and WT. Cortical and hippocampal proteins exhibiting differential regulation between BTBR and control mice were analyzed for potential functional pathway interactions using KEGG (A-cortex, B-hippocampus) and Ingenuity Canonical Signaling pathway analysis (C-cortex, D-hippocampus). For (A,B), the top 10 most significantly-populated (calculated with Hybrid scores: enrichment factor (R) * (−log10 enrichment probability, P) neuronally-specific KEGG or Canonical signaling pathways are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150363&req=5

Figure 5: Signaling pathway analysis of cortical and hippocampal proteins differentially regulated BTBR and WT. Cortical and hippocampal proteins exhibiting differential regulation between BTBR and control mice were analyzed for potential functional pathway interactions using KEGG (A-cortex, B-hippocampus) and Ingenuity Canonical Signaling pathway analysis (C-cortex, D-hippocampus). For (A,B), the top 10 most significantly-populated (calculated with Hybrid scores: enrichment factor (R) * (−log10 enrichment probability, P) neuronally-specific KEGG or Canonical signaling pathways are shown.
Mentions: While GO annotation indicates some degree of functional commonality between groups of proteins, associating multiple proteins with classically-identified molecular signaling paradigms provides additional functional information regarding the potential physiological ramifications of specific group of differentially-regulated factors. We therefore performed both KEGG and Ingenuity-base pathway analysis upon our cortical and hippocampal BTBR protein sets. Inspecting the top ten highest scoring KEGG pathways from cortical proteins (Figure 5A: Table 3) a strong population of metabolic (Glutathione metabolism, Insulin signaling pathway, Metabolic pathways), neurotransmission/degenerative (Neurotrophic signaling pathway, Alzheimer's disease) and ultrastructural (Gap junction, Tight junction, Spliceosome) signaling pathways was evident. Applying the same analysis to the hippocampus an intense population of signaling systems linked to oxidative metabolism [Oxidative phosphorylation, Pyruvate metabolism, Citrate cycle (TCA cycle)] and central neurodegeneration (Alzheimer's disease, Huntington's disease, Parkinson's disease, Long-term potentiation) was clear (Figure 5B: Table 4). Extraction of potential physiological meaning from complex data sets is best performed using multiple informatics tools. Therefore, we also sought interpretation of the potential signaling pathways enriched in the BTBR tissues using canonical signaling pathway analysis (Ingenuity). Canonical signaling analysis of the cortex revealed a strong bias toward cytokine signaling (Leptin signaling in obesity, JAK family kinases in IL-6-type signaling), neurodegenerative disease related activity (Amyloid processing, CDK5 signaling, CNTF signaling) and energy metabolism (IGF-1 signaling) (Figure 5C: Table 5). Similar pathway processing of hippocampal data again revealed a strong prediction of metabolism-related activity (Oxidative phosphorylation, Mitochondrial dysfunction, G protein signaling mediated by Tubby), neurodegenerative activity (Huntington's disease signaling) and interestingly, given the strong presentation of, Melanocyte development and pigmentation signaling' in the cortex (Figure 5C), melatonin-related activity (Melatonin signaling) (Figure 5D: Table 6).

Bottom Line: 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.We found that a reduction in social behavior persists into old age in male BTBR T + tf/j 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.

View Article: PubMed Central - PubMed

Affiliation: Metabolism Unit, Laboratory of Clinical Investigation, National Institutes of Health, National Institute on Aging Baltimore, MD, USA ; Department of Neurology, Johns Hopkins University School of Medicine, Kennedy Krieger Institute Baltimore, MD, USA.

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.

No MeSH data available.


Related in: MedlinePlus