scholarly journals Molecular mechanisms regulating presynaptic neurotransmitter release and their impact on neuronal circuit function

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Samuel M Young
Keyword(s):  
Neurotransmitter Release ◽  
Molecular Mechanisms ◽  
Neuronal Circuit ◽  
Circuit Function

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

scholarly journals Molecular Mechanisms of Fast Neurotransmitter Release

2018 ◽  
Vol 47 (1) ◽  
pp. 469-497 ◽  
Author(s):  
Axel T. Brunger ◽  
Ucheor B. Choi ◽  
Ying Lai ◽  
Jeremy Leitz ◽  
Qiangjun Zhou
Keyword(s):  
Synaptic Vesicle ◽  
Neurotransmitter Release ◽  
High Speed ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Vesicle Fusion ◽  
Synaptic Proteins ◽  
Functional Studies ◽  
Protein Receptors ◽  
Synaptic Vesicle Fusion

This review summarizes current knowledge of synaptic proteins that are central to synaptic vesicle fusion in presynaptic active zones, including SNAREs (soluble N-ethylmaleimide sensitive factor attachment protein receptors), synaptotagmin, complexin, Munc18 (mammalian uncoordinated-18), and Munc13 (mammalian uncoordinated-13), and highlights recent insights in the cooperation of these proteins for neurotransmitter release. Structural and functional studies of the synaptic fusion machinery suggest new molecular models of synaptic vesicle priming and Ca2+-triggered fusion. These studies will be a stepping-stone toward answering the question of how the synaptic vesicle fusion machinery achieves such high speed and sensitivity.

scholarly journals Fife organizes synaptic vesicles and calcium channels for high-probability neurotransmitter release

2016 ◽  
Vol 216 (1) ◽  
pp. 231-246 ◽  
Author(s):  
Joseph J. Bruckner ◽  
Hong Zhan ◽  
Scott J. Gratz ◽  
Monica Rao ◽  
Fiona Ukken ◽  
...  
Keyword(s):  
Neural Plasticity ◽  
Active Zone ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Motor Behavior ◽  
Molecular Organization ◽  
Electrophysiological Studies ◽  
Circuit Function ◽  
Synaptic Vesicle Release ◽  
Ca2 Channels

The strength of synaptic connections varies significantly and is a key determinant of communication within neural circuits. Mechanistic insight into presynaptic factors that establish and modulate neurotransmitter release properties is crucial to understanding synapse strength, circuit function, and neural plasticity. We previously identified Drosophila Piccolo-RIM-related Fife, which regulates neurotransmission and motor behavior through an unknown mechanism. Here, we demonstrate that Fife localizes and interacts with RIM at the active zone cytomatrix to promote neurotransmitter release. Loss of Fife results in the severe disruption of active zone cytomatrix architecture and molecular organization. Through electron tomographic and electrophysiological studies, we find a decrease in the accumulation of release-ready synaptic vesicles and their release probability caused by impaired coupling to Ca2+ channels. Finally, we find that Fife is essential for the homeostatic modulation of neurotransmission. We propose that Fife organizes active zones to create synaptic vesicle release sites within nanometer distance of Ca2+ channel clusters for reliable and modifiable neurotransmitter release.

Temperature and neuronal circuit function: compensation, tuning and tolerance

2012 ◽  
Vol 22 (4) ◽  
pp. 724-734 ◽  
Author(s):  
R Meldrum Robertson ◽  
Tomas GA Money
Keyword(s):  
Neuronal Circuit ◽  
Circuit Function

scholarly journals Function and Plasticity of Electrical Synapses in the Mammalian Brain: Role of Non-Junctional Mechanisms

2021 ◽  
Author(s):  
Sebastian Curti ◽  
Federico Davoine ◽  
Antonella Dapino
Keyword(s):  
Molecular Mechanisms ◽  
Mammalian Brain ◽  
Synaptic Membrane ◽  
Electrical Transmission ◽  
Electrical Synapses ◽  
Electrophysiological Properties ◽  
Voltage Dependent ◽  
Theoretical Evidence ◽  
Circuit Function

Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals are mostly composed of the protein connexin (Cx)36. Circuits of electrically coupled neurons are widespread in these animals, plus, experimental and theoretical evidence supports the notion that, beyond synchronicity, these circuits are able to perform sophisticated operations like lateral excitation and inhibition, noise reduction, as well as the ability to selectively respond upon coincident excitatory inputs. Although once considered stereotyped and unmodifiable, we now know that electrical synapses are subject to modulation and, by reconfiguring neural circuits, these modulations can alter relevant operations. The strength of electrical synapses depends on gap junction conductance, as well as on its functional interaction with the electrophysiological properties of coupled neurons. In particular, voltage dependent channels of the non-synaptic membrane critically determine the efficacy of transmission at these contacts. Consistently, modulatory actions on these channels have been shown to represent relevant mechanisms of plasticity of electrical synaptic transmission. Here we review recent evidence on the regulation of electrical synapses of mammals, the underlying molecular mechanisms, and the possible ways in which they affect circuit function.

scholarly journals Complexin induces a conformational change at the membrane-proximal C-terminal end of the SNARE complex

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ucheor B Choi ◽  
Minglei Zhao ◽  
Yunxiang Zhang ◽  
Ying Lai ◽  
Axel T Brunger
Keyword(s):  
Conformational Change ◽  
Single Molecule ◽  
Neurotransmitter Release ◽  
Plasma Membranes ◽  
Molecular Mechanisms ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Snare Complex ◽  
Spontaneous Release ◽  
Trans Conformation

Complexin regulates spontaneous and activates Ca2+-triggered neurotransmitter release, yet the molecular mechanisms are still unclear. Here we performed single molecule fluorescence resonance energy transfer experiments and uncovered two conformations of complexin-1 bound to the ternary SNARE complex. In the cis conformation, complexin-1 induces a conformational change at the membrane-proximal C-terminal end of the ternary SNARE complex that specifically depends on the N-terminal, accessory, and central domains of complexin-1. The complexin-1 induced conformation of the ternary SNARE complex may be related to a conformation that is juxtaposing the synaptic vesicle and plasma membranes. In the trans conformation, complexin-1 can simultaneously interact with a ternary SNARE complex via the central domain and a binary SNARE complex consisting of syntaxin-1A and SNAP-25A via the accessory domain. The cis conformation may be involved in activation of synchronous neurotransmitter release, whereas both conformations may be involved in regulating spontaneous release.

Internalization of Carbon Nano-onions by Hippocampal Cells Preserves Neuronal Circuit Function and Recognition Memory

2018 ◽  
Vol 10 (20) ◽  
pp. 16952-16963 ◽  
Author(s):  
Massimo Trusel ◽  
Michele Baldrighi ◽  
Roberto Marotta ◽  
Francesca Gatto ◽  
Mattia Pesce ◽  
...  
Keyword(s):  
Recognition Memory ◽  
Neuronal Circuit ◽  
Circuit Function

scholarly journals Cadherins regulate nuclear topography and function of developing ocular motor circuitry

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Athene Knüfer ◽  
Giovanni Diana ◽  
Gregory S Walsh ◽  
Jonathan DW Clarke ◽  
Sarah Guthrie
Keyword(s):  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Ocular Motor ◽  
Optokinetic Reflex ◽  
Classical Cadherins ◽  
Oculomotor Neurons ◽  
Dorsal Cells ◽  
And Function ◽  
Circuit Function

In the vertebrate central nervous system, groups of functionally related neurons, including cranial motor neurons of the brainstem, are frequently organised as nuclei. The molecular mechanisms governing the emergence of nuclear topography and circuit function are poorly understood. Here we investigate the role of cadherin-mediated adhesion in the development of zebrafish ocular motor (sub)nuclei. We find that developing ocular motor (sub)nuclei differentially express classical cadherins. Perturbing cadherin function in these neurons results in distinct defects in neuronal positioning, including scattering of dorsal cells and defective contralateral migration of ventral subnuclei. In addition, we show that cadherin-mediated interactions between adjacent subnuclei are critical for subnucleus position. We also find that disrupting cadherin adhesivity in dorsal oculomotor neurons impairs the larval optokinetic reflex, suggesting that neuronal clustering is important for co-ordinating circuit function. Our findings reveal that cadherins regulate distinct aspects of cranial motor neuron positioning and establish subnuclear topography and motor function.

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