Myosin II regulates activity dependent compensatory endocytosis at central synapses

Indra Chandrasekar, James E. Huettner, Stephen G. Turney, Paul C. Bridgman

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Recent evidence suggests that endocytosis, not exocytosis, can be rate limiting for neurotransmitter release at excitatory CNS synapses during sustained activity and therefore may be a principal determinant of synaptic fatigue. At low stimulation frequencies, the probability of synaptic release is linked to the probability of synaptic retrievalsuchthatevokedrelease results in proportional retrievalevenfor release of singlesynaptic vesicles. The exact mechanism by which the retrieval rates are coupled to release rates,knownas compensatory endocytosis, remains unknown. Here we show that inactivation of presynaptic myosin II (MII) decreases the probability of synaptic retrieval. To be able to differentiate between the presynaptic and postsynaptic functions of MII, we developed a live cell substrate patterning technique to create defined neural circuits composedof smallnumbersofembryonicmousehippocampalneuronsandphysically isolatedfromthesurroundingculture. Acuteapplication of blebbistatin to inactivate MII in circuits strongly inhibited evoked release but not spontaneous release. In circuits incorporating both control and MIIB knock-out cells, loss of presynaptic MIIB function correlated with a large decrease in the amplitude of evoked release. Using activitydependentmarkersFM1-43andhorseradish peroxidase,wefoundthatMIIinactivation greatlyslowedvesicular replenishment of the recycling pool but did not impede synaptic release. These results indicate that MII-driven tension or actin dynamics regulate the major pathway for synaptic vesicle retrieval. Changes in retrieval rates determine the size of the recycling pool. The resulting effect on release rates, in turn, brings about changes in synaptic strength.

Original languageEnglish
Pages (from-to)16131-16145
Number of pages15
JournalJournal of Neuroscience
Volume33
Issue number41
DOIs
StatePublished - Oct 14 2013

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