Paralogs of the Calcium-Dependent Activator Protein for Secretion Differentially Regulate Synaptic Transmission and Peptide Secretion in Sensory Neurons

Shaib, Ali; Staudt, Angelina; Harb, Ali; Klose, Margarete; Shaaban, Ahmed; Schirra, Claudia; Mohrmann, Ralf; Rettig, Jens; Becherer, Ute

doi:10.3389/fncel.2018.00304

Cited by 15 publications

(31 citation statements)

References 65 publications

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“…There is evidence for involvement of SNAREs [soluble N -ethyl maleimide (NEM)-sensitive factor attachment protein receptor protein family] (Sudhof, 2014) in release from magnocellular dendrites (Schwab et al, 2001; de Kock et al, 2003; Ovsepian and Dolly, 2011). Results from studies on CAPS2-dependant neuropeptide release from soma of dorsal root ganglion neurons (Bost et al, 2017; Shaib et al, 2018) may also be relevant for dendritic/somatic release in the brain. Galanin may be released from soma and dendrites in the LC (Pieribone et al, 1995; Vila-Porcile et al, 2009) (Figure 6).…”

Section: Galanin Inhibits Rat Locus Coeruleus Neuronsmentioning

confidence: 99%

Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness

Hökfelt

Barde

et al. 2018

Front. Neural Circuits

108

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Neuropeptides are auxiliary messenger molecules that always co-exist in nerve cells with one or more small molecule (classic) neurotransmitters. Neuropeptides act both as transmitters and trophic factors, and play a role particularly when the nervous system is challenged, as by injury, pain or stress. Here neuropeptides and coexistence in mammals are reviewed, but with special focus on the 29/30 amino acid galanin and its three receptors GalR1, -R2 and -R3. In particular, galanin’s role as a co-transmitter in both rodent and human noradrenergic locus coeruleus (LC) neurons is addressed. Extensive experimental animal data strongly suggest a role for the galanin system in depression–like behavior. The translational potential of these results was tested by studying the galanin system in postmortem human brains, first in normal brains, and then in a comparison of five regions of brains obtained from depressed people who committed suicide, and from matched controls. The distribution of galanin and the four galanin system transcripts in the normal human brain was determined, and selective and parallel changes in levels of transcripts and DNA methylation for galanin and its three receptors were assessed in depressed patients who committed suicide: upregulation of transcripts, e.g., for galanin and GalR3 in LC, paralleled by a decrease in DNA methylation, suggesting involvement of epigenetic mechanisms. It is hypothesized that, when exposed to severe stress, the noradrenergic LC neurons fire in bursts and release galanin from their soma/dendrites. Galanin then acts on somato-dendritic, inhibitory galanin autoreceptors, opening potassium channels and inhibiting firing. The purpose of these autoreceptors is to act as a ‘brake’ to prevent overexcitation, a brake that is also part of resilience to stress that protects against depression. Depression then arises when the inhibition is too strong and long lasting – a maladaption, allostatic load, leading to depletion of NA levels in the forebrain. It is suggested that disinhibition by a galanin antagonist may have antidepressant activity by restoring forebrain NA levels. A role of galanin in depression is also supported by a recent candidate gene study, showing that variants in genes for galanin and its three receptors confer increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events. In summary, galanin, a neuropeptide coexisting in LC neurons, may participate in the mechanism underlying resilience against a serious and common disorder, MDD. Existing and further results may lead to an increased understanding of how this illness develops, which in turn could provide a basis for its treatment.

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Section: Galanin Inhibits Rat Locus Coeruleus Neuronsmentioning

confidence: 99%

Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness

Hökfelt

Barde

et al. 2018

Front. Neural Circuits

108

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“…While hsa-miR-302a-5p is essential for neuronal differentiation and neural tube closure the present study for the first time hints toward the implication of the miR-25 family in nociceptor development and suppression of synapse machinery related genes (94)(95)(96)(97). Yet, it is unclear how the exocytotic release machinery from these two vesicle types in nociceptive neurons is differentially regulated, wherein synaptic transmission and neuropeptide release are equally important (98). To further investigate timepoint specific mRNA and miRNA regulation, we developed the open access NOCICEPTRA tool to extract expression patterns and time trajectories of miRNAs and their target gene space for mechanistic studies.…”

Section: Differentiation Of the Synaptic Release Machinerymentioning

confidence: 71%

NOCICEPTRA: Gene and microRNA signatures and their trajectories characterizing human iPSC-derived nociceptor maturation

Zeidler

Kummer

Schoepf

et al. 2021

Preprint

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Nociceptors are primary afferent neurons serving the reception of acute pain but also the transit into maladaptive pain disorders. Since native human nociceptors are hardly available for mechanistic functional research, and rodent models do not necessarily mirror human pathologies in all aspects, human iPSC-derived nociceptors (iDN) offer superior advantages as a human model system. Unbiased mRNA::microRNA co-sequencing, immunofluorescence staining and qPCR validations, revealed expression trajectories as well as miRNA target spaces throughout the transition of pluripotent cells into iDNs. mRNA and miRNA candidates emerged as regulatory hubs for neurite outgrowth, synapse development and ion channel expression. The exploratory data analysis tool NOCICEPTRA is provided as a containerized platform to retrieve experimentally determined expression trajectories, and to query custom gene sets for pathway and disease enrichments. Querying NOCICEPTRA for marker genes of cortical neurogenesis revealed distinct similarities and differences for cortical and peripheral neurons. The platform provides a public domain neuroresource to exploit the entire data sets and explore miRNA and mRNA as hubs regulating human nociceptor differentiation and function.

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“…All experimental procedures involving animals were performed according to guidelines established by the Animal Studies Committee at Washington University in St Louis. Homozygous Synaptobrevin2-mRFP knock-in mice (kindly provided by Dr. Jens Rettig, Saarland University) 13 and PSD95-mVenus knock-in mice (kindly provided by Dr. Haining Zhong, Oregon Health and Science University) 14 were cross bred to produce double heterozygous transgenic mice that express mRFP labeled Synaptobrevein2 (VAMP2) and mVenus labeled PSD95 at endogenous levels [13][14][15] . Homozygous 3xTg-AD transgenic mice 24 were obtained from The Jackson Laboratory and were bred in our animal facility.…”

Section: Methodsmentioning

confidence: 99%

“…Both PSD95-mVenus and VAMP2-mRFP are under endogenous regulatory control. Of critical importance, both lines of mice show normal synaptic structure and function [13][14][15] , which may be more physiologically relevant to the native synaptic properties in vitro compared with other methods using transfection based overexpressed synaptic proteins 10,16 . PSD95 and VAMP2 are two well-studied and widely-used synaptic markers and can persist at the synapse for several days [17][18][19] .…”

mentioning

confidence: 99%

Live Neuron High-Content Screening Reveals Synaptotoxic Activity in Alzheimer Mouse Model Homogenates

Jiang

Esparza

Zhong

et al. 2020

Sci Rep

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Accurate quantification of synaptic changes is essential for understanding the molecular mechanisms of synaptogenesis, synaptic plasticity, and synaptic toxicity. Here we demonstrate a robust high-content imaging method for the assessment of synaptic changes and apply the method to brain homogenates from an Alzheimer's disease mouse model. Our method uses serial imaging of endogenous fluorescent labeled presynaptic VAMP2 and postsynaptic PSD95 in long-term cultured live primary neurons in 96 well microplates, and uses automatic image analysis to quantify the number of colocalized mature synaptic puncta for the assessment of synaptic changes in live neurons. As a control, we demonstrated that our synaptic puncta assay is at least 10-fold more sensitive to the toxic effects of glutamate than the Mtt assay. Using our assay, we have compared synaptotoxic activities in size-exclusion chromatography fractioned protein samples from 3xTg-AD mouse model brain homogenates. Multiple synaptotoxic activities were found in high and low molecular weight fractions. Amyloid-beta immunodepletion alleviated some but not all of the synaptotoxic activities. Although the biochemical entities responsible for the synaptotoxic activities have yet to be determined, these proof-of-concept results demonstrate that this novel assay may have many potential mechanistic and therapeutic applications. Synapses are asymmetric intercellular junctions that permit neurons to transmit electrical or chemical signals to other neurons. Dysregulated synaptic function, abnormal synaptic plasticity and synaptic loss are involved in many neurodevelopmental and neurodegenerative disorders, in particular Alzheimer's disease (AD) 1-3. As the most common dementing disorder in the elderly, AD is tightly correlated with synaptic loss in vulnerable brain regions, which has led to the hypothesis that loss of synaptic terminals is a key event in early cognitive decline 4. Accurate quantification of mammalian central nervous system synaptic changes is important for understanding the molecular mechanisms of synaptogenesis, synaptic plasticity, and developmental or pathological synapse elimination. As many neurodegenerative conditions are known to affect synapses, quantification of synapses is also critical for identifying synaptotoxic factors and for screening of potential therapeutic agents. However, few efficient methods are available for this purpose. Electrophysiology, electron microscopy, and most light microscopy approaches are costly, time-consuming, and labor-intensive. Unbiased, high throughput screening for synaptotoxic substances in brain disorders such as AD would provide a better understanding of the disease process and an opportunity to identifying new therapeutic targets and drug candidates. High content screening (HCS) combines the efficiency of high-throughput, multi-well plate-based techniques with quantitative image analysis at subcellular resolution 5-7. Recent advances in HCS have made high-throughput analysis of synaptic changes in live neurons po...

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Paralogs of the Calcium-Dependent Activator Protein for Secretion Differentially Regulate Synaptic Transmission and Peptide Secretion in Sensory Neurons

Cited by 15 publications

References 65 publications

Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness

Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness

NOCICEPTRA: Gene and microRNA signatures and their trajectories characterizing human iPSC-derived nociceptor maturation

Live Neuron High-Content Screening Reveals Synaptotoxic Activity in Alzheimer Mouse Model Homogenates

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