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

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 81
Author(s):  
Sebastian Curti ◽  
Federico Davoine ◽  
Antonella Dapino
Keyword(s):  
Molecular Mechanisms ◽  
Mammalian Brain ◽  
Synaptic Membrane ◽  
Electrical Transmission ◽  
Electrical Synapses ◽  
Electrophysiological Properties ◽  
Theoretical Evidence ◽  
Circuit Function ◽  
Lateral Excitation

Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals, they are mostly composed of the protein connexin36. 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 such as 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 the gap junction resistance, as well as on its functional interaction with the electrophysiological properties of coupled neurons. In particular, voltage and ligand gated 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 Response to coincident inputs in electrically coupled primary afferents is heterogeneous and is enhanced by H-current (IH) modulation

2019 ◽  
Vol 122 (1) ◽  
pp. 151-175
Author(s):  
Federico Davoine ◽  
Sebastian Curti
Keyword(s):  
Neuronal Excitability ◽  
Signal To Noise Ratio ◽  
Electrical Coupling ◽  
Primary Afferents ◽  
Coincidence Detection ◽  
Mammalian Brain ◽  
Electrical Transmission ◽  
Electrical Synapses ◽  
Electrophysiological Properties ◽  
Cationic Current

Electrical synapses represent a widespread modality of interneuronal communication in the mammalian brain. These contacts, by lowering the effectiveness of random or temporally uncorrelated inputs, endow circuits of coupled neurons with the ability to selectively respond to simultaneous depolarizations. This mechanism may support coincidence detection, a property involved in sensory perception, organization of motor outputs, and improvement signal-to-noise ratio. While the role of electrical coupling is well established, little is known about the contribution of the cellular excitability and its modulations to the susceptibility of groups of neurons to coincident inputs. Here, we obtained dual whole cell patch-clamp recordings of pairs of mesencephalic trigeminal (MesV) neurons in brainstem slices from rats to evaluate coincidence detection and its determinants. MesV neurons are primary afferents involved in the organization of orofacial behaviors whose cell bodies are electrically coupled mainly in pairs through soma-somatic gap junctions. We found that coincidence detection is highly heterogeneous across the population of coupled neurons. Furthermore, combined electrophysiological and modeling approaches reveal that this heterogeneity arises from the diversity of MesV neuron intrinsic excitability. Consistently, increasing these cells’ excitability by upregulating the hyperpolarization-activated cationic current ( IH) triggered by cGMP results in a dramatic enhancement of the susceptibility of coupled neurons to coincident inputs. In conclusion, the ability of coupled neurons to detect coincident inputs is critically shaped by their intrinsic electrophysiological properties, emphasizing the relevance of neuronal excitability for the many functional operations supported by electrical transmission in mammals. NEW & NOTEWORTHY We show that the susceptibility of pairs of coupled mesencephalic trigeminal (MesV) neurons to coincident inputs is highly heterogenous and depends on the interaction between electrical coupling and neuronal excitability. Additionally, upregulating the hyperpolarization-activated cationic current ( IH) by cGMP results in a dramatic increase of this susceptibility. The IH and electrical synapses have been shown to coexist in many neuronal populations, suggesting that modulation of this conductance could represent a common strategy to regulate circuit operation supported by electrical coupling.

scholarly journals Wnt-Frizzled Signaling Regulates Activity-Mediated Synapse Formation

2021 ◽  
Vol 14 ◽  
Author(s):  
Samuel Teo ◽  
Patricia C. Salinas
Keyword(s):  
Wnt Signaling ◽  
Neuronal Activity ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Model Systems ◽  
Mammalian Brain ◽  
Excitatory Synapses ◽  
Wnt Ligands

The formation of synapses is a tightly regulated process that requires the coordinated assembly of the presynaptic and postsynaptic sides. Defects in synaptogenesis during development or in the adult can lead to neurodevelopmental disorders, neurological disorders, and neurodegenerative diseases. In order to develop therapeutic approaches for these neurological conditions, we must first understand the molecular mechanisms that regulate synapse formation. The Wnt family of secreted glycoproteins are key regulators of synapse formation in different model systems from invertebrates to mammals. In this review, we will discuss the role of Wnt signaling in the formation of excitatory synapses in the mammalian brain by focusing on Wnt7a and Wnt5a, two Wnt ligands that play an in vivo role in this process. We will also discuss how changes in neuronal activity modulate the expression and/or release of Wnts, resulting in changes in the localization of surface levels of Frizzled, key Wnt receptors, at the synapse. Thus, changes in neuronal activity influence the magnitude of Wnt signaling, which in turn contributes to activity-mediated synapse formation.

scholarly journals The Neurobiology of Selenium: Looking Back and to the Future

2021 ◽  
Vol 15 ◽  
Author(s):  
Ulrich Schweizer ◽  
Simon Bohleber ◽  
Wenchao Zhao ◽  
Noelia Fradejas-Villar
Keyword(s):  
Cell Biology ◽  
Molecular Mechanisms ◽  
Human Genetics ◽  
Epileptic Seizures ◽  
Cell Types ◽  
Mammalian Brain ◽  
The Individual ◽  
The Brain ◽  
Looking Back

Eighteen years ago, unexpected epileptic seizures in Selenop-knockout mice pointed to a potentially novel, possibly underestimated, and previously difficult to study role of selenium (Se) in the mammalian brain. This mouse model was the key to open the field of molecular mechanisms, i.e., to delineate the roles of selenium and individual selenoproteins in the brain, and answer specific questions like: how does Se enter the brain; which processes and which cell types are dependent on selenoproteins; and, what are the individual roles of selenoproteins in the brain? Many of these questions have been answered and much progress is being made to fill remaining gaps. Mouse and human genetics have together boosted the field tremendously, in addition to traditional biochemistry and cell biology. As always, new questions have become apparent or more pressing with solving older questions. We will briefly summarize what we know about selenoproteins in the human brain, glance over to the mouse as a useful model, and then discuss new questions and directions the field might take in the next 18 years.

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.

scholarly journals Amino acid substitutions in the FXYD motif enhance phospholemman-induced modulation of cardiac L-type calcium channels

2010 ◽  
Vol 299 (5) ◽  
pp. C1203-C1211 ◽  
Author(s):  
Kai Guo ◽  
Xianming Wang ◽  
Guofeng Gao ◽  
Congxin Huang ◽  
Keith S. Elmslie ◽  
...  
Keyword(s):  
Amino Acid ◽  
Calcium Channels ◽  
Molecular Mechanisms ◽  
Channel Gating ◽  
Fine Tuning ◽  
Amino Acid Substitutions ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
Kinetics Of

We have found that phospholemman (PLM) associates with and modulates the gating of cardiac L-type calcium channels (Wang et al., Biophys J 98: 1149–1159, 2010). The short 17 amino acid extracellular NH2-terminal domain of PLM contains a highly conserved PFTYD sequence that defines it as a member of the FXYD family of ion transport regulators. Although we have learned a great deal about PLM-dependent changes in calcium channel gating, little is known regarding the molecular mechanisms underlying the observed changes. Therefore, we investigated the role of the PFTYD segment in the modulation of cardiac calcium channels by individually replacing Pro-8, Phe-9, Thr-10, Tyr-11, and Asp-12 with alanine (P8A, F9A, T10A, Y11A, D12A). In addition, Asp-12 was changed to lysine (D12K) and cysteine (D12C). As expected, wild-type PLM significantly slows channel activation and deactivation and enhances voltage-dependent inactivation (VDI). We were surprised to find that amino acid substitutions at Thr-10 and Asp-12 significantly enhanced the ability of PLM to modulate CaV1.2 gating. T10A exhibited a twofold enhancement of PLM-induced slowing of activation, whereas D12K and D12C dramatically enhanced PLM-induced increase of VDI. The PLM-induced slowing of channel closing was abrogated by D12A and D12C, whereas D12K and T10A failed to impact this effect. These studies demonstrate that the PFXYD motif is not necessary for the association of PLM with CaV1.2. Instead, since altering the chemical and/or physical properties of the PFXYD segment alters the relative magnitudes of opposing PLM-induced effects on CaV1.2 channel gating, PLM appears to play an important role in fine tuning the gating kinetics of cardiac calcium channels and likely plays an important role in shaping the cardiac action potential and regulating Ca2+ dynamics in the heart.

The Role of ASIC1a in Epilepsy: A Potential Therapeutic Target

2021 ◽  
Vol 19 ◽  
Author(s):  
Yu Cheng ◽  
Wuqiong Zhang ◽  
Yue Li ◽  
Ting Jiang ◽  
Buhajar Mamat ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Brain Diseases ◽  
Mammalian Brain ◽  
Acid Sensing Ion Channels ◽  
Promising Therapeutic Target ◽  
Pathological Mechanism ◽  
Tissue Acidosis ◽  
Epileptogenic Foci

Background: Epilepsy represents one of the most common brain diseases among humans. Tissue acidosis is a common phenomenon in epileptogenic foci. This said, its roles in epileptogenesis remain unclear. Acid-sensing ion channel-1a (ASIC1a) represents a potential way to assess new therapies. ASIC1a, mainly expressed in the mammalian brain, is a type of protein-gated cation channel. It has been shown to play an important role in the pathological mechanism of various diseases, including stroke, epilepsy, and multiple sclerosis. Methods: Data were collected from Web of Science, Medline, PubMed, through searching for these keywords: "Acid-sensing ion channels 1a" or "ASIC1a" and "epilepsy" or "seizure". Results: The role of ASIC1a in epilepsy remains controversial; it may represent a promising therapeutic target of epilepsy. Conclusion:This review is intended to provide an overview of the structure, trafficking, and molecular mechanisms of ASIC1a in order to further elucidate the role of ASIC1a in epilepsy.

scholarly journals Opioids potentiate electrical transmission at mixed synapses on the Mauthner cell

2015 ◽  
Vol 114 (1) ◽  
pp. 689-697 ◽  
Author(s):  
Roger Cachope ◽  
Alberto E. Pereda
Keyword(s):  
Opioid Receptors ◽  
Mammalian Brain ◽  
Mu Opioid Receptors ◽  
Electrical Transmission ◽  
Electrical Synapses ◽  
Mu Opioid ◽  
Mauthner Cell ◽  
Connexin 36 ◽  
Mixed Synapses ◽  
Lateral Dendrite

Opioid receptors were shown to modulate a variety of cellular processes in the vertebrate central nervous system, including synaptic transmission. While the effects of opioid receptors on chemically mediated transmission have been extensively investigated, little is known of their actions on gap junction-mediated electrical synapses. Here we report that pharmacological activation of mu-opioid receptors led to a long-term enhancement of electrical (and glutamatergic) transmission at identifiable mixed synapses on the goldfish Mauthner cells. The effect also required activation of both dopamine D1/5 receptors and postsynaptic cAMP-dependent protein kinase A, suggesting that opioid-evoked actions are mediated indirectly via the release of dopamine from varicosities known to be located in the vicinity of the synaptic contacts. Moreover, inhibitory inputs situated in the immediate vicinity of these excitatory synapses on the lateral dendrite of the Mauthner cell were not affected by activation of mu-opioid receptors, indicating that their actions are restricted to electrical and glutamatergic transmissions co-existing at mixed contacts. Thus, as their chemical counterparts, electrical synapses can be a target for the modulatory actions of the opioid system. Because gap junctions at these mixed synapses are formed by fish homologs of the neuronal connexin 36, which is widespread in mammalian brain, it is likely that this regulatory property applies to electrical synapses elsewhere as well.

scholarly journals GABA—from Inhibition to Cognition: Emerging Concepts

2017 ◽  
Vol 24 (5) ◽  
pp. 501-515 ◽  
Author(s):  
T. Schmidt-Wilcke ◽  
E. Fuchs ◽  
K. Funke ◽  
A. Vlachos ◽  
F. Müller-Dahlhaus ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Brain Regions ◽  
Mammalian Brain ◽  
Resonance Spectroscopy ◽  
Inhibitory Neurotransmitter ◽  
Electrophysiological Properties ◽  
Potential Strategy ◽  
The One ◽  
And Behavior

Neural functioning and plasticity can be studied on different levels of organization and complexity ranging from the molecular and synaptic level to neural circuitry of whole brain networks. Across neuroscience different methods are being applied to better understand the role of various neurotransmitter systems in the evolution of perception and cognition. GABA is the main inhibitory neurotransmitter in the adult mammalian brain and, depending on the brain region, up to 25% of the total number of cortical neurons are GABAergic interneurons. At the one end of the spectrum, GABAergic neurons have been accurately described with regard to cell morphological, molecular, and electrophysiological properties; at the other end researchers try to link GABA concentrations in specific brain regions to human behavior using magnetic resonance spectroscopy. One of the main challenges of modern neuroscience currently is to integrate knowledge from highly specialized subfields at distinct biological scales into a coherent picture that bridges the gap between molecules and behavior. In the current review, recent findings from different fields of GABA research are summarized delineating a potential strategy to develop a more holistic picture of the function and role of GABA.

scholarly journals Dynamic Control of Synaptic Adhesion and Organizing Molecules in Synaptic Plasticity

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Gabby Rudenko
Keyword(s):  
Information Transfer ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Scale Up ◽  
Autism Spectrum ◽  
Synaptic Activity ◽  
Mammalian Brain ◽  
Synaptic Membrane ◽  
Protein Partners

Synapses play a critical role in establishing and maintaining neural circuits, permitting targeted information transfer throughout the brain. A large portfolio of synaptic adhesion/organizing molecules (SAMs) exists in the mammalian brain involved in synapse development and maintenance. SAMs bind protein partners, forming trans-complexes spanning the synaptic cleft or cis-complexes attached to the same synaptic membrane. SAMs play key roles in cell adhesion and in organizing protein interaction networks; they can also provide mechanisms of recognition, generate scaffolds onto which partners can dock, and likely take part in signaling processes as well. SAMs are regulated through a portfolio of different mechanisms that affect their protein levels, precise localization, stability, and the availability of their partners at synapses. Interaction of SAMs with their partners can further be strengthened or weakened through alternative splicing, competing protein partners, ectodomain shedding, or astrocytically secreted factors. Given that numerous SAMs appear altered by synaptic activity, in vivo, these molecules may be used to dynamically scale up or scale down synaptic communication. Many SAMs, including neurexins, neuroligins, cadherins, and contactins, are now implicated in neuropsychiatric and neurodevelopmental diseases, such as autism spectrum disorder, schizophrenia, and bipolar disorder and studying their molecular mechanisms holds promise for developing novel therapeutics.

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