Cortical Malformations: Lessons in Human Brain Development.

Lakshmi Subramanian,Mercedes F Paredes,Maria Elisa Calcagnotto

doi:10.3389/fncel.2019.00576

Lakshmi Subramanian, Mercedes F Paredes + Show 1 more

Open Access

https://doi.org/10.3389/fncel.2019.00576

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Abstract

Creating a functional cerebral cortex requires a series of complex and well-coordinated developmental steps. These steps have evolved across species with the emergence of cortical gyrification and coincided with more complex behaviors. The presence of diverse progenitor cells, a protracted timeline for neuronal migration and maturation, and diverse neuronal types are developmental features that have emerged in the gyrated cortex. These factors could explain how the human brain has expanded in size and complexity. However, their complex nature also renders new avenues of vulnerability by providing additional cell types that could contribute to disease and longer time windows that could impact the composition and organization of the cortical circuit. We aim to discuss the unique developmental steps observed in human corticogenesis and propose how disruption of these species-unique processes could lead to malformations of cortical development.

Highlights

We explore the neuro-developmental sequence in the human brain (Figure 1) and discuss various Malformations of cortical development (MCD) associated with each of these stages, highlighting areas where human neurodevelopment differs from processes observed in mouse and rat models
Common themes that emerge from human studies, when compared to mouse analyses, are the expansion of unique progenitor populations that contribute to neurogenesis and the protracted developmental timeline over which progenitor proliferation and neuronal migration can occur
This has likely provided the substrate to allow for a larger cortex with complex connections, as in the human brain

Summary

Introduction

Malformations of cortical development (MCD) are an important and complex collection of neurodevelopmental disorders that underlie over 40% of medically refractory childhood seizures (Kuzniecky, 1994, 1995) with over three-quarters patients with MCD developing a seizure disorder (Leventer et al, 1999). The heterogeneity in the genetic and phenotypic presentations that underlie MCD have limited our ability to classify these disorders and coincide with challenges to predict and manage these diseases. The most frequently used to investigate the etiologies of MCD, have substantiated the clinical relevance of MCD-associated genetic mutations but have been unable to fully recapitulate the gross phenotypes observed in the clinical condition (Wong and Roper, 2016). A deeper understanding of human cortical development is necessary to more effectively apply the mechanistic findings from animal models to the disease state

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