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. 2020 Jan 24;13:576.
doi: 10.3389/fncel.2019.00576. eCollection 2019.

Cortical Malformations: Lessons in Human Brain Development

Free PMC article

Cortical Malformations: Lessons in Human Brain Development

Lakshmi Subramanian et al. Front Cell Neurosci. .
Free PMC article


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.

Keywords: MCD = malformation of cortical development; connectivity; human cortical development; neuronal migration; progenitors cells.


Human cortical development and stages of malformation. The human cerebral cortex forms early in the first trimester in the dorsal part of the telencephalon (forebrain). The human brain shows a rapid expansion in size and complexity during the 40 weeks of gestation as a result of extensive progenitor proliferation, migratory expansion and the generation of a complex connectivity pattern. During the first trimester, NE cells undergo symmetric division to expand the progenitor pool. NE cells elongate and convert into RG. By the end of the first trimester, RG are well established and can generate neurons (identified as migrating neuroblasts) directly through asymmetric division or indirectly by generation of IPCs. IPCs function as transient amplifying cells and can divide symmetrically one or more times to generate clones of neurons. Genetic mutations or environmental insults at this stage can cause microcephaly. In the second trimester, RG begin to give rise to RG-like cells that lack apical contact in the outer SVZ. These outer SVZ radial glia-like cells (oRG) are especially abundant in humans and other mammals with complex gyrencephalic cortices. oRG cells can generate neurons through IPCs and may contribute particularly to the generation of upper layer neurons. By the end of the second trimester, RG cells transform into truncated tRG. At this stage the RG scaffold is composed of the basal processes of the oRG cells. Proliferation errors or progenitor apoptosis in the second trimester can cause microcephaly or lissencephaly. Somatic mutations in mTOR pathway genes in NE, RG or oRG progenitors can result in FCD, HME or ME. Excitatory cortical pyramidal neurons are generated from RG and oRG progenitors via IPCs at the end of the first trimester. These neurons begin to migrate radially along the RG scaffold and until the middle of the third trimester. The pyramidal neurons maintain a radial organization as they migrate into and establish the cortical plate in an inside out manner, with the earliest generated neurons forming the deeper cortical layers while the youngest neurons contribute to the superficial layers. Errors in neuronal migration can result in heterotopias and lissencephaly. As they migrate, cortical pyramidal neurons begin to connect locally through transient connections in the subplate while they also begin to project axons that are myelinated by oligodendrocytes to form the cortical white matter. Errors in network connectivity can cause many forms of epilepsy, both de novo or secondary to other malformations along with ASD and schizophrenia. Errors of axonal projection lead to large scale connectivity defects like agenesis of corpus callosum. Toward the end of the second trimester, a combination of increased progenitor and neuronal numbers and rapidly expanding neuronal networks begins to generate physical stresses that contribute to the appearance of the main gyri. Over the course of the third trimester the secondary and tertiary gyrification of the cortex is established. Failure of gyrification may occur at any developmental stage leading to a range of malformations such as lissencephaly, polymicrogyria or pachygyria. Inhibitory interneurons migrate from ventrally located ganglionic eminences and appear in the cortex early in the second trimester. They migrate tangentially in the cortex along the marginal zone or in the subplate and SVZ and then move radially along the RG scaffold to integrate into the cortical circuits. Human interneurons continue to migrate into the cortex for a prolonged period through birth and early infancy. Failures of interneuron development, such as abnormal migration, arborization or maturation, can cause disinhibition within the cortical circuits resulting in epilepsy and cognitive dysfunction. Malformations of Cortical Development (MCD) (shown schematically at the bottom) arise at different stages along development. MZ, marginal zone; CP, cortical plate; IZ, intermediate zone, oSVZ, outer subventricular zone; iSVZ, inner sub-ventricular zone; VZ, ventricular zone; NE, neuroepithelium; RG, radial glia.

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