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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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Development of the Variance-to-Mean Ratio (VMR) for Synapsin and Synaptophysin (A), as well as PSD-95 and Gephyrin (B). (A) Synapsin (open circles, dashed line, weighted average function) had 3 peaks in VMR across the lifespan (1 year, 5–10 years, and older adults). Synaptophysin (filled dots, solid line; a * exp(b/x + c * x), R = 0.86, p < 0.0001) had a peak in VMR around 1 year of age. (B) PSD-95 (open circles, dashed line; a * exp(b/x + c * x), R = 0.82, p < 0.0001) had a peak in VMR throughout childhood. Gephyrin (filled dots, solid line; a + (b − a)/(1 + (x/c)d), R = 0.88, p < 0.0001) had a decline in VMR starting at about 5 years of age (inflection point = 5.2 years +/− 0.9).
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Figure 4: Development of the Variance-to-Mean Ratio (VMR) for Synapsin and Synaptophysin (A), as well as PSD-95 and Gephyrin (B). (A) Synapsin (open circles, dashed line, weighted average function) had 3 peaks in VMR across the lifespan (1 year, 5–10 years, and older adults). Synaptophysin (filled dots, solid line; a * exp(b/x + c * x), R = 0.86, p < 0.0001) had a peak in VMR around 1 year of age. (B) PSD-95 (open circles, dashed line; a * exp(b/x + c * x), R = 0.82, p < 0.0001) had a peak in VMR throughout childhood. Gephyrin (filled dots, solid line; a + (b − a)/(1 + (x/c)d), R = 0.88, p < 0.0001) had a decline in VMR starting at about 5 years of age (inflection point = 5.2 years +/− 0.9).

Mentions: Many studies of human brain development and function have found large inter-individual variations. We noticed greater inter-individual variability in expression of synaptic proteins in human cortex than we had found for rat cortex (Pinto et al., 2013). To quantify that inter-individual variability and determine if it changes across the lifespan we calculated the Fano factor (VMR) for a running window across 3 adjacent ages and then fit functions (Synaptophysin, PSD-95, Gephyrin) or a weighted average (Synapsin) to the VMRs to capture the pattern of change (Figure 4). The VMR for Synapsin and Synaptophysin showed waves of inter-individual variability across the lifespan (Figure 4A). Synaptophysin had a prominent peak in the VMR at 1 year of age and a smaller bump later in adulthood (curve fit, R = 0.86, p < 0.0001). Synapsin variability also had a peak at about 1 year, then a second peak during late childhood (5–10 years), and a third one during late adulthood. The post-synaptic proteins had different patterns of inter-individual variability (Figure 4B). Gephyrin VMR was high during early development up to about 5 years of age (inflection point = 5.2 years +/− 0.9), then declined through later childhood and remained low during adolescence and adulthood (curve fit, R = 0.88, p < 0.0001). In contrast, the VMR for PSD-95 expression was low in infants (<1 year) and adults (>20 years) but had a prominent peak during childhood and was elevated throughout adolescence (curve fit, R = 0.82, p < 0.0001). The waves of inter-individual variability for the synaptic proteins highlight developmental stages when there is greater variation in synaptic development and those may signify ages of vulnerability for specific aspects of synaptic maturation.


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)

Development of the Variance-to-Mean Ratio (VMR) for Synapsin and Synaptophysin (A), as well as PSD-95 and Gephyrin (B). (A) Synapsin (open circles, dashed line, weighted average function) had 3 peaks in VMR across the lifespan (1 year, 5–10 years, and older adults). Synaptophysin (filled dots, solid line; a * exp(b/x + c * x), R = 0.86, p < 0.0001) had a peak in VMR around 1 year of age. (B) PSD-95 (open circles, dashed line; a * exp(b/x + c * x), R = 0.82, p < 0.0001) had a peak in VMR throughout childhood. Gephyrin (filled dots, solid line; a + (b − a)/(1 + (x/c)d), R = 0.88, p < 0.0001) had a decline in VMR starting at about 5 years of age (inflection point = 5.2 years +/− 0.9).
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Figure 4: Development of the Variance-to-Mean Ratio (VMR) for Synapsin and Synaptophysin (A), as well as PSD-95 and Gephyrin (B). (A) Synapsin (open circles, dashed line, weighted average function) had 3 peaks in VMR across the lifespan (1 year, 5–10 years, and older adults). Synaptophysin (filled dots, solid line; a * exp(b/x + c * x), R = 0.86, p < 0.0001) had a peak in VMR around 1 year of age. (B) PSD-95 (open circles, dashed line; a * exp(b/x + c * x), R = 0.82, p < 0.0001) had a peak in VMR throughout childhood. Gephyrin (filled dots, solid line; a + (b − a)/(1 + (x/c)d), R = 0.88, p < 0.0001) had a decline in VMR starting at about 5 years of age (inflection point = 5.2 years +/− 0.9).
Mentions: Many studies of human brain development and function have found large inter-individual variations. We noticed greater inter-individual variability in expression of synaptic proteins in human cortex than we had found for rat cortex (Pinto et al., 2013). To quantify that inter-individual variability and determine if it changes across the lifespan we calculated the Fano factor (VMR) for a running window across 3 adjacent ages and then fit functions (Synaptophysin, PSD-95, Gephyrin) or a weighted average (Synapsin) to the VMRs to capture the pattern of change (Figure 4). The VMR for Synapsin and Synaptophysin showed waves of inter-individual variability across the lifespan (Figure 4A). Synaptophysin had a prominent peak in the VMR at 1 year of age and a smaller bump later in adulthood (curve fit, R = 0.86, p < 0.0001). Synapsin variability also had a peak at about 1 year, then a second peak during late childhood (5–10 years), and a third one during late adulthood. The post-synaptic proteins had different patterns of inter-individual variability (Figure 4B). Gephyrin VMR was high during early development up to about 5 years of age (inflection point = 5.2 years +/− 0.9), then declined through later childhood and remained low during adolescence and adulthood (curve fit, R = 0.88, p < 0.0001). In contrast, the VMR for PSD-95 expression was low in infants (<1 year) and adults (>20 years) but had a prominent peak during childhood and was elevated throughout adolescence (curve fit, R = 0.82, p < 0.0001). The waves of inter-individual variability for the synaptic proteins highlight developmental stages when there is greater variation in synaptic development and those may signify ages of vulnerability for specific aspects of synaptic maturation.

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