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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 PSD-95 (A,B) and Gephyrin (C,D) expression in human visual cortex. (A,C) Gray dots are results from all runs, and black dots are the average for each sample. Example bands are shown above the graphs. (B,D) Group means and standard error for each developmental stage are plotted. (A) A Gaussian function was fit to all the PSD-95 data points (R = 0.58; p < 0.0001), and a peak in expression was reached at 8 years of age (peak = 8.0 +/− 0.7 years). (B) There was a significant difference in expression of PSD-95 between the groups (ANOVA, p < 0.0001), and the statistical significance 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) A Gaussian function was fit to all the Gephyrin data points (R = 0.48; p < 0.0005), and a peak in expression was reached at 10.0 years of age. (D) There was a significant difference in expression of Gephyrin between the groups (ANOVA, p < 0.005), and the statistical significance 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).
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Figure 3: Developmental changes in PSD-95 (A,B) and Gephyrin (C,D) expression in human visual cortex. (A,C) Gray dots are results from all runs, and black dots are the average for each sample. Example bands are shown above the graphs. (B,D) Group means and standard error for each developmental stage are plotted. (A) A Gaussian function was fit to all the PSD-95 data points (R = 0.58; p < 0.0001), and a peak in expression was reached at 8 years of age (peak = 8.0 +/− 0.7 years). (B) There was a significant difference in expression of PSD-95 between the groups (ANOVA, p < 0.0001), and the statistical significance 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) A Gaussian function was fit to all the Gephyrin data points (R = 0.48; p < 0.0005), and a peak in expression was reached at 10.0 years of age. (D) There was a significant difference in expression of Gephyrin between the groups (ANOVA, p < 0.005), and the statistical significance 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).

Mentions: Development of PSD-95 and Gephyrin expression followed similar developmental trajectories, increasing into late childhood and then declining into adulthood. Development of PSD-95 increased ~10-fold to reach a peak at 8 years of age (Figure 3A; peak = 8.0 +/− 0.7 years; curve fit, R = 0.58; p < 0.0001), and then declined ~5-fold. Comparison of PSD-95 expression levels among developmental stages (Figure 3B; ANOVA, p < 0.0001) showed that it was significantly higher in Older Children (5–11 years) relative to all other age groups: Neonates (<0.3 years; Tukey’s, p < 0.0001), Infants (0.3–1 Year; Tukey’s, p < 0.0001), Young Children (1–4 years; Tukey’s, p < 0.001), Teens (12–20 years; Tukey’s, p < 0.01), Young Adults (21–55 years; Tukey’s, p < 0.0001), Older Adults (55+ years; Tukey’s, p < 0.0001). We also found that teens (12–21 years) had higher expression levels of PSD-95 than Neonates (<0.3 years; Tukey’s, p < 0.05).


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 PSD-95 (A,B) and Gephyrin (C,D) expression in human visual cortex. (A,C) Gray dots are results from all runs, and black dots are the average for each sample. Example bands are shown above the graphs. (B,D) Group means and standard error for each developmental stage are plotted. (A) A Gaussian function was fit to all the PSD-95 data points (R = 0.58; p < 0.0001), and a peak in expression was reached at 8 years of age (peak = 8.0 +/− 0.7 years). (B) There was a significant difference in expression of PSD-95 between the groups (ANOVA, p < 0.0001), and the statistical significance 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) A Gaussian function was fit to all the Gephyrin data points (R = 0.48; p < 0.0005), and a peak in expression was reached at 10.0 years of age. (D) There was a significant difference in expression of Gephyrin between the groups (ANOVA, p < 0.005), and the statistical significance 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).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4325922&req=5

Figure 3: Developmental changes in PSD-95 (A,B) and Gephyrin (C,D) expression in human visual cortex. (A,C) Gray dots are results from all runs, and black dots are the average for each sample. Example bands are shown above the graphs. (B,D) Group means and standard error for each developmental stage are plotted. (A) A Gaussian function was fit to all the PSD-95 data points (R = 0.58; p < 0.0001), and a peak in expression was reached at 8 years of age (peak = 8.0 +/− 0.7 years). (B) There was a significant difference in expression of PSD-95 between the groups (ANOVA, p < 0.0001), and the statistical significance 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) A Gaussian function was fit to all the Gephyrin data points (R = 0.48; p < 0.0005), and a peak in expression was reached at 10.0 years of age. (D) There was a significant difference in expression of Gephyrin between the groups (ANOVA, p < 0.005), and the statistical significance 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).
Mentions: Development of PSD-95 and Gephyrin expression followed similar developmental trajectories, increasing into late childhood and then declining into adulthood. Development of PSD-95 increased ~10-fold to reach a peak at 8 years of age (Figure 3A; peak = 8.0 +/− 0.7 years; curve fit, R = 0.58; p < 0.0001), and then declined ~5-fold. Comparison of PSD-95 expression levels among developmental stages (Figure 3B; ANOVA, p < 0.0001) showed that it was significantly higher in Older Children (5–11 years) relative to all other age groups: Neonates (<0.3 years; Tukey’s, p < 0.0001), Infants (0.3–1 Year; Tukey’s, p < 0.0001), Young Children (1–4 years; Tukey’s, p < 0.001), Teens (12–20 years; Tukey’s, p < 0.01), Young Adults (21–55 years; Tukey’s, p < 0.0001), Older Adults (55+ years; Tukey’s, p < 0.0001). We also found that teens (12–21 years) had higher expression levels of PSD-95 than Neonates (<0.3 years; Tukey’s, p < 0.05).

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