Neurons contact each other mostly by synaptic transmission at synapses. Synaptic transmission is mediated by calcium-triggered vesicle fusion with the plasma membrane, which releases transmitter molecules that act on postsynaptic transmitter receptors. My goal is to improve our understanding on the cellular and molecular mechanisms underlying synaptic vesicle exocytosis, which are the building block for synaptic transmission and thus the signaling process in the neuronal network. My progress in the last year is mostly in the study of how calcium channels control transmitter release at the single active zone. Synapses with different release properties serve for different neuronal circuit functions. What makes synapses heterogeneous in release is poorly understood. We have developed a technique to isolate the release face of the nerve terminal and to perform cell-attached recordings at single active zones for the first time in the synatpic trnasmission field. This technical breakthrough allowed us to characterize for the first time the basic information of the active zone structure with respect to calcium channels and transmitter release. we found that single active zones contained 5 − 218 (mean:42) calcium channels, 1 −  10 (mean:5) readily releasable vesicles (RRVs), and released 0 − 5 vesicles during a 2 ms depolarization. Large calcium channel number variation caused the wide release strength variation as measured during 2 ms depolarization by critically influencing the RRVs release probability (PRRV) and number. By determining PRRV, the calcium channel number decided whether release is facilitated or depressed during repetitive stimuli. Regulation of the calcium channel density at active zones may thus be a major mechanism to yield synapses with different release properties and short-term plasticity. These findings may reconcile the large differences reported at individual synapses regarding release strength (release of 0,1,or multiple vesicles), PRRV, short-term plasticity, calcium transients, and the requisite calcium channel number for triggering release. In summary, we have discovered a principle by which the strength of a synapse can be designed - control of the calcium channel number at the active zone lead to the control of the synaptic strength. We expect this finding to have wide impact for our study of how synapses with different strengths are designed and developed in the brain.

Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2012
Total Cost
$1,610,334
Indirect Cost
City
State
Country
Zip Code
Wen, Peter J; Grenklo, Staffan; Arpino, Gianvito et al. (2016) Actin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane. Nat Commun 7:12604
Baydyuk, Maryna; Xu, Jianhua; Wu, Ling-Gang (2016) The calyx of Held in the auditory system: Structure, function, and development. Hear Res 338:22-31
Zhao, Wei-Dong; Hamid, Edaeni; Shin, Wonchul et al. (2016) Hemi-fused structure mediates and controls fusion and fission in live cells. Nature 534:548-52
Wu, Xin-Sheng; Lee, Sung Hoon; Sheng, Jiansong et al. (2016) Actin Is Crucial for All Kinetically Distinguishable Forms of Endocytosis at Synapses. Neuron 92:1020-1035
Baydyuk, Maryna; Wu, Xin-Sheng; He, Liming et al. (2015) Brain-derived neurotrophic factor inhibits calcium channel activation, exocytosis, and endocytosis at a central nerve terminal. J Neurosci 35:4676-82
Wu, Ling-Gang; Hamid, Edaeni; Shin, Wonchul et al. (2014) Exocytosis and endocytosis: modes, functions, and coupling mechanisms. Annu Rev Physiol 76:301-31
Xiong, Wei; Chen, Shao-Rui; He, Liming et al. (2014) Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease. Nat Neurosci 17:232-9
Cai, Zhenyu; Jitkaew, Siriporn; Zhao, Jie et al. (2014) Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol 16:55-65
Zhou, Di; Zhang, Zhen; He, Li-Ming et al. (2014) Conversion of fibroblasts to neural cells by p53 depletion. Cell Rep 9:2034-42
Sun, Chong-Kui; Zhou, Di; Zhang, Zhen et al. (2014) Senescence impairs direct conversion of human somatic cells to neurons. Nat Commun 5:4112

Showing the most recent 10 out of 18 publications