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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

Protein expression in wild type and BTBR mouse cortex. Western blotting was performed using mouse cortical protein lysates (A). Protein levels were measured in BTBR and control mice with respect to the following proteins in the cortex: pro-BDNF (B), mature BDNF (C), phospho-TrkB (D), total TrkB (E), Akt (F) phospho-synapsin 1 (G), synapsin 1 (H) synaptophysin (I), PSD95 (J), spinophilin (K), Neuronal cell marker NeuN (L). 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, n = 3 for each group.
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Figure 2: Protein expression in wild type and BTBR mouse cortex. Western blotting was performed using mouse cortical protein lysates (A). Protein levels were measured in BTBR and control mice with respect to the following proteins in the cortex: pro-BDNF (B), mature BDNF (C), phospho-TrkB (D), total TrkB (E), Akt (F) phospho-synapsin 1 (G), synapsin 1 (H) synaptophysin (I), PSD95 (J), spinophilin (K), Neuronal cell marker NeuN (L). 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, n = 3 for each group.

Mentions: Commensurate with an extant ASD phenotype aged BTBR mice demonstrated no sociability preference between an object or another mouse, while WT controls spent significantly more time with another mouse compared to an object (Figure 1A). Relative percentage of time spent with either the mouse or the object was used to calculate a social discrimination index [DI: (novel time/total time-same time/total time) × 100] (Figure 2B). WT and BTBR mice performed similarly in the novel object preference test of learning and memory, with both groups spending significantly more time with a novel object compared to a familiar object (Figures 1C,D). Both WT and BTBR mice significantly preferred to explore the peripheral areas of the chamber over the center of the chamber, though the BTBR mice did show a significantly higher preference for the periphery over the center (Figure 1E). No significant differences in total distance traveled (Figure 1F) or number of ambulatory episodes (Figure 1G) were found. BTBR mice however demonstrated significantly less jumping activity compared to WT (Figure 1H). In light-dark exploration tests 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 elevated plus maze test of anxiety, both WT and BTBR mice significantly preferred closed arms to open arms (Figure 1J). Motor coordination, assessed using a Rotarod test was similar in both groups (Figure 1K).


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)

Protein expression in wild type and BTBR mouse cortex. Western blotting was performed using mouse cortical protein lysates (A). Protein levels were measured in BTBR and control mice with respect to the following proteins in the cortex: pro-BDNF (B), mature BDNF (C), phospho-TrkB (D), total TrkB (E), Akt (F) phospho-synapsin 1 (G), synapsin 1 (H) synaptophysin (I), PSD95 (J), spinophilin (K), Neuronal cell marker NeuN (L). 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, n = 3 for each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Protein expression in wild type and BTBR mouse cortex. Western blotting was performed using mouse cortical protein lysates (A). Protein levels were measured in BTBR and control mice with respect to the following proteins in the cortex: pro-BDNF (B), mature BDNF (C), phospho-TrkB (D), total TrkB (E), Akt (F) phospho-synapsin 1 (G), synapsin 1 (H) synaptophysin (I), PSD95 (J), spinophilin (K), Neuronal cell marker NeuN (L). 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, n = 3 for each group.
Mentions: Commensurate with an extant ASD phenotype aged BTBR mice demonstrated no sociability preference between an object or another mouse, while WT controls spent significantly more time with another mouse compared to an object (Figure 1A). Relative percentage of time spent with either the mouse or the object was used to calculate a social discrimination index [DI: (novel time/total time-same time/total time) × 100] (Figure 2B). WT and BTBR mice performed similarly in the novel object preference test of learning and memory, with both groups spending significantly more time with a novel object compared to a familiar object (Figures 1C,D). Both WT and BTBR mice significantly preferred to explore the peripheral areas of the chamber over the center of the chamber, though the BTBR mice did show a significantly higher preference for the periphery over the center (Figure 1E). No significant differences in total distance traveled (Figure 1F) or number of ambulatory episodes (Figure 1G) were found. BTBR mice however demonstrated significantly less jumping activity compared to WT (Figure 1H). In light-dark exploration tests 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 elevated plus maze test of anxiety, both WT and BTBR mice significantly preferred closed arms to open arms (Figure 1J). Motor coordination, assessed using a Rotarod test was similar in both groups (Figure 1K).

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