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.

Highlights

  • Neuroplasticity is tightly regulated by synaptic mechanisms that promote or limit changes in neural circuits

  • PRINCIPAL COMPONENT ANALYSIS A multivariate analysis of the expression pattern for all proteins in human visual cortex was done using principal component analysis (PCA) using procedures we developed for analyzing synaptic proteins in cat (Beston et al, 2010) and rat (Pinto et al, 2013) visual cortex

  • DEVELOPMENT OF PRE-SYNAPTIC VESICLE CYCLING MECHANISMS To examine pre-synaptic development in human visual cortex across the lifespan, we quantified the expression of two proteins, Synapsin and Synaptophysin

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Summary

Introduction

Neuroplasticity is tightly regulated by synaptic mechanisms that promote or limit changes in neural circuits. These mechanisms determine how we see, hear, feel, learn, and think. The synaptic mechanisms regulating plasticity in the cortex are best understood for sensory areas. Tapping into adaptive neuroplasticity could improve therapies for conditions such as brain injury, neuropsychiatric disorders, neurodevelopmental disorders, and neurodegeneration. An NIH report about neuroplasticity research, noted that few of advances have translated from the lab into established clinical interventions (Cramer et al, 2011). Successful translation hinges on a good fit of the animal model with the human condition, which for neuroplasticity, relies on the ability to align developmental stages between animals and humans

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