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Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior

Understanding the mechanisms underlying the many forms of vertebrate behavior is a central objective of neuroscience and, although studied extensively at the cellular and circuit levels, very little is known about the underlying molecular evolutionary events. How did genome evolution give rise to the many forms of learning, emotional behavior and motor functions and generate the subtlety of synaptic regulation that is manifest in the mammalian brain?

Two genome duplications early in the vertebrate lineage expanded gene families, including GluN2 subunits of the NMDA receptor. Diversification between the four mammalian GluN2 proteins occurred primarily at their intracellular C-terminal domains (CTDs). To identify shared ancestral functions and diversified subunit-specific functions, the authors exchanged the exons encoding the GluN2A (also known as Grin2a) and GluN2B (also known as Grin2b) CTDs in two knock-in mice and analyzed the mice's biochemistry, synaptic physiology, and multiple learned and innate behaviors. The eight behaviors were genetically separated into four groups, including one group comprising three types of learning linked to conserved GluN2A/B regions. In contrast, the remaining five behaviors exhibited subunit-specific regulation. GluN2A/B CTD diversification conferred differential binding to cytoplasmic MAGUK proteins and differential forms of long-term potentiation. These data indicate that vertebrate behavior and synaptic signaling acquired increased complexity from the duplication and diversification of ancestral GluN2 genes.

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