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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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Transformation of rat data to human age. The sum of the four synaptic proteins (synaptic protein expression) is plotted for human (black dots, age in years), rat (red dots, age in days), and the rat results transformed into human age (open red dots). Human data was fit with a Gaussian function (R = 0.74, p < 0.0001), and reached a peak in expression at 9 years of age (Peak: x-axis = 9.4 years, y-axis = 5.7). Rat data was fit with a decay function (R = 0.92, p < 0.0001), and reached maximum expression at P55 (Peak: x-axis = 54.5 days, y-axis = 5.2). The human and rat alignment was done by normalizing to the peak expression (Human Expression at 9 Years/Rat Expression at 55 Days), then determining the offset on the x-axis to align the rat curve (dotted red curve) with the human curve (solid black curve) of synaptic protein expression, and then applying that transformation to each of the rat data points. The transformed rat data was plotted (open red dots, dotted red curve) in human equivalent units. A large portion of the human (black) and transformed rat (dotted red) curves approximated a linear increase, allowing for a simple alignment of rats age in days with human post-conception age in years (Rat Age (Days) = 11 + 5.5 * Human Post Conception Age (Years)).
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Figure 8: Transformation of rat data to human age. The sum of the four synaptic proteins (synaptic protein expression) is plotted for human (black dots, age in years), rat (red dots, age in days), and the rat results transformed into human age (open red dots). Human data was fit with a Gaussian function (R = 0.74, p < 0.0001), and reached a peak in expression at 9 years of age (Peak: x-axis = 9.4 years, y-axis = 5.7). Rat data was fit with a decay function (R = 0.92, p < 0.0001), and reached maximum expression at P55 (Peak: x-axis = 54.5 days, y-axis = 5.2). The human and rat alignment was done by normalizing to the peak expression (Human Expression at 9 Years/Rat Expression at 55 Days), then determining the offset on the x-axis to align the rat curve (dotted red curve) with the human curve (solid black curve) of synaptic protein expression, and then applying that transformation to each of the rat data points. The transformed rat data was plotted (open red dots, dotted red curve) in human equivalent units. A large portion of the human (black) and transformed rat (dotted red) curves approximated a linear increase, allowing for a simple alignment of rats age in days with human post-conception age in years (Rat Age (Days) = 11 + 5.5 * Human Post Conception Age (Years)).

Mentions: The PCA identified the sum of the 4 proteins as the main source of variance for development of human visual cortex. In another study, we quantified expression of the same synaptic proteins (Synapsin, Synaptophysin, PSD-95, and Gephyrin) in developing rat cortex, and using PCA analysis found that the largest portion of the variance was also accounted for by the sum of the four proteins (Pinto et al., 2013). Together, these data sets provide a unique opportunity to run a parallel comparison between human and rat cortical development, and to determine how to translate synaptic age between these species. First, we quantified the sum of the synaptic proteins in human visual cortex and plotted that as a function of post-conception age (Figure 8, black dots and curve). In human visual cortex, development of synaptic protein expression (black dots) followed a trajectory that was well fit by a Gaussian function with the peak of expression at ~9 years of age (Figure 8; curve-fit, R = 0.7376, p < 0.0001). Second, we plotted the development of synaptic protein expression in rat visual cortex (Pinto et al., 2013; Figure 8) and transformed rat ages (P4–P93) to post-conception days. In rat visual cortex (open red dots), development of synaptic protein expression for the range of ages followed a decay function that reached a maximum expression at 55 days post-conception (Figure 8; curve-fit, R = 0.9215, p < 0.0001).


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)

Transformation of rat data to human age. The sum of the four synaptic proteins (synaptic protein expression) is plotted for human (black dots, age in years), rat (red dots, age in days), and the rat results transformed into human age (open red dots). Human data was fit with a Gaussian function (R = 0.74, p < 0.0001), and reached a peak in expression at 9 years of age (Peak: x-axis = 9.4 years, y-axis = 5.7). Rat data was fit with a decay function (R = 0.92, p < 0.0001), and reached maximum expression at P55 (Peak: x-axis = 54.5 days, y-axis = 5.2). The human and rat alignment was done by normalizing to the peak expression (Human Expression at 9 Years/Rat Expression at 55 Days), then determining the offset on the x-axis to align the rat curve (dotted red curve) with the human curve (solid black curve) of synaptic protein expression, and then applying that transformation to each of the rat data points. The transformed rat data was plotted (open red dots, dotted red curve) in human equivalent units. A large portion of the human (black) and transformed rat (dotted red) curves approximated a linear increase, allowing for a simple alignment of rats age in days with human post-conception age in years (Rat Age (Days) = 11 + 5.5 * Human Post Conception Age (Years)).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 8: Transformation of rat data to human age. The sum of the four synaptic proteins (synaptic protein expression) is plotted for human (black dots, age in years), rat (red dots, age in days), and the rat results transformed into human age (open red dots). Human data was fit with a Gaussian function (R = 0.74, p < 0.0001), and reached a peak in expression at 9 years of age (Peak: x-axis = 9.4 years, y-axis = 5.7). Rat data was fit with a decay function (R = 0.92, p < 0.0001), and reached maximum expression at P55 (Peak: x-axis = 54.5 days, y-axis = 5.2). The human and rat alignment was done by normalizing to the peak expression (Human Expression at 9 Years/Rat Expression at 55 Days), then determining the offset on the x-axis to align the rat curve (dotted red curve) with the human curve (solid black curve) of synaptic protein expression, and then applying that transformation to each of the rat data points. The transformed rat data was plotted (open red dots, dotted red curve) in human equivalent units. A large portion of the human (black) and transformed rat (dotted red) curves approximated a linear increase, allowing for a simple alignment of rats age in days with human post-conception age in years (Rat Age (Days) = 11 + 5.5 * Human Post Conception Age (Years)).
Mentions: The PCA identified the sum of the 4 proteins as the main source of variance for development of human visual cortex. In another study, we quantified expression of the same synaptic proteins (Synapsin, Synaptophysin, PSD-95, and Gephyrin) in developing rat cortex, and using PCA analysis found that the largest portion of the variance was also accounted for by the sum of the four proteins (Pinto et al., 2013). Together, these data sets provide a unique opportunity to run a parallel comparison between human and rat cortical development, and to determine how to translate synaptic age between these species. First, we quantified the sum of the synaptic proteins in human visual cortex and plotted that as a function of post-conception age (Figure 8, black dots and curve). In human visual cortex, development of synaptic protein expression (black dots) followed a trajectory that was well fit by a Gaussian function with the peak of expression at ~9 years of age (Figure 8; curve-fit, R = 0.7376, p < 0.0001). Second, we plotted the development of synaptic protein expression in rat visual cortex (Pinto et al., 2013; Figure 8) and transformed rat ages (P4–P93) to post-conception days. In rat visual cortex (open red dots), development of synaptic protein expression for the range of ages followed a decay function that reached a maximum expression at 55 days post-conception (Figure 8; curve-fit, R = 0.9215, p < 0.0001).

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