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

Quantitative proteomic and bioinformatics analysis of BTBR CNS tissues. Log2transformed iTRAQ ratio data (BTBR:WT) snake plot of the proteins identified in the cortex (A) and hippocampus (B) are depicted. Upregulated proteins are highlighted in red, while downregulated proteins are highlighted in green. Three proteins identified by iTRAQ were validated via western blot and results correlated to the iTRAQ results (C, D). Data are expressed as means ± s.e.m. Asterisks represent p-values as shown: *p < 0.05. Statistical significance was measured using a Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Quantitative proteomic and bioinformatics analysis of BTBR CNS tissues. Log2transformed iTRAQ ratio data (BTBR:WT) snake plot of the proteins identified in the cortex (A) and hippocampus (B) are depicted. Upregulated proteins are highlighted in red, while downregulated proteins are highlighted in green. Three proteins identified by iTRAQ were validated via western blot and results correlated to the iTRAQ results (C, D). Data are expressed as means ± s.e.m. Asterisks represent p-values as shown: *p < 0.05. Statistical significance was measured using a Student's t-test.

Mentions: To gain an unbiased appreciation of the multiple tissue protein expression pattern changes generated in the BTBR mice compare to WT we applied quantitative isobaric mass-tag labeling (iTRAQ) to cortical and hippocampal tissue extracts. In the cortex we identified and generated relative expression profiles for 674 proteins (Figure 4A: Table S1), while in the hippocampus 656 proteins were identified and quantified in BTBR mice (Figure 4B: Table S2). Log2-transformed iTRAQ expression ratios were employed to generate snake plot graphs of individual proteins. To initially validate some of the iTRAQ data we chose three random proteins, Rab3A, CaMKIID and Cplx1 and found that at the western level of detection our results were comparable to our iTRAQ expression ratio data (Figures 4C,D).


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)

Quantitative proteomic and bioinformatics analysis of BTBR CNS tissues. Log2transformed iTRAQ ratio data (BTBR:WT) snake plot of the proteins identified in the cortex (A) and hippocampus (B) are depicted. Upregulated proteins are highlighted in red, while downregulated proteins are highlighted in green. Three proteins identified by iTRAQ were validated via western blot and results correlated to the iTRAQ results (C, D). Data are expressed as means ± s.e.m. Asterisks represent p-values as shown: *p < 0.05. Statistical significance was measured using a Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Quantitative proteomic and bioinformatics analysis of BTBR CNS tissues. Log2transformed iTRAQ ratio data (BTBR:WT) snake plot of the proteins identified in the cortex (A) and hippocampus (B) are depicted. Upregulated proteins are highlighted in red, while downregulated proteins are highlighted in green. Three proteins identified by iTRAQ were validated via western blot and results correlated to the iTRAQ results (C, D). Data are expressed as means ± s.e.m. Asterisks represent p-values as shown: *p < 0.05. Statistical significance was measured using a Student's t-test.
Mentions: To gain an unbiased appreciation of the multiple tissue protein expression pattern changes generated in the BTBR mice compare to WT we applied quantitative isobaric mass-tag labeling (iTRAQ) to cortical and hippocampal tissue extracts. In the cortex we identified and generated relative expression profiles for 674 proteins (Figure 4A: Table S1), while in the hippocampus 656 proteins were identified and quantified in BTBR mice (Figure 4B: Table S2). Log2-transformed iTRAQ expression ratios were employed to generate snake plot graphs of individual proteins. To initially validate some of the iTRAQ data we chose three random proteins, Rab3A, CaMKIID and Cplx1 and found that at the western level of detection our results were comparable to our iTRAQ expression ratio data (Figures 4C,D).

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