Limits...
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

Identification of coherent regulatory protein signatures in BTBR CNS tissues. Vennplex diagram analysis of the upregulated (BTBR:WT iTRAQ ratio > 1.2) or downregulated (iTRAQ ratio < 0.8) proteins in both the hippocampus and cortex are depicted (A). A small coherently-regulated protein subset across both tissues was evident and comprised a focused protein set strongly linked to human ASD-like conditions (B). Textrous!-based collective processing interrogation of the coherently-regulated BTBR protein set revealed, in the resultant hierarchical word-cloud, a strong potential role of skeletal modeling activity in this protein set (C). This skeletal signaling dependence of ASD was confirmed using the individual processing module of Textrous!(D). In this heatmap output correlation strength between protein and functional term is indicated by the intensity of the teal-colored blocks.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4150363&req=5

Figure 6: Identification of coherent regulatory protein signatures in BTBR CNS tissues. Vennplex diagram analysis of the upregulated (BTBR:WT iTRAQ ratio > 1.2) or downregulated (iTRAQ ratio < 0.8) proteins in both the hippocampus and cortex are depicted (A). A small coherently-regulated protein subset across both tissues was evident and comprised a focused protein set strongly linked to human ASD-like conditions (B). Textrous!-based collective processing interrogation of the coherently-regulated BTBR protein set revealed, in the resultant hierarchical word-cloud, a strong potential role of skeletal modeling activity in this protein set (C). This skeletal signaling dependence of ASD was confirmed using the individual processing module of Textrous!(D). In this heatmap output correlation strength between protein and functional term is indicated by the intensity of the teal-colored blocks.

Mentions: Along with our global analysis of protein set data from the two tissues we also investigated the predicted functional nature of the divergent expression polarity subsets of BTBR-specific proteins uniquely regulated in either the cortex or hippocampus. Using VennPlex (Figure 6A: Table 7) (Cai et al., 2013) we were able to identify multiple groups of coherently-controlled proteins across multiple CNS tissues. Using our previously developed informatics application, Textrous!, we generated physiological predictions extracted from multiple databases using latent semantic analysis (Chen et al., 2013). Using the collective processing capacity of Textrous!. which generates interactive hierarchical word-clouds, we found that the tissue-unique up or down regulated sets of proteins generated quite distinct functional signatures in the cortex or hippocampus. For example, the specifically upregulated proteins in the cortex were strongly focused into activity controlling excitatory amino acid synaptic activity (Figure S1A: Table S3), while the downregulated cortical only proteins demonstrated a strong link to a reduction of protein kinase activity (Figure S1B: Table S4). With respect to the hippocampus, the upregulated protein set appeared to be linked to increases in heat-shock factors and synaptic pathophysiology (Figure S2A: Table S5), while the downregulated hippocampal protein set suggested a reduction in oligodendrocyte generation and CNS myelination (Figure S2B: Table S6).


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)

Identification of coherent regulatory protein signatures in BTBR CNS tissues. Vennplex diagram analysis of the upregulated (BTBR:WT iTRAQ ratio > 1.2) or downregulated (iTRAQ ratio < 0.8) proteins in both the hippocampus and cortex are depicted (A). A small coherently-regulated protein subset across both tissues was evident and comprised a focused protein set strongly linked to human ASD-like conditions (B). Textrous!-based collective processing interrogation of the coherently-regulated BTBR protein set revealed, in the resultant hierarchical word-cloud, a strong potential role of skeletal modeling activity in this protein set (C). This skeletal signaling dependence of ASD was confirmed using the individual processing module of Textrous!(D). In this heatmap output correlation strength between protein and functional term is indicated by the intensity of the teal-colored blocks.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Identification of coherent regulatory protein signatures in BTBR CNS tissues. Vennplex diagram analysis of the upregulated (BTBR:WT iTRAQ ratio > 1.2) or downregulated (iTRAQ ratio < 0.8) proteins in both the hippocampus and cortex are depicted (A). A small coherently-regulated protein subset across both tissues was evident and comprised a focused protein set strongly linked to human ASD-like conditions (B). Textrous!-based collective processing interrogation of the coherently-regulated BTBR protein set revealed, in the resultant hierarchical word-cloud, a strong potential role of skeletal modeling activity in this protein set (C). This skeletal signaling dependence of ASD was confirmed using the individual processing module of Textrous!(D). In this heatmap output correlation strength between protein and functional term is indicated by the intensity of the teal-colored blocks.
Mentions: Along with our global analysis of protein set data from the two tissues we also investigated the predicted functional nature of the divergent expression polarity subsets of BTBR-specific proteins uniquely regulated in either the cortex or hippocampus. Using VennPlex (Figure 6A: Table 7) (Cai et al., 2013) we were able to identify multiple groups of coherently-controlled proteins across multiple CNS tissues. Using our previously developed informatics application, Textrous!, we generated physiological predictions extracted from multiple databases using latent semantic analysis (Chen et al., 2013). Using the collective processing capacity of Textrous!. which generates interactive hierarchical word-clouds, we found that the tissue-unique up or down regulated sets of proteins generated quite distinct functional signatures in the cortex or hippocampus. For example, the specifically upregulated proteins in the cortex were strongly focused into activity controlling excitatory amino acid synaptic activity (Figure S1A: Table S3), while the downregulated cortical only proteins demonstrated a strong link to a reduction of protein kinase activity (Figure S1B: Table S4). With respect to the hippocampus, the upregulated protein set appeared to be linked to increases in heat-shock factors and synaptic pathophysiology (Figure S2A: Table S5), while the downregulated hippocampal protein set suggested a reduction in oligodendrocyte generation and CNS myelination (Figure S2B: Table S6).

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