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Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex.

Pinto JG, Jones DG, Williams CK, Murphy KM - Front Neural Circuits (2015)

Bottom Line: In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (<1 year) when only Gephyrin has high inter-individual variability.We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the 1 year or 2 of life.Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.

View Article: PubMed Central - PubMed

Affiliation: McMaster Integrative Neuroscience Discovery and Study (MiNDS) Program, McMaster University Hamilton, ON, Canada.

ABSTRACT
Although many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin) and found that synaptic development in human primary visual cortex (V1) continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (<1 year) when only Gephyrin has high inter-individual variability. We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the 1 year or 2 of life. A multidimensional analysis (principle component analysis) showed that most of the variance was captured by the sum of the four synaptic proteins. We used that sum to compare development of human and rat visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.

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Developmental changes in the principal components 1 and 2 in human visual cortex. (A) Principal component 1. A logistics function was fit to the data. Principal component 1 had a peak in expression at 9 years of age (Figure 6; Peak = 9.2 +/− 0.7 years; curve-fit, R = 0.52, p < 0.0001). (B) Group mean and standard error for each developmental stage are plotted and the statistical significance (ANOVA, p < 0.0001) of the difference between pairs of development stages as determined by Tukey’s post hoc comparisons are plotted (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001). (C) Principal component 2. A linear function was fit to the data (R = 0.43, p < 0.005). (D) Group mean and standard error for each developmental stage are plotted and there were no significant differences in expression among experimental groups (ANOVA, p = 0.11).
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Figure 7: Developmental changes in the principal components 1 and 2 in human visual cortex. (A) Principal component 1. A logistics function was fit to the data. Principal component 1 had a peak in expression at 9 years of age (Figure 6; Peak = 9.2 +/− 0.7 years; curve-fit, R = 0.52, p < 0.0001). (B) Group mean and standard error for each developmental stage are plotted and the statistical significance (ANOVA, p < 0.0001) of the difference between pairs of development stages as determined by Tukey’s post hoc comparisons are plotted (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001). (C) Principal component 2. A linear function was fit to the data (R = 0.43, p < 0.005). (D) Group mean and standard error for each developmental stage are plotted and there were no significant differences in expression among experimental groups (ANOVA, p = 0.11).

Mentions: We plotted PCA 1 (Figures 7A,B) and PCA 2 (Figures 7C,D) as a function of age, and the binned developmental age groups. The first principal component was strongly correlated with the sum of the 4 proteins (R = 0.9764, p < 0.0001) and was well fit by a logistic function with peak expression at ~9 years of age (Figure 7A; Peak = 9.2 +/− 0.7 years; curve-fit, R = 0.52, p < 0.0001) (Figures 7A,B). We found a similar developmental profile when comparing the age groups (Figure 7B). There were significant differences in expression among the developmental stages (ANOVA, p < 0.0001), with Older Children (5–11 years) having significantly higher PCA 1 than all other age groups. Teens (12–20) also had relative higher PCA 1 when compare with Neonates (<0.3 years; Tukey’s, p < 0.01), and Infants (0.3–1 Year; Tukey’s, p < 0.05), while Neonates (<0.3 years) had relatively less when compare with Young Children (1–4 years; Tukey’s, p < 0.05), and Young Adults (21–55 years; Tukey’s, p < 0.05). Together, these results show a prolonged developmental increase in synaptic protein expression that continues into older children, and suggests a long period of synaptic stabilization in human visual cortex.


Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex.

Pinto JG, Jones DG, Williams CK, Murphy KM - Front Neural Circuits (2015)

Developmental changes in the principal components 1 and 2 in human visual cortex. (A) Principal component 1. A logistics function was fit to the data. Principal component 1 had a peak in expression at 9 years of age (Figure 6; Peak = 9.2 +/− 0.7 years; curve-fit, R = 0.52, p < 0.0001). (B) Group mean and standard error for each developmental stage are plotted and the statistical significance (ANOVA, p < 0.0001) of the difference between pairs of development stages as determined by Tukey’s post hoc comparisons are plotted (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001). (C) Principal component 2. A linear function was fit to the data (R = 0.43, p < 0.005). (D) Group mean and standard error for each developmental stage are plotted and there were no significant differences in expression among experimental groups (ANOVA, p = 0.11).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 7: Developmental changes in the principal components 1 and 2 in human visual cortex. (A) Principal component 1. A logistics function was fit to the data. Principal component 1 had a peak in expression at 9 years of age (Figure 6; Peak = 9.2 +/− 0.7 years; curve-fit, R = 0.52, p < 0.0001). (B) Group mean and standard error for each developmental stage are plotted and the statistical significance (ANOVA, p < 0.0001) of the difference between pairs of development stages as determined by Tukey’s post hoc comparisons are plotted (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001). (C) Principal component 2. A linear function was fit to the data (R = 0.43, p < 0.005). (D) Group mean and standard error for each developmental stage are plotted and there were no significant differences in expression among experimental groups (ANOVA, p = 0.11).
Mentions: We plotted PCA 1 (Figures 7A,B) and PCA 2 (Figures 7C,D) as a function of age, and the binned developmental age groups. The first principal component was strongly correlated with the sum of the 4 proteins (R = 0.9764, p < 0.0001) and was well fit by a logistic function with peak expression at ~9 years of age (Figure 7A; Peak = 9.2 +/− 0.7 years; curve-fit, R = 0.52, p < 0.0001) (Figures 7A,B). We found a similar developmental profile when comparing the age groups (Figure 7B). There were significant differences in expression among the developmental stages (ANOVA, p < 0.0001), with Older Children (5–11 years) having significantly higher PCA 1 than all other age groups. Teens (12–20) also had relative higher PCA 1 when compare with Neonates (<0.3 years; Tukey’s, p < 0.01), and Infants (0.3–1 Year; Tukey’s, p < 0.05), while Neonates (<0.3 years) had relatively less when compare with Young Children (1–4 years; Tukey’s, p < 0.05), and Young Adults (21–55 years; Tukey’s, p < 0.05). Together, these results show a prolonged developmental increase in synaptic protein expression that continues into older children, and suggests a long period of synaptic stabilization in human visual cortex.

Bottom Line: In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (<1 year) when only Gephyrin has high inter-individual variability.We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the 1 year or 2 of life.Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.

View Article: PubMed Central - PubMed

Affiliation: McMaster Integrative Neuroscience Discovery and Study (MiNDS) Program, McMaster University Hamilton, ON, Canada.

ABSTRACT
Although many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin) and found that synaptic development in human primary visual cortex (V1) continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (<1 year) when only Gephyrin has high inter-individual variability. We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the 1 year or 2 of life. A multidimensional analysis (principle component analysis) showed that most of the variance was captured by the sum of the four synaptic proteins. We used that sum to compare development of human and rat visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.

Show MeSH