Abstract
The postsynaptic density (PSD) is a protein dense complex on the postsynaptic membrane of excitatory synapses that is implicated in normal nervous system functions such as synaptic plasticity, and also contains an enrichment of proteins involved in neuropsychiatric disorders. It has recently been reported that the genes encoding PSD proteins evolved more slowly than other genes in the human brain, but the underlying evolutionary advantage for this is not clear. Here, we show that cortical gene expression levels could explain most of this effect, indicating that expression level is a primary contributor to the evolution of these genes in the brain. Furthermore, we identify a positive correlation between the expression of PSD genes and cortical layers, with PSD genes being more highly expressed in deep layers, likely as a result of layer-enriched transcription factors. As the cortical layers of the mammalian brain have distinct functions and anatomical projections, our results indicate that the emergence of the unique six-layered mammalian cortex may have provided differential functional constraints on the evolution of PSD genes. More superficial cortical layers contain PSD genes with less constraint and these layers are primarily involved in intracortical projections, connections that may be particularly important for evolved cognitive functions. Therefore, the differential expression and evolutionary constraint of PSD genes in neocortical laminae may be critical not only for neocortical architecture but the cognitive functions that are dependent on this structure.
Highlights
The postsynaptic density (PSD) is a unique complex of the excitatory synapse containing hundreds of proteins, many of which are critical for complex neurological processes such as synaptic plasticity [1,2,3]
We confirmed that PSD genes have lower evolutionary rates than all other genes in the mouse genome
We focused on genes encoding for PSD proteins since these proteins have been strongly implicated in neuropsychiatric disorders [5,30,31]
Summary
The postsynaptic density (PSD) is a unique complex of the excitatory synapse containing hundreds of proteins, many of which are critical for complex neurological processes such as synaptic plasticity [1,2,3]. Recent work has demonstrated that human PSD genes, along with many other genes, are implicated in over 100 neurological and psychiatric diseases, and these genes evolved more slowly when compared to the other genes in the genome, and when compared to other brain-related genes [5] The conservation of these genes in the brain indicates that there are more evolutionary constraints on the sequences of these genes compared to other brain-related genes, but the underlying functional impetus for this finding is not fully understood. Genes in the brain are usually nonuniformly expressed, with specific patterns of gene expression in distinct areas of the brain that include large regional differences [7], and differences in more neuroanatomically refined areas such the neocortical layers [8] Taking this idea one step further, a recent study has shown that there are subregional differences in gene expression among different strains of mice [9], indicating that genetic variation drives additional variation in gene expression. The evolutionary importance of these expression patterns remains unknown
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