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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 hippocampus. Western blotting was performed using mouse hippocampal protein lysates (A). Protein levels were measured in BTBR and control mice with respect to the following proteins in the hippocampus: 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, **p < 0.01. Statistical significance was measured using a Student's t-test, n = 3 for each group.
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Figure 3: Protein expression in wild type and BTBR mouse hippocampus. Western blotting was performed using mouse hippocampal protein lysates (A). Protein levels were measured in BTBR and control mice with respect to the following proteins in the hippocampus: 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, **p < 0.01. Statistical significance was measured using a Student's t-test, n = 3 for each group.

Mentions: In the hippocampus we again found no significant differences in the levels of pro-BDNF between BTBR and WT (Figure 3B) that was coincident with a significant reduction in extant BDNF levels (Figure 3C). Phosphorylated TrkB expression was unchanged in BTBR mice compared to WT (Figure 3D), while there was a trend, similar to that in the cortex, to reductions of total TrkB receptor expression in the BTBR mice (Figure 3E). As with the cortex no significant alterations in Akt1 were observed (Figure 3F). Significant potentiation of both phosphorylated (Figure 3G) and non-phosphorylated synapsin 1 (Figure 3H) expression levels was seen in the BTBR hippocampus. In accordance with the cortical data we found no significant BTBR-induced changes in the hippocampal expression of synaptophysin (Figure 3I) or PSD95 (Figure 3J). Levels of both spinophilin (Figure 3K) and NeuN (Figure 3L) were again significantly potentiated in the BTBR mice, mirroring our previous cortical data.


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 hippocampus. Western blotting was performed using mouse hippocampal protein lysates (A). Protein levels were measured in BTBR and control mice with respect to the following proteins in the hippocampus: 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, **p < 0.01. 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 3: Protein expression in wild type and BTBR mouse hippocampus. Western blotting was performed using mouse hippocampal protein lysates (A). Protein levels were measured in BTBR and control mice with respect to the following proteins in the hippocampus: 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, **p < 0.01. Statistical significance was measured using a Student's t-test, n = 3 for each group.
Mentions: In the hippocampus we again found no significant differences in the levels of pro-BDNF between BTBR and WT (Figure 3B) that was coincident with a significant reduction in extant BDNF levels (Figure 3C). Phosphorylated TrkB expression was unchanged in BTBR mice compared to WT (Figure 3D), while there was a trend, similar to that in the cortex, to reductions of total TrkB receptor expression in the BTBR mice (Figure 3E). As with the cortex no significant alterations in Akt1 were observed (Figure 3F). Significant potentiation of both phosphorylated (Figure 3G) and non-phosphorylated synapsin 1 (Figure 3H) expression levels was seen in the BTBR hippocampus. In accordance with the cortical data we found no significant BTBR-induced changes in the hippocampal expression of synaptophysin (Figure 3I) or PSD95 (Figure 3J). Levels of both spinophilin (Figure 3K) and NeuN (Figure 3L) were again significantly potentiated in the BTBR mice, mirroring our previous cortical data.

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