scholarly journals Action potential-coupled Rho GTPase signaling drives presynaptic plasticity

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Shataakshi Dube O'Neil ◽  
Bence Rácz ◽  
Walter Evan Brown ◽  
Yudong Gao ◽  
Erik J Soderblom ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Rho Gtpase ◽  
Calcium Influx ◽  
Inhibitory Synapses ◽  
Fluorescence Lifetime Imaging ◽  
Short Term ◽  
Adult Mice ◽  
Rac1 Activity ◽  
Presynaptic Plasticity

In contrast to their postsynaptic counterparts, the contributions of activity-dependent cytoskeletal signaling to presynaptic plasticity remain controversial and poorly understood. To identify and evaluate these signaling pathways, we conducted a proteomic analysis of the presynaptic cytomatrix using in vivo biotin identification (iBioID). The resultant proteome was heavily enriched for actin cytoskeleton regulators, including Rac1, a Rho GTPase that activates the Arp2/3 complex to nucleate branched actin filaments. Strikingly, we find Rac1 and Arp2/3 are closely associated with synaptic vesicle membranes in adult mice. Using three independent approaches to alter presynaptic Rac1 activity (genetic knockout, spatially restricted inhibition, and temporal optogenetic manipulation), we discover that this pathway negatively regulates synaptic vesicle replenishment at both excitatory and inhibitory synapses, bidirectionally sculpting short-term synaptic depression. Finally, we use two-photon fluorescence lifetime imaging to show that presynaptic Rac1 activation is coupled to action potentials by voltage-gated calcium influx. Thus, this study uncovers a previously unrecognized mechanism of actin-regulated short-term presynaptic plasticity that is conserved across excitatory and inhibitory terminals. It also provides a new proteomic framework for better understanding presynaptic physiology, along with a blueprint of experimental strategies to isolate the presynaptic effects of ubiquitously expressed proteins.

scholarly journals Action potential-coupled Rho GTPase signaling drives presynaptic plasticity

2020 ◽  
Author(s):  
Shataakshi Dube ◽  
Bence Rácz ◽  
Walter E. Brown ◽  
Yudong Gao ◽  
Erik J. Soderblom ◽  
...  
Keyword(s):  
Rho Gtpase ◽  
Calcium Influx ◽  
Cell Types ◽  
Inhibitory Synapses ◽  
Fluorescence Lifetime Imaging ◽  
Short Term ◽  
Lifetime Imaging ◽  
Presynaptic Plasticity ◽  
Presynaptic Vesicle

ABSTRACTIn contrast to their postsynaptic counterparts, the contributions of activity-dependent cytoskeletal signaling to presynaptic plasticity remain controversial and poorly understood. To identify and evaluate these signaling pathways, we conducted a proteomic analysis of the presynaptic cytomatrix using in vivo biotin identification (iBioID). The resultant proteome was heavily enriched for actin cytoskeleton regulators, including Rac1, a Rho GTPase that activates the Arp2/3 complex to nucleate branched actin filaments. Strikingly, we find Rac1 and Arp2/3 are closely associated with presynaptic vesicle membranes and negatively regulate synaptic vesicle replenishment at both excitatory and inhibitory synapses. Using optogenetics and fluorescence lifetime imaging, we show this pathway bidirectionally sculpts short-term synaptic depression and that its presynaptic activation is coupled to action potentials by voltage-gated calcium influx. Thus, this study provides a new proteomic framework for understanding presynaptic physiology and uncovers a previously unrecognized mechanism of actin-regulated short-term presynaptic plasticity that is conserved across cell types.

Short-Term Plasticity at Inhibitory Synapses in Rat Striatum and Its Effects on Striatal Output

2001 ◽  
Vol 85 (5) ◽  
pp. 2088-2099 ◽  
Author(s):  
John S. Fitzpatrick ◽  
Garnik Akopian ◽  
John P. Walsh
Keyword(s):  
Action Potentials ◽  
Brain Slices ◽  
Current Injection ◽  
Inhibitory Synapses ◽  
Rat Striatum ◽  
Short Term ◽  
Short Term Plasticity ◽  
Adult Rat ◽  
Glutamate Receptor Antagonists

Two forms of short-term plasticity at inhibitory synapses were investigated in adult rat striatal brain slices using intracellular recordings. Intrastriatal stimulation in the presence of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (20 μM) andd,l-2-amino-5-phosphonovaleric acid (50 μM) produced an inhibitory postsynaptic potential (IPSP) that reversed polarity at −76 ± 1 (SE) mV and was sensitive to bicuculline (30 μM). The IPSP rectified at hyperpolarized membrane potentials due in part to activation of K+ channels. The IPSP exhibited two forms of short-term plasticity, paired-pulse depression (PPD) and synaptic augmentation. PPD lasted for several seconds and was greatest at interstimulus intervals (ISIs) of several hundred milliseconds, reducing the IPSP to 80 ± 2% of its control amplitude at an ISI of 200 ms. Augmentation of the IPSP, elicited by a conditioning train of 15 stimuli applied at 20 Hz, was 119 ± 1% of control when sampled 2 s after the conditioning train. Augmentation decayed with a time constant of 10 s. We tested if PPD and augmentation modify the ability of the IPSP to prevent the generation of action potentials. A train of action potentials triggered by a depolarizing current injection of constant amplitude could be interrupted by stimulation of an IPSP. If this IPSP was the second in a pair of IPSPs, it was less effective in blocking spikes due to PPD. By contrast, augmented IPSPs were more effective in blocking spikes. The same results were achieved when action potentials were triggered by a depolarizing current injection of varying amplitude, a manipulation that produces nearly identical spike times from trial to trial and approximates the in vivo behavior of these neurons. These results demonstrate that short-term plasticity of inhibition can modify the output of the striatum and thus may be an important component of information processing during behaviors that involve the striatum.

scholarly journals Synaptic plasticity of inhibitory synapses onto medial olivocochlear efferent neurons

2022 ◽  
Author(s):  
Lester Torres Cadenas ◽  
Hui Cheng ◽  
Catherine J.C. Weisz
Keyword(s):  
Brain Slices ◽  
Synaptic Depression ◽  
Extracellular Calcium ◽  
Outer Hair Cells ◽  
Inhibitory Synapses ◽  
Short Term ◽  
Sound Stimulation ◽  
Efferent Neurons ◽  
Medial Olivocochlear

The descending auditory system modulates the ascending system at every level. The final descending, or efferent stage, is comprised of lateral olivocochlear (LOC) and medial olivocochlear (MOC) neurons. MOC somata in the ventral brainstem project axons to the cochlea to synapse onto outer hair cells (OHC), inhibiting OHC-mediated cochlear amplification. MOC suppression of OHC function is implicated in cochlear gain control with changing sound intensity, detection of salient stimuli, attention, and protection against acoustic trauma. Thus, sound excites MOC neurons to provide negative feedback of the cochlea. Sound also inhibits MOC neurons via medial nucleus of the trapezoid body (MNTB) neurons. However, MNTB-MOC synapses exhibit short-term depression, suggesting reduced MNTB-MOC inhibition during sustained stimuli. Further, due to high rates of both baseline and sound-evoked activity in MNTB neurons in vivo, MNTB-MOC synapses may be tonically depressed. To probe this, we characterized short-term plasticity of MNTB-MOC synapses in mouse brain slices. We mimicked in vivo-like temperature and extracellular calcium conditions, and in vivo-like activity patterns of fast synaptic activation rates, sustained activation, and prior tonic activity. Synaptic depression was sensitive to extracellular calcium concentration and temperature. During rapid MNTB axon stimulation, post-synaptic currents (PSCs) in MOC neurons summated but with concurrent depression, resulting in smaller, sustained currents, suggesting tonic inhibition of MOC neurons during rapid circuit activity. Low levels of baseline MNTB activity did not significantly reduce responses to subsequent rapid activity that mimics sound stimulation, indicating that, in vivo, MNTB inhibition of MOC neurons persists despite tonic synaptic depression.

scholarly journals A dual role for α-synuclein in facilitation and depression of dopamine release from substantia nigra neurons in vivo

2020 ◽  
Vol 117 (51) ◽  
pp. 32701-32710
Author(s):  
Mahalakshmi Somayaji ◽  
Stefano Cataldi ◽  
Se Joon Choi ◽  
Robert H. Edwards ◽  
Eugene V. Mosharov ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Action Potential ◽  
Synaptic Vesicle ◽  
Neuronal Activity ◽  
Dopamine Release ◽  
Short Intervals ◽  
Presynaptic Plasticity ◽  
Presynaptic Calcium ◽  
Synaptic Vesicle Fusion

α-Synuclein is expressed at high levels at presynaptic terminals, but defining its role in the regulation of neurotransmission under physiologically relevant conditions has proven elusive. We report that, in vivo, α-synuclein is responsible for the facilitation of dopamine release triggered by action potential bursts separated by short intervals (seconds) and a depression of release with longer intervals between bursts (minutes). These forms of presynaptic plasticity appear to be independent of the presence of β- and γ-synucleins or effects on presynaptic calcium and are consistent with a role for synucleins in the enhancement of synaptic vesicle fusion and turnover. These results indicate that the presynaptic effects of α-synuclein depend on specific patterns of neuronal activity.

Rho GTPase Rac1 is critical for neutrophil migration into the lung

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1257-1264 ◽  
Author(s):  
Marie-Dominique Filippi ◽  
Kathleen Szczur ◽  
Chad E. Harris ◽  
Pierre-Yves Berclaz
Keyword(s):  
Inflammatory Process ◽  
Rho Gtpase ◽  
Bone Marrow Cells ◽  
Neutrophil Migration ◽  
Neutrophil Recruitment ◽  
In Vivo Models ◽  
Rac1 Activity ◽  
Inflammatory Processes

Abstract Neutrophils are critical in the inflammatory process by moving rapidly to tissue sites of inflammation. Members of the small Rho GTPase family, Rac1, Rac2, CDC42, and RhoA, are central regulators of cell migration by cytoskeleton rearrangement. The role of Rac1 in neutrophil migration related to inflammatory processes has remained elusive and has yet to be determined in physiologic in vivo models. We previously demonstrated a role for Rac1 in tail retraction. Here, we present evidence that Rac1-mediated uropod formation may be due to crosstalk with a related Rho GTPase RhoA. To assess the physiologic relevance of these findings, we used adoptive transfer of Rac1flox/flox bone marrow cells which allows postengraftment in vivo deletion of Rac1 only in blood cells. We examined the specific role of Rac1 in neutrophil migration into the lung during the inflammatory process induced by formyl-methionyl-leucyl-phenylalanine exposure. The loss of Rac1 activity in neutrophils is associated with a significant decreased neutrophil recruitment into lung alveolar and attenuation of emphysematous lesions. Overall, this study suggests that Rac1 is a physiologic integrator of signals for neutrophil recruitment into lung tissue during an inflammatory response.

RIM proteins and their role in synapse function

2010 ◽  
Vol 391 (6) ◽  
Author(s):  
Tobias Mittelstaedt ◽  
Elena Alvaréz-Baron ◽  
Susanne Schoch
Keyword(s):  
Synaptic Vesicle ◽  
Active Zone ◽  
Neurotransmitter Release ◽  
Multidomain Proteins ◽  
Short Term ◽  
Presynaptic Nerve Terminal ◽  
Presynaptic Plasticity ◽  
Active Zones ◽  
Synaptic Vesicle Release ◽  
The Brain

Abstract Active zones are specialized areas of the plasma membrane in the presynaptic nerve terminal that mediate neurotransmitter release and synaptic plasticity. The multidomain proteins RIM1 and RIM2 are integral components of the cytomatrix at the active zone, interacting with most other active zone-enriched proteins as well as synaptic vesicle proteins. In the brain, RIMs are present in multiple isoforms (α, β, γ) diverging in their structural composition, which mediate overlapping and distinct functions. Here, we summarize recent findings about the specific roles of the various RIM isoforms in basic synaptic vesicle release as well as long- and short-term presynaptic plasticity.

scholarly journals Distinct roles for Cav2.1–2.3 in activity-dependent synaptic dynamics

2014 ◽  
Vol 111 (12) ◽  
pp. 2404-2413 ◽  
Author(s):  
Ulises M. Ricoy ◽  
Matthew E. Frerking
Keyword(s):  
Synaptic Transmission ◽  
Calcium Influx ◽  
Family Members ◽  
Low Frequency ◽  
Complex Stimulus ◽  
Short Term ◽  
Frequency Components ◽  
Synaptic Dynamics ◽  
Activity Dependent

Synaptic transmission throughout most of the CNS is steeply dependent on presynaptic calcium influx through the voltage-gated calcium channels Cav2.1–Cav2.3. In addition to triggering exocytosis, this calcium influx also recruits short-term synaptic plasticity. During the complex patterns of presynaptic activity that occur in vivo, several forms of plasticity combine to generate a synaptic output that is dynamic, in which the size of a given excitatory postsynaptic potential (EPSP) in response to a given spike depends on the short-term history of presynaptic activity. It remains unclear whether the different Cav2 channels play distinct roles in defining these synaptic dynamics and, if so, under what conditions different Cav2 family members most effectively determine synaptic output. We examined these questions by measuring the effects of calcium channel-selective toxins on synaptic transmission at the Schaffer collateral synapse in hippocampal slices from adult mice in response to both low-frequency stimulation and complex stimulus trains derived from in vivo recordings. Blockade of Cav2.1 had a greater inhibitory effect on synaptic transmission during low-frequency components of the stimulus train than on synaptic transmission during high-frequency components of the train, indicating that Cav2.1 had a greater fractional contribution to synaptic transmission at low frequencies than at high frequencies. Relative to Cav2.1, Cav2.2 had a disproportionately reduced contribution to synaptic transmission at frequencies >20 Hz, while Cav2.3 had a disproportionately increased contribution to synaptic transmission at frequencies >1 Hz. These activity-dependent effects of different Cav2 family members shape the filtering characteristics of GABAB receptor-mediated presynaptic inhibition. Thus different Cav2 channels vary in their coupling to synaptic transmission over different frequency ranges, with consequences for the frequency tuning of both synaptic dynamics and presynaptic neuromodulation.

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