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Abstract
Non-evoked miniature release of neurotransmitters is increasingly recognized as playing an important role in neural function and is implicated in synaptic plasticity, metaplasticity, and homeostasis. Spontaneous miniature release events (minis) are usually measured electrophysiologically by recording the miniature postsynaptic currents (mEPSCs) that they evoke. However, this indirect technique can be confounded by changes within the postsynaptic neuron. Here, using the fluorescent probe SynaptopHluorin 2×, we have developed an optical method for the measurement of minis that enables direct assessment of release events. We use the technique to reveal that the frequency of minis following incubation of hippocampal neurons with Amyloid β oligomers (Aβo) is increased. Electrophysiological mEPSC recordings obtained under the same conditions report a decrease in frequency, with the discrepancy likely due to Aβo-induced changes in quantal size. Optical quantal analysis of minis may therefore have a role in the study of minis in both normal physiology and disease, as it can circumvent potential confounds caused by postsynaptic changes.
Highlights
It is well documented that, in addition to neurotransmitter release evoked by action potential (AP) invasion into boutons, neurons occasionally release vesicles of neurotransmitter in a non-evoked or spontaneous manner
Spontaneous miniature excitatory postsynaptic currents amplitude and frequency reflect previous activity at the synapse (Turrigiano et al, 1998; Liu et al, 2000; Bacci et al, 2001), and may play a role in metaplasticity, with increased miniature postsynaptic currents (mEPSCs) amplitude and frequency accompanying long-term potentiation (LTP; Oliet et al, 1996) and lowered mEPSC amplitude and frequency correlating with the strength of Summative Measurement of Miniature Release long-term depression (LTD) induction (Zhang et al, 2005)
Following exposure to diseaserelevant assembly states and concentrations of the Alzheimer’s disease (AD)-associated peptide amyloid β (Aβ), in particular highly pathogenic Aβ oligomers (Aβo; Viola and Klein, 2015), multiple studies have shown that mini frequency is reduced (Kamenetz et al, 2003; Shankar et al, 2007; Nimmrich et al, 2008; Talantova et al, 2013), in one study this reduction was preceded by a short-lived frequency increase (Parodi et al, 2010)
Summary
It is well documented that, in addition to neurotransmitter release evoked by action potential (AP) invasion into boutons, neurons occasionally release vesicles of neurotransmitter in a non-evoked or spontaneous manner. Following exposure to diseaserelevant assembly states and concentrations of the AD-associated peptide amyloid β (Aβ), in particular highly pathogenic Aβ oligomers (Aβo; Viola and Klein, 2015), multiple studies have shown that mini frequency is reduced (Kamenetz et al, 2003; Shankar et al, 2007; Nimmrich et al, 2008; Talantova et al, 2013), in one study this reduction was preceded by a short-lived frequency increase (Parodi et al, 2010) These Aβoinduced changes in mini frequency have usually been explained by a presumed presynaptic weakening over time, there is no direct evidence for this. There is, a well-established process of postsynaptic weakening and depression which begins rapidly following the addition of Aβo (Sheng et al, 2012)
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