Somatic mutations in disorders with disrupted brain connectivity

Abstract

Mutations occur during cell division in all somatic lineages. Because neurogenesis persists throughout human life, somatic mutations in the brain arise during development and accumulate with the aging process. The human brain consists of 100 billion neurons that form an extraordinarily intricate network of connections to achieve higher level cognitive functions. Due to this network architecture, perturbed neuronal functions are rarely restricted to a focal area; instead, they are often spread via the neuronal network to affect other connected areas. Although somatic diversity is an evident feature of the brain, the extent to which somatic mutations affect the neuronal structure and function and their contribution to neurological disorders associated with disrupted brain connectivity remain largely unexplored. Notably, recent reports indicate that brain somatic mutations can indeed play a critical role that leads to the structural and functional abnormalities of the brain observed in several neurodevelopmental disorders. Here, I review the extent and significance of brain somatic mutations and provide my perspective regarding these mutations as potential molecular lesions underlying relatively common conditions with disrupted brain connectivity. Moreover, I discuss emerging technical platforms that will facilitate the detection of low-frequency somatic mutations and validate the biological functions of the identified mutations in the context of brain connectivity.

Figure 1

Regions of neural stem cells and the occurrence of somatic mutations in the human brain. (a) The figure shows the subventricular zones (red) along with the wall of the lateral ventricle and the dentate gyrus (blue) in the hippocampus, from which neural stem cells have been isolated in the human brain. (b) The schematic figure shows the concept of a mosaic brain with somatic mutations that can arise during development or over aging. Depending on the timing and location of the mutations, somatic mutations may be present in the regional brain structures of various sizes or even in the entire brain.

Figure 2

Low-level somatic mutations in a focal brain region cause the synchronized electrical discharge of the entire brain network. (a) Post-op MRI and pathology from focal cortical dysplasia II (FCDII) with intractable epilepsy show the resected brain region (white arrow) and the scattered dysplastic neurons (black arrow) with the mTOR-activating somatic mutation (p.Leu2427Pro). Within the resected brain tissue, deep WES detected 6.9% mutated alleles. Scale bar, 50 μm (b) In utero electroporation of the mTOR p.Leu2427Pro mutant plasmid into the focal area of the embryonic brain (E14) followed by monitoring of the mTOR mutant expression using a GFP reporter. Imaging of the GFP signal in the coronal sections of an electroporated mouse brain at ~3 months of age shows a small fraction of GFP-positive cells expressing the mutated mTOR, accounting for 1.30% of all the DAPI-positive cells in the left cerebral cortex. Scale bar, 500 μm. (c) The in utero electroporated mouse exhibits a synchronized epileptic discharge with behavioral seizures by video-electroencephalograph (EEG) monitoring. LF, left frontal electrode; LT, left temporal electrode; RF, right frontal electrode; RT, right temporal electrode. (d) The schematic figure shows how somatic mutations in a focal region can affect the function of the entire brain via the brain connectivity. (a, c) are adopted from ref. . GFP, green fluorescent protein; MRI, magnetic resonance imaging.