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.he immense computational power of the central nervous system depends on the formation of functional neuronal networks, which are further refined and adapted to environmental changes by processes of neuronal plasticity throughout the entire life span of an individual. The majority of synapses in highly plastic regions, such as the neocortex and hippocampus, are located at dendritic spines, tiny protoplasmatic membrane protrusions that build the postsynaptic compartment. Changes in spine shape are directly associated with the dynamic actin cytoskeleton, which is highly enriched in dendritic spines (1-6). In fact, up to 80% of actin filaments turn over in less than 2 min in the spine head (7). Hence, an understanding of the detailed molecular machinery and identification of key molecules that control actin polymerization in space and time will help to reveal details of spine function and plasticity, and might eventually also provide a better understanding of neurological disorders characterized by defects in spinogenesis and spine maintenance (8, 9).The small actin-binding protein profilin-present in the mammalian CNS in two different isoforms, profilin1 (PFN1) and profilin2a (PFN2a) (10)-has been described as such a promising candidate because its activity-dependent translocation into dendritic spines could be shown both in vitro and in vivo (11-13). However, recent studies exploiting knockout animals for either PFN1 or PFN2a demonstrated a surprising lack of a spine phenotype for both isoforms (14, 15). One explanation might reside in the crucial importance of tightly restricted actin dynamics for virtually all aspects of neuronal function that might be preserved in knockout animals by means of compensational effects acting on the ...