Desperately Seeking a Synapse

Abstract

During development of the central nervous system, both presynaptic and postsynaptic structures exhibit rapid actin-based movements, which are believed to play a role in the formation and rearrangement of developing synapses. The role of neuronal activity, which influences many neurodevelopmental processes, in regulating these movements is controversial. Tashiro et al. used two-photon microscopy to investigate the role of neuronal activity on the motility of filopodia on the terminals of mossy fibers extending from granule cells labeled with green fluorescent protein in neonatal mouse hippocampal slice cultures. Filopodia in fresh slices and in slices cultured for 2 weeks were highly motile; filopodial motility, which correlated with free extracellular space and was inversely associated with contact with target cells, was greatly reduced after 3 weeks in culture. Pharmacological analysis indicated that this reduction in motility depended on activation of kainate receptors. Kainate showed a dose-dependent bidirectional effect on filopodial motility, with relatively low doses enhancing motility and higher doses inhibiting it. Pharmacological analysis indicated that different downstream pathways mediated kainate's activation and inhibition of filopodial motility; activation was inhibited by blockade of voltage-sensitive calcium channels, whereas inhibition was sensitive to tetrodotoxin, which blocks sodium channels, and pertussis toxin, which inhibits some heterotrimeric guanine-nucleotide-binding protein pathways. Synaptically released glutamate enhanced motility in 2-week cultures but inhibited it in older cultures. The authors proposed a two-step model in which glutamate released from growing filopodia enhances motility in filopodia searching for synaptic connections, but stabilizes "mature" filopodia that have begun to form synaptic connections. A. Tashiro, A. Dunaevsky, R. Blazeski, C. A. Mason, R. Yuste, Bidirectional regulation of hippocampal mossy fiber filopodial motility by kainate receptors: A two-step model of synaptogenesis. Neuron 38 , 773-784 (2003). [Online Journal]