A new mechanism of synapse elimination
The immediate early gene Arc mediates activity-dependent synapse elimination
Graduate School of Medicine / Faculty of Medicine
Disorder in proper neural circuit formation during development is thought to underlie the pathogenesis of schizophrenia and neurodevelopmental diseases. Neural circuits are shaped by activity-dependent elimination of unnecessary synapses during postnatal development. This process is known as synapse elimination and is widely considered to be a critical step in creating mature neural circuits. Neural activity has been shown to be essential for synapse elimination, but the underlying mechanisms remain largely unknown.
Professor Masanobu Kano and his colleagues at the Graduate School of Medicine have reported that the immediate early gene Arc, one of a class of genes that respond transiently and rapidly to cellular stimuli, mediates activity-dependent synapse elimination in the developing cerebellum. First, they showed that the elevation of Purkinje cell activity in the mouse cerebellum accelerated climbing fiber synapse elimination. Then, they elucidated that the expression of Arc induced by Ca2+ influx into Purkinje cells was crucial for the acceleration of synapse elimination. Furthermore, they demonstrated that Arc is essential for accomplishing synapse elimination by removing the redundant climbing fiber synapses on the cell bodies of Purkinje cells.
Disordered expression of Arc has recently been reported in several mouse models of neurodevelopmental diseases, including Fragile X syndrome and tuberous sclerosis. This study may provide a new approach to unraveling the pathogenesis of such diseases in the light of synapse elimination.
This work was published in Neuron on June 19, 2013. This study was supported by Grants-in-Aid for Scientific Research and the Strategic Research Program for Brain Sciences (Development of biomarker candidates for social behavior) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
Press release [PDF] (Japanese)
Takayasu Mikuni, Naofumi Uesaka, Hiroyuki Okuno, Hirokazu Hirai, Karl Deisseroth, Haruhiko Bito, Masanobu Kano,
“Arc/Arg3.1 is a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum”,
Neuron 78, (2013/6/19):1024?1035, doi: 10.1016/j.neuron.2013.04.036.