Limits...
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.

Show MeSH

Related in: MedlinePlus

Developmental changes in the pre-synaptic (A,B) and post-synaptic (C,D) index 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) An exponential decay function was fit to all the pre-synaptic index data points (R = 0.67, p < 0.0001), and adult levels are defined as 3t (3t = 11.7 +/− 4.1 months). (B) There was a significant difference in expression of the pre-synaptic index between age groups (ANOVA, p < 0.0005) 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) An exponential decay function was fit to all the post-synaptic index data points (R = 0.51, p < 0.0001), and adult levels were defined as 3t (3.5 +/− 1.8 months). (D) There were no significant differences in expression of the post-synaptic index among the developmental stages (ANOVA, p = 0.18).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4325922&req=5

Figure 5: Developmental changes in the pre-synaptic (A,B) and post-synaptic (C,D) index 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) An exponential decay function was fit to all the pre-synaptic index data points (R = 0.67, p < 0.0001), and adult levels are defined as 3t (3t = 11.7 +/− 4.1 months). (B) There was a significant difference in expression of the pre-synaptic index between age groups (ANOVA, p < 0.0005) 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) An exponential decay function was fit to all the post-synaptic index data points (R = 0.51, p < 0.0001), and adult levels were defined as 3t (3.5 +/− 1.8 months). (D) There were no significant differences in expression of the post-synaptic index among the developmental stages (ANOVA, p = 0.18).

Mentions: Both the pre- and post-synaptic indices developed very rapidly in the first year (Figure 5). On the pre-synaptic side, there was an early switch from relatively more Synaptophysin expression to slightly more Synapsin expression, and mature-levels were reached by ~12 months of age (Figure 5A; 3τ = 11.7 +/− 4.1 months; curve fit, R = 0.67, p < 0.0001). We found a similar developmental profile with a significant switch in expression of the pre-synaptic index among the age groups (Figure 5B; ANOVA, p < 0.0005). Expression levels switched from more Synaptophysin in Neonates (<0.3 years) to more Synapsin in Younger Children (1–4 years; Tukey’s, p < 0.05) and that persisted through Older Adults (55+ years; Tukey’s, p < 0.05). This switch in the balance between Synapsin and Synaptophysin suggests that pre-synaptic function of vesicle endo- and exo-cytosis matures within the first year.


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 pre-synaptic (A,B) and post-synaptic (C,D) index 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) An exponential decay function was fit to all the pre-synaptic index data points (R = 0.67, p < 0.0001), and adult levels are defined as 3t (3t = 11.7 +/− 4.1 months). (B) There was a significant difference in expression of the pre-synaptic index between age groups (ANOVA, p < 0.0005) 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) An exponential decay function was fit to all the post-synaptic index data points (R = 0.51, p < 0.0001), and adult levels were defined as 3t (3.5 +/− 1.8 months). (D) There were no significant differences in expression of the post-synaptic index among the developmental stages (ANOVA, p = 0.18).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Developmental changes in the pre-synaptic (A,B) and post-synaptic (C,D) index 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) An exponential decay function was fit to all the pre-synaptic index data points (R = 0.67, p < 0.0001), and adult levels are defined as 3t (3t = 11.7 +/− 4.1 months). (B) There was a significant difference in expression of the pre-synaptic index between age groups (ANOVA, p < 0.0005) 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) An exponential decay function was fit to all the post-synaptic index data points (R = 0.51, p < 0.0001), and adult levels were defined as 3t (3.5 +/− 1.8 months). (D) There were no significant differences in expression of the post-synaptic index among the developmental stages (ANOVA, p = 0.18).
Mentions: Both the pre- and post-synaptic indices developed very rapidly in the first year (Figure 5). On the pre-synaptic side, there was an early switch from relatively more Synaptophysin expression to slightly more Synapsin expression, and mature-levels were reached by ~12 months of age (Figure 5A; 3τ = 11.7 +/− 4.1 months; curve fit, R = 0.67, p < 0.0001). We found a similar developmental profile with a significant switch in expression of the pre-synaptic index among the age groups (Figure 5B; ANOVA, p < 0.0005). Expression levels switched from more Synaptophysin in Neonates (<0.3 years) to more Synapsin in Younger Children (1–4 years; Tukey’s, p < 0.05) and that persisted through Older Adults (55+ years; Tukey’s, p < 0.05). This switch in the balance between Synapsin and Synaptophysin suggests that pre-synaptic function of vesicle endo- and exo-cytosis matures within the first year.

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
Related in: MedlinePlus