Altered synaptic plasticity and central pattern generator dysfunction in a Drosophila model of PNKD3 paroxysmal dyskinesia

Mapping Intimacies ◽

10.1101/2020.02.20.957639 ◽

2020 ◽

Author(s):

Simon Lowe ◽

Patrick Kratschmer ◽

James E.C. Jepson

Keyword(s):

Synaptic Plasticity ◽

Central Pattern Generator ◽

Neurotransmitter Release ◽

Ex Vivo ◽

Pattern Generator ◽

Bk Channels ◽

Video Tracking ◽

Bk Channel ◽

Short Term

ABSTRACTBackgroundParoxysmal non-kinesigenic dyskinesia type-3 (PNKD3) has been linked to gain-of-function (GOF) mutations in the hSlo1 BK potassium channel, in particular a dominant mutation (D434G) that enhances Ca2+-sensitivity. However, while BK channels play well-known roles in regulating neurotransmitter release, it is unclear whether the D434G mutation alters neurotransmission and synaptic plasticity in vivo. Furthermore, the subtypes of movement-regulating circuits impacted by this mutation are unknown.ObjectivesWe aimed to use a larval Drosophila model of PNKD3 (sloE366G/+) to examine how BK channel GOF in dyskinesia alters synaptic properties and motor circuit function.MethodsWe used video-tracking to test for movement defects in sloE366G/+ larvae, and sharp-electrode recordings to assess the fidelity of Ca2+-dependent neurotransmitter release and short-term plasticity at the neuromuscular junction. We then combined sharp-electrode recording with ex vivo Ca2+-imaging to investigate the functionality of the central pattern generator (CPG) driving foraging behavior in sloE366G/+ larvae.ResultsWe show that the PNKD3 mutation leads to Ca2+-dependent alterations in synaptic release and paired-pulse facilitation. Furthermore, we identify robust alterations in locomotor behaviors in sloE366G/+ larvae which were mirrored by dysfunction of the upstream, movement-generating CPG in the larval ventral nerve cord.ConclusionOur results demonstrate that a BK channel GOF mutation can alter neurotransmitter release and short-term synaptic plasticity, and result in CPG dysfunction, in Drosophila larvae. These data add to a growing body of work linking paroxysmal dyskinesias to aberrant neuronal excitability and synaptic plasticity in pre-motor circuits.

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Nitric oxide-soluble guanylyl cyclase signaling regulates corticostriatal transmission and short-term synaptic plasticity of striatal projection neurons recorded in vivo

Neuropharmacology ◽

10.1016/j.neuropharm.2009.11.011 ◽

2010 ◽

Vol 58 (3) ◽

pp. 624-631 ◽

Cited By ~ 27

Author(s):

Stephen Sammut ◽

Sarah Threlfell ◽

Anthony R. West

Keyword(s):

Nitric Oxide ◽

Synaptic Plasticity ◽

Guanylyl Cyclase ◽

Soluble Guanylyl Cyclase ◽

Projection Neurons ◽

Short Term ◽

Striatal Projection Neurons

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Disruption of TRPV1-mediated coupling of coronary blood flow to cardiac metabolism in diabetic mice: role of nitric oxide and BK channels

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00011.2012 ◽

2012 ◽

Vol 303 (2) ◽

pp. H216-H223 ◽

Cited By ~ 32

Author(s):

Giacinta Guarini ◽

Vahagn A. Ohanyan ◽

John G. Kmetz ◽

Daniel J. DelloStritto ◽

Roslin J. Thoppil ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Coronary Blood Flow ◽

Cardiac Metabolism ◽

Bk Channels ◽

Bk Channel ◽

Transient Receptor Potential Vanilloid ◽

Trpv1 Channels ◽

Channel Dependent

We have previously shown transient receptor potential vanilloid subtype 1 (TRPV1) channel-dependent coronary function is compromised in pigs with metabolic syndrome (MetS). However, the mechanisms through which TRPV1 channels couple coronary blood flow to metabolism are not fully understood. We employed mice lacking TRPV1 [TRPV1(−/−)], db/db diabetic, and control C57BKS/J mice to determine the extent to which TRPV1 channels modulate coronary function and contribute to vascular dysfunction in diabetic cardiomyopathy. Animals were subjected to in vivo infusion of the TRPV1 agonist capsaicin to examine the hemodynamic actions of TRPV1 activation. Capsaicin (1–100 μg·kg−1·min−1) dose dependently increased coronary blood flow in control mice, which was inhibited by the TRPV1 antagonist capsazepine or the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (l-NAME). In addition, the capsaicin-mediated increase in blood flow was attenuated in db/db mice. TRPV1(−/−) mice exhibited no changes in coronary blood flow in response to capsaicin. Vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was inhibited by the TRPV1 inhibitor SB366791 l-NAME and to the large conductance calcium-sensitive potassium channel (BK) inhibitors iberiotoxin and Penetrim A. Similar to in vivo responses, capsaicin-mediated relaxation was impaired in db/db mice compared with controls. Changes in pH (pH 7.4–6.0) relaxed coronary vessels contracted to the thromboxane mimetic U46619 in all three groups of mice; however, pH-mediated relaxation was blunted in vessels obtained from TRPV1(−/−) and db/db mice compared with controls. Western blot analysis revealed decreased myocardial TRPV1 protein expression in db/db mice compared with controls. Our data reveal TRPV1 channels mediate coupling of myocardial blood flow to cardiac metabolism via a nitric oxide-dependent, BK channel-dependent pathway that is corrupted in diabetes.

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Properties of Short-Term Synaptic Depression at Larval Neuromuscular Synapses in Wild-Type and Temperature-Sensitive Paralytic Mutants of Drosophila

Journal of Neurophysiology ◽

10.1152/jn.01108.2004 ◽

2005 ◽

Vol 93 (5) ◽

pp. 2396-2405 ◽

Cited By ~ 26

Author(s):

Ying Wu ◽

Fumiko Kawasaki ◽

Richard W. Ordway

Keyword(s):

Neurotransmitter Release ◽

Functional Characterization ◽

Neuromuscular Synapse ◽

Synaptic Depression ◽

Temperature Sensitive ◽

Short Term ◽

Low Frequencies ◽

Neuromuscular Synapses ◽

The Impact

The larval neuromuscular synapse of Drosophila serves as an important model for genetic and molecular analysis of synaptic development and function. Further functional characterization of this synapse, as well as adult neuromuscular synapses, will greatly enhance the impact of this model system on our understanding of synaptic transmission. Here we describe a form of short-term synaptic depression observed at larval, but not adult, neuromuscular synapses and explore the underlying mechanisms. Larval neuromuscular synapses exhibited a form of short-term depression that was strongly dependent on stimulation frequency over a narrow range of low frequencies (0.1–1 Hz). This form of synaptic depression, referred to here as low-frequency short-term depression (LF-STD), results from an activity-dependent reduction in neurotransmitter release. However, in contrast to the predictions of depletion models, the degree of depression was independent of the initial level of neurotransmitter release over a range of extracellular calcium concentrations. This conclusion was confirmed in two temperature-sensitive (TS) paralytic mutants, cacophony and shibire, which exhibit reduced neurotransmitter release resulting from conditional disruption of presynaptic calcium channels and dynamin, respectively. Higher stimulation frequencies (40 or 60 Hz) produced two components of depression that appeared to include LF-STD as well as a more conventional component of short-term depression. These findings reveal novel properties of short-term synaptic depression and suggest that complementary genetic analysis of larval and adult neuromuscular synapses will further define the in vivo mechanisms of neurotransmitter release and short-term synaptic plasticity.

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Short-term synaptic plasticity in the auditory brain stem by using in-vivo-like stimulation parameters

Hearing Research ◽

10.1016/j.heares.2011.05.011 ◽

2011 ◽

Vol 279 (1-2) ◽

pp. 51-59 ◽

Cited By ~ 6

Author(s):

Achim Klug

Keyword(s):

Synaptic Plasticity ◽

Brain Stem ◽

Short Term ◽

Stimulation Parameters ◽

Auditory Brain Stem

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Modeling the short-term dynamics of in vivo excitatory spike transmission

10.1101/475178 ◽

2018 ◽

Cited By ~ 3

Author(s):

Abed Ghanbari ◽

Naixin Ren ◽

Christian Keine ◽

Carl Stoelzel ◽

Bernhard Englitz ◽

...

Keyword(s):

Synaptic Plasticity ◽

Large Scale ◽

Auditory Brainstem ◽

Postsynaptic Neuron ◽

Intracellular Recordings ◽

Short Term ◽

Functional Connection ◽

Synaptic Dynamics ◽

Synaptic Effects

AbstractInformation transmission in neural networks is influenced by both short-term synaptic plasticity (STP) as well as non-synaptic factors, such as after-hyperpolarization currents and changes in excitability. Although these effects have been widely characterized in vitro using intracellular recordings, how they interact in vivo is unclear. Here we develop a statistical model of the short-term dynamics of spike transmission that aims to disentangle the contributions of synaptic and non-synaptic effects based only on observed pre- and postsynaptic spiking. The model includes a dynamic functional connection with short-term plasticity as well as effects due to the recent history of postsynaptic spiking and slow changes in postsynaptic excitability. Using paired spike recordings, we find that the model accurately describes the short-term dynamics of in vivo spike transmission at a diverse set of identified and putative excitatory synapses, including a thalamothalamic connection in mouse, a thalamocortical connection in a female rabbit, and an auditory brainstem synapse in a female gerbil. We illustrate the utility of this modeling approach by showing how the spike transmission patterns captured by the model may be sufficient to account for stimulus-dependent differences in spike transmission in the auditory brainstem (endbulb of Held). Finally, we apply this model to large-scale multi-electrode recordings to illustrate how such an approach has the potential to reveal cell-type specific differences in spike transmission in vivo. Although short-term synaptic plasticity parameters estimated from ongoing pre- and postsynaptic spiking are highly uncertain, our results are partially consistent with previous intracellular observations in these synapses.Significance StatementAlthough synaptic dynamics have been extensively studied and modeled using intracellular recordings of post-synaptic currents and potentials, inferring synaptic effects from extracellular spiking is challenging. Whether or not a synaptic current contributes to postsynaptic spiking depends not only on the amplitude of the current, but also on many other factors, including the activity of other, typically unobserved, synapses, the overall excitability of the postsynaptic neuron, and how recently the postsynaptic neuron has spiked. Here we developed a model that, using only observations of pre- and postsynaptic spiking, aims to describe the dynamics of in vivo spike transmission by modeling both short-term synaptic plasticity and non-synaptic effects. This approach may provide a novel description of fast, structured changes in spike transmission.

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Short-term synaptic plasticity in the rat geniculo-cortical pathway during development in vivo

Neuroscience Letters ◽

10.1016/j.neulet.2005.12.054 ◽

2006 ◽

Vol 398 (1-2) ◽

pp. 73-77 ◽

Cited By ~ 4

Author(s):

Fan Jia ◽

Haiyang Wei ◽

Xiangrui Li ◽

Xiaoqiao Xie ◽

Yifeng Zhou

Keyword(s):

Synaptic Plasticity ◽

Short Term

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Urodynamic properties and neurotransmitter dependence of urinary bladder contractility in the BK channel deletion model of overactive bladder

AJP Renal Physiology ◽

10.1152/ajprenal.00060.2005 ◽

2005 ◽

Vol 289 (3) ◽

pp. F604-F610 ◽

Cited By ~ 68

Author(s):

K. S. Thorneloe ◽

A. L. Meredith ◽

A. M. Knorn ◽

R. W. Aldrich ◽

M. T. Nelson

Keyword(s):

Urinary Bladder ◽

Overactive Bladder ◽

Bk Channels ◽

Bk Channel ◽

Bladder Pressure ◽

Bladder Smooth Muscle ◽

Medical Issues ◽

Urinary Bladder Smooth Muscle ◽

Important Therapeutic Target

Overactive bladder and incontinence are major medical issues, which lack effective therapy. Previously, we showed (Meredith AL, Thornloe KS, Werner ME, Nelson MT, and Aldrich RW. J Biol Chem 279: 36746–36752, 2004) that the gene mSlo1 encodes large-conductance Ca2+-activated K+ (BK) channels of urinary bladder smooth muscle (UBSM) and that ablation of mSlo1 leads to enhanced myogenic and nerve-mediated contractility and increased urination frequency. Here, we examine the in vivo urodynamic consequences and neurotransmitter dependence in the absence of the BK channel. The sensitivity of contractility to nerve stimulation was greatly enhanced in UBSM strips from Slo−/− mice. The stimulation frequency required to obtain a 50% maximal contraction was 8.3 ± 0.9 and 19.1 ± 1.8 Hz in Slo−/− and Slo +/+ mice, respectively. This enhancement is at least partially due to alterations in UBSM excitability, as muscarinic-induced Slo−/− contractility is elevated in the absence of neuronal activity. Muscarinic-induced Slo−/− contractility was mimicked by blocking BK channels with iberiotoxin (IBTX) in Slo +/+ strips, whereas IBTX had no effect on Slo−/− strips. IBTX also enhanced purinergic contractions of Slo +/+ UBSM but was without effect on purinergic contractions of Slo−/− strips. In vivo bladder pressure and urine output measurements (cystometry) were performed on conscious, freely moving mice. Slo−/− mice exhibited increased bladder pressures, pronounced pressure oscillations, and urine dripping. Our results indicate that the BK channel in UBSM has a very significant role in urinary function and dysfunction and as such likely represents an important therapeutic target.

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Preclinical Rationale for Targeting the PD-1/PD-L1 Axis in Combination with a CD38 Antibody in Multiple Myeloma and Other CD38-Positive Malignancies

Cancers ◽

10.3390/cancers12123713 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3713

Author(s):

Christie P. M. Verkleij ◽

Amy Jhatakia ◽

Marloes E. C. Broekmans ◽

Kristine A. Frerichs ◽

Sonja Zweegman ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Ex Vivo ◽

Suppressor Cells ◽

Newly Diagnosed ◽

Short Term ◽

Expression Levels ◽

Cell Immunity

The CD38-targeting antibody daratumumab mediates its anti-myeloma activities not only through Fc-receptor-dependent effector mechanisms, but also by its effects on T-cell immunity through depletion of CD38+ regulatory T-cells, regulatory B-cells, and myeloid-derived suppressor cells. Therefore, combining daratumumab with modulators of other potent immune inhibitory pathways, such as the PD-1/PD-L1 axis, may further improve its efficacy. We show that multiple myeloma (MM) cells from relapsed/refractory patients have increased expression of PD-L1, compared to newly diagnosed patients. Furthermore, PD-1 is upregulated on T-cells from both newly diagnosed and relapsed/refractory MM patients, compared to healthy controls. In short-term experiments with bone marrow samples from MM patients, daratumumab-mediated lysis was mainly associated with the MM cells’ CD38 expression levels and the effector (NK-cells/monocytes/T-cells)-to-target ratio, but not with the PD-L1 expression levels or PD-1+ T-cell frequencies. Although PD-1 blockade with nivolumab did not affect MM cell viability or enhanced daratumumab-mediated lysis in short-term ex vivo experiments, nivolumab resulted in a mild but clear increase in T-cell numbers. Moreover, with a longer treatment duration, PD-1 blockade markedly improved anti-CD38 antibody-mediated cytotoxicity in vivo in murine CD38+ tumor models. In conclusion, dual targeting of CD38 and PD-1 may represent a promising strategy for treating MM and other CD38-positive malignancies.

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A Role for Short-Term Synaptic Facilitation and Depression in the Processing of Intensity Information in the Auditory Brain Stem

Journal of Neurophysiology ◽

10.1152/jn.01030.2006 ◽

2007 ◽

Vol 97 (4) ◽

pp. 2863-2874 ◽

Cited By ~ 37

Author(s):

K. M. MacLeod ◽

T. K. Horiuchi ◽

C. E. Carr

Keyword(s):

Synaptic Plasticity ◽

Brain Stem ◽

Time Constant ◽

Cochlear Nucleus ◽

Auditory Nerve ◽

Brain Slices ◽

Fast Time ◽

Short Term ◽

Intensity Information

The nature of the synaptic connection from the auditory nerve onto the cochlear nucleus neurons has a profound impact on how sound information is transmitted. Short-term synaptic plasticity, by dynamically modulating synaptic strength, filters information contained in the firing patterns. In the sound-localization circuits of the brain stem, the synapses of the timing pathway are characterized by strong short-term depression. We investigated the short-term synaptic plasticity of the inputs to the bird's cochlear nucleus angularis (NA), which encodes intensity information, by using chick embryonic brain slices and trains of electrical stimulation. These excitatory inputs expressed a mixture of short-term facilitation and depression, unlike those in the timing nuclei that only depressed. Facilitation and depression at NA synapses were balanced such that postsynaptic response amplitude was often maintained throughout the train at high firing rates (>100 Hz). The steady-state input rate relationship of the balanced synapses linearly conveyed rate information and therefore transmits intensity information encoded as a rate code in the nerve. A quantitative model of synaptic transmission could account for the plasticity by including facilitation of release (with a time constant of ∼40 ms), and a two-step recovery from depression (with one slow time constant of ∼8 s, and one fast time constant of ∼20 ms). A simulation using the model fit to NA synapses and auditory nerve spike trains from recordings in vivo confirmed that these synapses can convey intensity information contained in natural train inputs.

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