A Novel Optical Quantal Analysis of Miniature Events Reveals Enhanced Frequency Following Amyloid β Exposure

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.

Amyloid-β in Alzheimer’s disease – front and centre after all?

“…Using pharmacological and optogenetic approaches in cultured brain slices, we confirmed that repeated administration of an NMDAR-dependent low frequency stimulation LTD induction protocol that is based on one used in physiological plasticity studies (but delivered in excess) indeed drives phosphorylation of endogenous tau at pathology-associated residues. We further implicated Aβ-induced increases in presynaptic probability of neurotransmitter release, which have been reported by us and others previously [ 126–128 ] in generating the low-frequency synaptic activity required to induce LTD [ 129 ]. This study provides evidence for a direct mechanistic link between the two key proteins of AD ( Figure 2 ) and suggests that LTD-associated proteins might constitute potential therapeutic targets.…”

Friend or Foe? The Varied Faces of Homeostatic Synaptic Plasticity in Neurodegenerative Disease

“…While this account of AD pathogenesis is highly consistent with existing experimental data obtained in a variety of model systems and with clinical observations, there is an alternative possible interpretation of the current evidence. It remains possible that postsynaptic weakening is a primary event, possibly the result of pathological signalling downstream of postsynaptic binding of pathogenic conformations of Aβ (Um et al, 2012;Kim et al, 2013), and this engages mechanisms of HSP to enhance presynaptic function and thereby synaptic activity in order to preserve synaptic strength (Taylor et al, 2020). Although this view seems much less favoured by the available evidence, it would again place HSP in an important role in pathogenesis, albeit as a maladaptive response to a pathological insult rather than as a primary, upstream event.…”