Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies

Alten, Barış; Zhou, Qiuhong; Shin, Ok-Ho; Esquivies, Luis; Lin, Pei-Yi; White, K. Ian; Sun, Runbin; Chung, Wendy K.; Monteggia, Lisa M.; Brunger, Axel T.; Kavalali, Ege T.

doi:10.1016/j.neuron.2020.10.012

Cited by 50 publications

(64 citation statements)

References 71 publications

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“…Previous studies have shown that munc18‐1 overexpression alone does not alter miniature endplate potential amplitudes at the neuromuscular junction and causes an increase in the RRP size of cultured hippocampal neurons which would be predicted to blunt synaptic depression, an effect opposite to our results (Toonen et al., 2006). Similarly, hippocampal neurons with a 50% reduction in SNAP‐25 expression have no changes in mEPSC amplitudes or frequencies and exhibit an increase in PPR, suggesting a decrease in release probability, which also contrasts with our results (Alten et al., 2021).…”

Section: Discussioncontrasting

confidence: 99%

RNA editing‐mediated regulation of calcium‐dependent activator protein for secretion (CAPS1) localization and its impact on synaptic transmission

Shumate

Tas

Kavalali

et al. 2021

Journal of Neurochemistry

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Calcium-dependent activator protein for secretion 1 (CAPS1) is a SNARE accessory protein that facilitates formation of the SNARE complex to enable neurotransmitter release. Messenger RNAs encoding CAPS1 are subject to a site-specific adenosineto-inosine (A-to-I) editing event resulting in a glutamate-to-glycine (E-to-G) substitution in the C-terminal domain of the encoded protein product. The C-terminal domain of CAPS1 is necessary for its synaptic enrichment and Cadps RNA editing has been shown previously to enhance the release of neuromodulatory transmitters. Using mutant mouse lines engineered to solely express CAPS1 protein isoforms encoded by either the non-edited or edited Cadps transcript, primary neuronal cultures from mouse hippocampus were used to explore the effect of Cadps editing on neurotransmission and CAPS1 synaptic localization at both glutamatergic and GABAergic synapses. While the editing of Cadps does not alter baseline evoked neurotransmission, it enhances short-term synaptic plasticity, specifically short-term depression, at inhibitory synapses. Cadps editing also alters spontaneous inhibitory neurotransmission. Neurons that solely express edited Cadps have a greater proportion of synapses that contain CAPS1 than neurons that solely express non-edited Cadps for both glutamatergic and GABAergic synapses. Editing of Cadps transcripts is regulated by neuronal activity, as global network stimulation increases the extent of transcripts edited in wild-type hippocampal neurons, whereas chronic network silencing decreases the level of Cadps editing. Taken together, these results provide key insights into the importance of Cadps editing in modulating its own synaptic localization, as well as the modulation of neurotransmission at inhibitory synapses in hippocampal neurons.

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Section: Discussioncontrasting

confidence: 99%

RNA editing‐mediated regulation of calcium‐dependent activator protein for secretion (CAPS1) localization and its impact on synaptic transmission

Shumate

Tas

Kavalali

et al. 2021

Journal of Neurochemistry

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“…However recent evidence suggests that spontaneous release has a specialized role in both regulating synapse and circuit development in addition to the maintenance of synapse dynamics in several organisms ( Huntwork and Littleton, 2007 ; Choi et al, 2014 ; Andreae and Burrone, 2015 ; Banerjee et al, 2021 ). Furthermore recent findings on the role of aberrant spontaneous neurotransmission in neurological disease as well as ketamine’s rapid antidepressant action arising from spontaneous release modulation reflect the utility of different modes of release at the synapse ( Autry et al, 2011 ; Alten et al, 2021 ). Ultimately revealing spontaneous neurotransmission as an autonomous mode of release involved in a broad range of functions ( Kavalali and Monteggia, 2020 ).…”

Section: Spontaneous Releasementioning

confidence: 99%

Nano-Organization at the Synapse: Segregation of Distinct Forms of Neurotransmission

Guzikowski

Kavalali

2021

Front. Synaptic Neurosci.

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Synapses maintain synchronous, asynchronous, and spontaneous modes of neurotransmission through distinct molecular and biochemical pathways. Traditionally a single synapse was assumed to have a homogeneous organization of molecular components both at the active zone and post-synaptically. However, recent advancements in experimental tools and the further elucidation of the physiological significance of distinct forms of release have challenged this notion. In comparison to rapid evoked release, the physiological significance of both spontaneous and asynchronous neurotransmission has only recently been considered in parallel with synaptic structural organization. Active zone nanostructure aligns with postsynaptic nanostructure creating a precise trans-synaptic alignment of release sites and receptors shaping synaptic efficacy, determining neurotransmission reliability, and tuning plasticity. This review will discuss how studies delineating synaptic nanostructure create a picture of a molecularly heterogeneous active zone tuned to distinct forms of release that may dictate diverse synaptic functional outputs.

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“…Moreover, spontaneous release can activate distinct downstream signaling pathways compared to evoked release (Horvath et al, 2021). Spontaneous release has also been implicated in mechanisms underlying neuropsychiatric and neurological diseases as well as their treatments separate from evoked release (Alten et al, 2021; Autry et al, 2011; Kavalali and Monteggia, 2012).…”

Section: Introductionmentioning

confidence: 99%

Probing the segregation of evoked and spontaneous neurotransmission via photobleaching and recovery of a fluorescent glutamate sensor

Wang

Chanaday

Monteggia

et al. 2021

Preprint

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Synapses maintain both action potential-evoked and spontaneous neurotransmitter release, however, organization of these two forms of release within an individual synapse remains unclear. Here, we used photobleaching properties of iGluSnFR, a fluorescent probe that detects glutamate, to investigate the subsynaptic organization of evoked and spontaneous release. In non-neuronal cells and neuronal dendrites, iGluSnFR fluorescence is intensely photobleached and recovers via diffusion of non-photobleached probes within 10-seconds. After photobleaching, while evoked iGluSnFR events could be rapidly suppressed, their recovery required several hours. In contrast, iGluSnFR responses to spontaneous release were comparatively resilient to photobleaching, unless the complete pool of iGluSnFR was activated by glutamate perfusion. This differential effect of photobleaching on different modes of neurotransmission is consistent with a subsynaptic organization where sites of evoked glutamate release are clustered and corresponding iGluSnFR probes are diffusion restricted, while spontaneous release sites are broadly spread across a synapse with readily diffusible iGluSnFR probes.

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Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies

Cited by 50 publications

References 71 publications

RNA editing‐mediated regulation of calcium‐dependent activator protein for secretion (CAPS1) localization and its impact on synaptic transmission

RNA editing‐mediated regulation of calcium‐dependent activator protein for secretion (CAPS1) localization and its impact on synaptic transmission

Nano-Organization at the Synapse: Segregation of Distinct Forms of Neurotransmission

Probing the segregation of evoked and spontaneous neurotransmission via photobleaching and recovery of a fluorescent glutamate sensor

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