Abstract
The phenotype of neurons and their connections depend on complex genetic and epigenetic processes that regulate the expression of genes in the nucleus during development and throughout life. Here we examined the distribution of nuclear chromatin patters in relation to the epigenetic landscape, phenotype and connections of neurons with a focus on the primate cerebral cortex. We show that nuclear patterns of chromatin in cortical neurons are related to neuron size and cortical connections. Moreover, we point to evidence that reveals an orderly sequence of events during development, linking chromatin and gene expression patterns, neuron morphology, function, and connections across cortical areas and layers. Based on this synthesis, we posit that systematic studies of changes in chromatin patterns and epigenetic marks across cortical areas will provide novel insights on the development and evolution of cortical networks, and their disruption in connectivity disorders of developmental origin, like autism. Achieving this requires embedding and interpreting genetic, transcriptional, and epigenetic studies within a framework that takes into consideration distinct types of neurons, local circuit interactions, and interareal pathways. These features vary systematically across cortical areas in parallel with laminar structure and are differentially affected in disorders. Finally, based on evidence that autism-associated genetic polymorphisms are especially prominent in excitatory neurons and connectivity disruption affects mostly limbic cortices, we employ this systematic approach to propose novel, targeted studies of projection neurons in limbic areas to elucidate the emergence and time-course of developmental disruptions in autism.
Highlights
Neurons are highly specialized cells that perform a wide variety of functions
Which are the cortical neurons most likely involved in autism spectrum disorders (ASD)? Genetic studies have described a large variety of polymorphisms in individuals with ASD [see Samaco et al, 2005; Hogart et al, 2007; Weiss et al, 2009; Gilman et al, 2011; Hallmayer et al, 2011; Hussman et al, 2011; Shulha et al, 2012a; reviewed in Geschwind (2011)], which are typically found in open chromatin regions of cortical excitatory neurons (Lake et al, 2017; Fan et al, 2018), most of which likely are projection neurons
The relationship of nuclear chromatin patterns in cortical neurons with cell morphology and connections can be traced to development
Summary
Neurons are highly specialized cells that perform a wide variety of functions. Functional specialization depends on morphological, biochemical and physiological features of neurons. We conclude that the nuclear pattern of chromatin and the epigenetic landscape in neurons across areas in the adult cortex is related to cortical connections, a relationship that can be traced to development.
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