Evidence for a relationship between glutamatergic afferent innervation and dendrite growth, and coincidence of developmental periods of maximal dendritogenesis and activity-dependent synaptogenesis14 leaves the question of what is the relationship between synaptogenesis and dendritic growth. In rat cortex, the majority of dendrite growth occurs in the first 3 postnatal weeks and closely parallels the time course of afferent innervation. Likewise, in the cerebellum, Purkinje neuron dendritic growth coincides with innervation from granule cells, and interfering with this afferent innervation causes abnormal Purkinje dendrite formation58,59. In the Xenopus tadpole tectum, neurons undergo extensive dendritic arborization while RGC axons are entering the tectum and forming new synapses to establish the retinotopic map56. Although filopodia are highly dynamic and turnover rapidly, they can possess synapses19,60. Expression of fluorescently tagged components of the pre- and postsynaptic assemblies has proven useful for detecting location of synapses, the time course of synapse formation and elimination, and the relationship between synaptogenesis and dendrite growth. In dissociated hippocampal cultures, presynaptic proteins cluster within 30 min, and postsynaptic proteins cluster within 45 min of axonal contact with dendritic filopodia61. Clusters of the postsynaptic density protein PSD-95 fused to GFP are found to rapidly coalesce, move, and dissociate over a time period of minutes in rat hippocampal organotypic cultures from postnatal day 4 to 762. PSD-95:GFP typically localized in close proximity to clustering of the presynaptic protein synapsin-1, suggesting that PSD-95: GFP clusters are indeed markers of functional synapses. Highly motile filopodia with short lifetimes tend not express PSD-95:GFP clusters, but PSD-95:GFP clusters were found in filopodia that persist62,63. A recent study by Niell and colleagues has extended these studies by using in vivo two-photon time-lapse microscopy to directly image filopodia behavior and clustering of synaptic proteins in developing neurons within the larval zebrafish optic tectum19. In this study, tectal neurons were labeled with the space-filling fluorophore DsRed for imaging filopodial morphology along with PSD-95:GFP to detect synapse locations. Zebrafish tectal neurons were repeatedly imaged using short intervals to capture filopodial motility and PSD-95:GFP clustering over minutes, as well as long-interval imaging to observe cumulative changes in arbor structure. They found that the number of PSD-95:GFP puncta increased in direct relation to dendritic arbor size over 5 days, demonstrating coincidence of morphogenesis and synaptogenesis. Using 20 min-interval imaging for up to 24 h allowed correlation of formation of PSD-95:GFP puncta with filopodial motility. Similar to that described in the Xenopus tadpole tectum25 and acute rat cortical slice13, zebrafish tectal neurons demonstrate highly dynamic dendritic filopodia that continuously extend and retract over a time course of minutes, leading to dendritic arbor remodeling over hours14,20,64. Niell and colleagues found both transient and persistent PSD-95:GFP puncta. PSD-95:GFP puncta appear through de novo coalescence at a specific site and not from the transport of large preassembled puncta as seen in rat hippocampus62,65. These puncta are lost in a similar fashion, by fading away, not moving en masse to new sites. As dendritic arbors mature, the proportion of stable to transient PSD-95 puncta increases. The majority (94%) of new stable PSD-95:GFP puncta appear on filopodia, with few occurring on dendritic shafts, and often more than one puncta will appear on a single filopodia. A functional relationship between synapses and cytoskeletal plasticity is evident from the finding that new filopodia extend from dendritic shafts at sites of stable PSD-95:GFP puncta. How do PSD-95:GFP puncta relate to filopodial motility, stabilization, and dendrite growth? Niell and colleagues observed that newly extending filopodia are devoid of puncta, but puncta appear approximately 30 min following extension if the new process had not retracted in that time. New puncta are dim, but increase in brightness and size with time. Filopodia containing PSD-95:GFP clusters exhibit continued dynamic extension and retraction, but typically do not retract beyond a stabilized PSD-95:GFP puncta. When filopodia with puncta do retract completely, the PSD-95:GFP cluster first disassembles over 20 min prior to retraction. Importantly, they found a direct relationship between puncta and filopodial stabilization. Filopodia stable for more than 1 h invariably possessed at least one puncta. In the developing tectum, filopodia puncta become shaft filopodia when the stabilized filopodia becomes a shaft with additional new filopodia extending from it. These findings demonstrate that dendritic filopodia are involved in both establishing synaptic contact and promoting growth of the dendritic arbor26,31,60. In the synaptotropic model, synaptogenesis and synapse strengthening induce local dendrite stabilization and promote further local growth, while weakened and lost synapses result in morphological retraction66. Since further growth provides additional potential sites for new synapses, synaptotropically driven growth represents a positive feed-forward mechanism to promote dendritic arborization in regions with appropriate innervation.
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