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Neuronal profilins in health and disease: Relevance for spine plasticity and Fragile X syndrome

Significance Neuronal morphology is tightly linked to the actin cytoskeleton, which provides stability for synapses while retaining the potential for changes during learning and memory processes (synaptic plasticity). Despite biochemical similarity, isoforms of the small actin-binding protein profilin perform astonishingly diverse tasks in neurons, influencing actin dynamics in an opposing manner. Although the ubiquitous isoform profilin1 supports synaptogenesis, the evolutionary more recent and brain-specific isoform profilin2a mediates synapse function and plasticity. Moreover, we show that in mammalia, only profilin1 is bound by Fragile X mental retardation protein, and therefore is most likely crucial in the cause of and in the devastating outcome of Fragile X syndrome, one of the most common forms of inherited cognitive impairment. Learning and memory, to a large extent, depend on functional changes at synapses. Actin dynamics orchestrate the formation of synapses, as well as their stabilization, and the ability to undergo plastic changes. Hence, profilins are of key interest as they bind to G-actin and enhance actin polymerization. However, profilins also compete with actin nucleators, thereby restricting filament formation. Here, we provide evidence that the two brain isoforms, profilin1 (PFN1) and PFN2a, regulate spine actin dynamics in an opposing fashion, and that whereas both profilins are needed during synaptogenesis, only PFN2a is crucial for adult spine plasticity. This finding suggests that PFN1 is the juvenile isoform important during development, whereas PFN2a is mandatory for spine stability and plasticity in mature neurons. In line with this finding, only PFN1 levels are altered in the mouse model of the developmental neurological disorder Fragile X syndrome. This finding is of high relevance because Fragile X syndrome is the most common monogenetic cause for autism spectrum disorder. Indeed, the expression of recombinant profilins rescued the impairment in spinogenesis, a hallmark in Fragile X syndrome, thereby linking the regulation of actin dynamics to synapse development and possible dysfunction.