Opto-vTrap, an optogenetic trap for reversible inhibition of vesicular release, synaptic transmission, and behavior

Neuron ◽  
2021 ◽  
Author(s):  
Joungha Won ◽  
Yuriy Pankratov ◽  
Minwoo Wendy Jang ◽  
Sunpil Kim ◽  
Yeon Ha Ju ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Reversible Inhibition ◽  
Vesicular Release ◽  
And Behavior

scholarly journals Reexamination of N-terminal domains of Syntaxin-1 in vesicle fusion from central murine synapses

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Gülçin Vardar ◽  
Andrea Salazar-Lázaro ◽  
Marisa M Brockmann ◽  
Marion Weber-Boyvat ◽  
Sina Zobel ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Neurotransmitter Release ◽  
Null Mouse ◽  
General View ◽  
Binding Modes ◽  
Short Term ◽  
Short Term Plasticity ◽  
Open Conformation ◽  
Vesicular Release ◽  
Mouse Model System

Syntaxin-1 (STX1) and Munc18-1 are two requisite components of synaptic vesicular release machinery, so much so synaptic transmission cannot proceed in their absence. They form a tight complex through two major binding modes: through STX1's N-peptide and through STX's closed conformation driven by its Habc- domain. However, physiological roles of these two reportedly different binding modes in synapses are still controversial. Here we characterized the roles of STX1's N-peptide, Habc-domain, and open conformation with and without N-peptide deletion using our STX1-null mouse model system and exogenous reintroduction of STX1A mutants. We show, on the contrary to the general view, that the Habc-domain is absolutely required and N-peptide is dispensable for synaptic transmission. However, STX1A's N-peptide plays a regulatory role, particularly in the Ca2+-sensitivity and the short-term plasticity of vesicular release, whereas STX1's open-conformation governs the vesicle fusogenicity. Strikingly, we also show neurotransmitter release still proceeds when the two interaction modes between STX1A and Munc18-1 are presumably intervened, necessitating a refinement of the conceptualization of STX1A-Munc18-1 interaction.

scholarly journals Early Low-Level Arsenic Exposure Impacts Post-Synaptic Hippocampal Function in Juvenile Mice

Toxics ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 206
Author(s):  
Karl F. W. Foley ◽  
Daniel Barnett ◽  
Deborah A. Cory-Slechta ◽  
Houhui Xia
Keyword(s):  
Synaptic Transmission ◽  
Early Development ◽  
Arsenic Exposure ◽  
Epidemiological Studies ◽  
Learning Deficits ◽  
High Exposure ◽  
Early Life Exposure ◽  
Electrophysiological Recordings ◽  
Vesicular Release ◽  
The Central Nervous System

Arsenic is a well-established carcinogen known to increase mortality, but its effects on the central nervous system are less well understood. Epidemiological studies suggest that early life exposure is associated with learning deficits and behavioral changes. Studies in arsenic-exposed rodents have begun to shed light on potential mechanistic underpinnings, including changes in synaptic transmission and plasticity. However, previous studies relied on extended exposure into adulthood, and little is known about the effect of arsenic exposure in early development. Here, we studied the effects of early developmental arsenic exposure in juvenile mice on synaptic transmission and plasticity in the hippocampus. C57BL/6J females were exposed to arsenic (0, 50 ppb, 36 ppm) via drinking water two weeks prior to mating, with continued exposure throughout gestation and parturition. Electrophysiological recordings were then performed on juvenile offspring prior to weaning. In this paradigm, the offspring are exposed to arsenic indirectly, via the mother. We found that high (36 ppm) and relatively low (50 ppb) arsenic exposure both decreased basal synaptic transmission. A compensatory increase in pre-synaptic vesicular release was only observed in the high-exposure group. These results suggest that indirect, ecologically relevant arsenic exposure in early development impacts hippocampal synaptic transmission and plasticity that could underlie learning deficits reported in epidemiological studies.

scholarly journals Functional interdependence of the actin regulators CAP1 and cofilin1 in control of dendritic spine morphology

2022 ◽  
Author(s):  
Anika Heinze ◽  
Cara Schuldt ◽  
Sharof Khudayberdiev ◽  
Bas van Bommel ◽  
Daniela Hacker ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Dendritic Spines ◽  
Brain Function ◽  
Hippocampal Neurons ◽  
Super Resolution ◽  
Actin Binding ◽  
Spine Morphology ◽  
Actin Organization ◽  
Major Structural Component ◽  
And Behavior

Abstract The vast majority of excitatory synapses are formed on small dendritic protrusions termed dendritic spines. Dendritic spines vary in size and density that are both crucial determinants of excitatory synaptic transmission. Aberrations in spine morphogenesis can compromise brain function and have been associated with neuropsychiatric disorders. Because actin filaments (F-actin) are the major structural component in spines, actin-binding proteins (ABP) that control F-actin dis-/assembly moved into the focus as critical regulators of brain function. Indeed, mouse studies identified the ABP cofilin1 as a key regulator of spine morphology, synaptic transmission and behavior. These studies emphasized the necessity for a tight control of cofilin1 to ensure proper brain function. We report spine enrichment of cyclase-associated protein 1 (CAP1), a conserved multidomain protein with largely unknown physiological functions. Super-resolution microscopy and live cell imaging of CAP1-deficient hippocampal neurons revealed impaired synaptic F-actin organization and dynamics associated with alterations in spine morphology. Mechanistically, we found that CAP1 cooperated with cofilin1 in spines and that its helical folded domain mediated this interaction. Moreover, our data proved functional interdependence of CAP1 and cofilin1 in control of spine morphology. In summary, we identified CAP1 as a novel regulator of the postsynaptic actin cytoskeleton that was essential for synaptic cofilin1 activity.

scholarly journals Altered synaptic connectivity and brain function in mice lacking microglial adapter protein Iba1

2021 ◽  
Author(s):  
Pablo J. Lituma ◽  
Evan Woo ◽  
Bruce F. O’Hara ◽  
Pablo E. Castillo ◽  
Nicholas E. S. Sibinga ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Neurodegenerative Disorders ◽  
Brain Function ◽  
Hippocampal Slices ◽  
Autism Spectrum ◽  
Excitatory Synapse ◽  
Adapter Protein ◽  
Acute Hippocampal Slices ◽  
And Behavior ◽  
Synaptic Pruning

AbstractGrowing evidence indicates that microglia impact brain function by regulating synaptic pruning and formation, as well as synaptic transmission and plasticity. Iba1 (Ionized Ca+2-binding adapter protein 1), encoded by the Allograft inflammatory factor 1 (Aif1) gene, is an actin-interacting protein in microglia. Although Iba1 has long been used as a cellular marker for microglia, its functional role remains unknown. Here, we used global Iba1-deficient (Aif1-/-) mice to characterize microglial activity, synaptic function and behavior. Microglial imaging in acute hippocampal slices and fixed tissues from juvenile mice revealed that Aif1-/- microglia display reductions in ATP-induced motility and ramification, respectively. Biochemical assays further demonstrated that Aif1-/- brain tissues exhibit an altered expression of microglial-enriched proteins associated with synaptic pruning. Consistent with these changes, juvenile Aif1-/- mice displayed deficits in excitatory synapse number and synaptic transmission assessed by neuronal labeling and whole-cell patch-clamp recording in acute hippocampal slices. Unexpectedly, microglial synaptic engulfment capacity was diminished in juvenile Aif1-/- mice. During early postnatal development when synapse formation is a predominant event in the hippocampus, excitatory synapse number was still reduced in Aif1-/- mice. Together these findings support an overall role of Iba1 in excitatory synaptic growth in juvenile mice. Lastly, postnatal synaptic deficits persisted in the adulthood and correlated with significant behavioral changes in adult Aif1-/- mice, which exhibited impairments in object recognition memory and social interaction. These results suggest that Iba1 critically contributes to microglial activity underlying essential neuro-glia developmental processes that may deeply influence behavior.SignificanceAbnormal microglia-neuron interaction is increasingly implicated in neurodevelopmental and neuropsychiatric conditions such as autism spectrum disorders and schizophrenia, as well as in neurodegenerative disorders such as Alzheimer’s disease. This study demonstrates that deletion of the microglia-specific protein Iba1, which has long been utilized as a selective microglial marker but whose role has remained unidentified, results in microglial structural and functional impairments that significantly impact synaptic development and behavior. These findings not only highlight the importance of microglia in brain function but may also suggest that modifying microglial function could provide a therapeutic strategy for treatment of neurodevelopmental, neuropsychiatric and neurodegenerative disorders.

scholarly journals Reexamination of N-terminal domains of Syntaxin-1 in vesicle fusion from central murine synapses

2021 ◽  
Author(s):  
Gülçin Vardar ◽  
Andrea Salazar-Lázaro ◽  
Marisa Brockmann ◽  
Marion Weber-Boyvat ◽  
Sina Zobel ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Null Mouse ◽  
Binary Complex ◽  
General View ◽  
Binding Modes ◽  
Short Term ◽  
Short Term Plasticity ◽  
Open Conformation ◽  
Vesicular Release ◽  
Mouse Model System

AbstractSyntaxin-1 (STX1) and Munc18-1 are two requisite components of synaptic vesicular release machinery, so much so synaptic transmission cannot proceed in their absence. They form a tight binary complex through two major binding modes: one through STX1’s N-peptide, the other through STX1’s closed conformation driven by its Habc-domain. However, physiological roles of these two reportedly different binding modes in synapses are still controversial. Here we characterized the roles of STX1’s N-peptide, Habc-domain, and open conformation with and without N-peptide deletion using our STX1-null mouse model system and exogenous reintroduction of STX1A mutants. We show, on the contrary to the general view, that the Habc-domain is absolutely required and N-peptide is dispensable for synaptic transmission. However, STX1’s N-peptide plays a regulatory role, particularly in the Ca2+-sensitivity and the short-term plasticity of vesicular release, whereas STX1’s open conformation governs the vesicle fusogenicity. Strikingly, we also show that neurotransmitter release still proceeds when both the interaction modes between STX1 and Munc18-1 are presumably intervened together, necessitating a refinement of the conceptualization of STX1–Munc18-1 interaction.

scholarly journals General Anesthesia During Neurodevelopment Reduces Autistic Behavior in Adult BTBR Mice, a Murine Model of Autism

2021 ◽  
Vol 15 ◽  
Author(s):  
Jianchen Cui ◽  
Jiho Park ◽  
Xianshu Ju ◽  
Yulim Lee ◽  
Boohwi Hong ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Critical Period ◽  
Repetitive Behavior ◽  
Sevoflurane Anesthesia ◽  
Autistic Behavior ◽  
Inhibitory Synaptic Transmission ◽  
Synaptic Changes ◽  
Bdnf Signaling ◽  
And Behavior

Preclinical studies suggest that repeated exposure to anesthetics during a critical period of neurodevelopment induces long-term changes in synaptic transmission, plasticity, and behavior. Such changes are of great concern, as similar changes have also been identified in animal models of neurodevelopmental disorders (NDDs) such as autism. Because of overlapping synaptic changes, it is also possible that anesthetic exposures have a more significant effect in individuals diagnosed with NDDs. Thus, we evaluated the effects of early, multiple anesthetic exposures in BTBR mice, an inbred strain that displays autistic behavior. We discovered that three cycles of sevoflurane anesthesia (2.5%, 1 h) with 2-h intervals between each exposure in late postnatal BTBR mice did not aggravate, but instead improved pathophysiological mechanisms involved with autistic behavior. Sevoflurane exposures restored E/I balance (by increasing inhibitory synaptic transmission), and increased mitochondrial respiration and BDNF signaling in BTBR mice. Most importantly, such changes were associated with reduced autistic behavior in BTBR mice, as sociability was increased in the three-chamber test and repetitive behavior was reduced in the self-grooming test. Our results suggest that anesthetic exposures during neurodevelopment may affect individuals diagnosed with NDDs differently.

scholarly journals Gαq signals via Trio RhoGEF to modulate synaptic transmission in a model serotonin motor circuit in C. elegans

2021 ◽  
Author(s):  
Pravat Dhakal ◽  
Sana Chaudhry ◽  
Kevin M. Collins
Keyword(s):  
Synaptic Transmission ◽  
Phorbol Esters ◽  
Rho Gtpase ◽  
Motor Behavior ◽  
Egg Laying ◽  
Genetic Rescue ◽  
C Elegans ◽  
Effector Pathways ◽  
And Behavior ◽  
Exogenous Treatment

Activated Gαq signals through Phospholipase-Cβ (PLCβ) and Trio, a Rho GTPase exchange factor (RhoGEF), but how these two effector pathways promote synaptic transmission remains poorly understood. We used the egg-laying behavior circuit of C. elegans to determine whether PLCβ and Trio mediate serotonin and Gαq signaling through independent or related biochemical pathways. Using genetic rescue experiments, we find that PLCβ functions in neurons while Trio functions in both neurons and the postsynaptic vulval muscles. While Gαq, PLCβ, and Trio RhoGEF mutants all fail to lay eggs in response to serotonin, optogenetic stimulation of the serotonin releasing HSN command neurons restores egg laying only in PLCβ mutants. Vulval muscle Ca2+ activity remained in PLCβ mutants but was eliminated in strong Gαq and Trio RhoGEF mutants. Exogenous treatment with Phorbol esters that mimic Diacylglycerol (DAG), a product of PIP2 hydrolysis, rescued egg-laying circuit activity and behavior defects of Gαq signaling mutants, suggesting both Phospholipase C and Rho signaling promote synaptic transmission and egg-laying via DAG production. DAG has been proposed to activate effectors including UNC-13, however, we find that phorbol esters, but not serotonin, stimulate egg laying in unc-13 mutants. Together, these results show that serotonin signaling through Gαq and PLCβ modulates UNC-13 activity to promote neurotransmitter release. Serotonin also signals through Gαq, Trio RhoGEF, and an unidentified PMA-responsive effector to promote postsynaptic muscle excitability. Thus, the same neuromodulator serotonin can signal in distinct cells and effector pathways to activate a motor behavior circuit.

scholarly journals Effect of Alcohol on Hippocampal-Dependent Plasticity and Behavior: Role of Glutamatergic Synaptic Transmission

2020 ◽  
Vol 13 ◽  
Author(s):  
Rodrigo G. Mira ◽  
Matias Lira ◽  
Cheril Tapia-Rojas ◽  
Daniela L. Rebolledo ◽  
Rodrigo A. Quintanilla ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Dependent Plasticity ◽  
Glutamatergic Synaptic Transmission ◽  
And Behavior

How Homo economicus lost her mind and how we can revive her

2018 ◽  
Vol 41 ◽  
Author(s):  
Peter DeScioli
Keyword(s):  
Economic Thought ◽  
History Of Economic Thought ◽  
Homo Economicus ◽  
Economic Theories ◽  
Target Article ◽  
History Of ◽  
The Mind ◽  
And Behavior

AbstractThe target article by Boyer & Petersen (B&P) contributes a vital message: that people have folk economic theories that shape their thoughts and behavior in the marketplace. This message is all the more important because, in the history of economic thought, Homo economicus was increasingly stripped of mental capacities. Intuitive theories can help restore the mind of Homo economicus.

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