Reduced release probability prevents vesicle depletion and transmission failure at dynamin mutant synapses.

Department of Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 02/2012; 109(8):E515-23. DOI: 10.1073/pnas.1121626109
Source: PubMed

ABSTRACT Endocytic recycling of synaptic vesicles after exocytosis is critical for nervous system function. At synapses of cultured neurons that lack the two "neuronal" dynamins, dynamin 1 and 3, smaller excitatory postsynaptic currents are observed due to an impairment of the fission reaction of endocytosis that results in an accumulation of arrested clathrin-coated pits and a greatly reduced synaptic vesicle number. Surprisingly, despite a smaller readily releasable vesicle pool and fewer docked vesicles, a strong facilitation, which correlated with lower vesicle release probability, was observed upon action potential stimulation at such synapses. Furthermore, although network activity in mutant cultures was lower, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity was unexpectedly increased, consistent with the previous report of an enhanced state of synapsin 1 phosphorylation at CaMKII-dependent sites in such neurons. These changes were partially reversed by overnight silencing of synaptic activity with tetrodotoxin, a treatment that allows progression of arrested endocytic pits to synaptic vesicles. Facilitation was also counteracted by CaMKII inhibition. These findings reveal a mechanism aimed at preventing synaptic transmission failure due to vesicle depletion when recycling vesicle traffic is backed up by a defect in dynamin-dependent endocytosis and provide new insight into the coupling between endocytosis and exocytosis.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the auditory system, sounds are processed in parallel frequency-tuned circuits, beginning in the cochlea. Activity of auditory nerve fibers reflects this frequency-specific topographic pattern, known as tonotopy, and imparts frequency tuning onto their postsynaptic target neurons in the cochlear nucleus. In birds, cochlear nucleus magnocellularis (NM) neurons encode the temporal properties of acoustic stimuli by "locking" discharges to a particular phase of the input signal. Physiological specializations exist in gradients corresponding to the tonotopic axis in NM that reflect the characteristic frequency (CF) of their auditory nerve fiber inputs. One feature of NM neurons that has not been investigated across the tonotopic axis is short-term synaptic plasticity. NM offers a rather homogeneous population of neurons with a distinct topographical distribution of synaptic properties that is ideal for the investigation of specialized synaptic plasticity. Here we demonstrate for the first time that short-term synaptic depression (STD) is expressed topographically, where unitary high CF synapses are more robust with repeated stimulation. Correspondingly, high CF synapses drive spiking more reliably than their low CF counterparts. We show that postsynaptic AMPA receptor desensitization does not contribute to the observed difference in STD. Further, rate of recovery from depression, a presynaptic property, does not differ tonotopically. Rather, we show that another presynaptic feature, readily releasable pool (RRP) size, is tonotopically distributed and inversely correlated with vesicle release probability. Mathematical model results demonstrate that these properties of vesicle dynamics are sufficient to explain the observed tonotopic distribution of STD.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 01/2014; 34(4):1314-24. DOI:10.1523/JNEUROSCI.3073-13.2014 · 6.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adrenal neuroendocrine chromaffin cells receive excitatory synaptic input from the sympathetic nervous system and secrete hormones into the peripheral circulation. Under basal sympathetic tone, modest amounts of freely-soluble catecholamine are selectively released through a restricted fusion pore formed between the secretory granule and plasma membrane. Upon activation of the sympatho-adrenal stress reflex, elevated stimulation drives fusion pore expansion, resulting in increased catecholamine secretion and facilitating release of co-packaged peptide hormones. Thus, regulated expansion of the secretory fusion pore is a control point for differential-hormone release of the sympatho-adrenal stress response. Previous work has shown syndapin 1 deletion to alter transmitter release and dynamin 1/syndapin 1 interaction as necessary for coupled endocytosis in neurons. Dynamin has also been shown to be involved in regulation of fusion pore expansion in neuroendocrine chromaffin cells through an activity-dependent association with syndapin. However, it is not known which syndapin isoform(s) contribute to pore dynamics in neuroendocrine cells. Nor is it known at what stage of the secretion process dynamin/syndapin associate to modulate pore expansion. Here we investigate the expression and localization of syndapin isoforms and determine which are involved in mediating fusion pore expansion. We show all syndapin isoforms are expressed in the adrenal medulla. Mutation of the SH3 dynamin-binding domain of all syndapin isoforms shows that fusion pore expansion and catecholamine release are limited specifically by the mutation of syndapin 3. The mutation also disrupts targeting of syndapin 3 to the cell periphery. Syndapin 3 exists in a persistent colocalized state with dynamin 1.
    AJP Cell Physiology 02/2014; 306(9). DOI:10.1152/ajpcell.00291.2013 · 3.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Synaptic vesicle recycling is one of the best-studied cellular pathways. Many of the proteins involved are known, and their interactions are becoming increasingly clear. However, as for many other pathways, it is still difficult to understand synaptic vesicle recycling as a whole. While it is generally possible to point out how synaptic reactions take place, it is not always easy to understand what triggers or controls them. Also, it is often difficult to understand how the availability of the reaction partners is controlled: how the reaction partners manage to find each other in the right place, at the right time. I present here an overview of synaptic vesicle recycling, discussing the mechanisms that trigger different reactions, and those that ensure the availability of reaction partners. A central argument is that synaptic vesicles bind soluble cofactor proteins, with low affinity, and thus control their availability in the synapse, forming a buffer for cofactor proteins. The availability of cofactor proteins, in turn, regulates the different synaptic reactions. Similar mechanisms, in which one of the reaction partners buffers another, may apply to many other processes, from the biogenesis to the degradation of the synaptic vesicle.
    The EMBO Journal 04/2014; 33(8). DOI:10.1002/embj.201386357 · 10.75 Impact Factor

Full-text (2 Sources)

Available from
Jul 2, 2014