Reduced endogenous Ca
            <sup>2+</sup>
            buffering speeds active zone Ca
            <sup>2+</sup>
            signaling

Delvendahl, Igor; Jablonski, Lukasz; Baade, Carolin; Matveev, Victor; Neher, Erwin; Hallermann, Stefan

doi:10.1073/pnas.1508419112

Cited by 53 publications

(83 citation statements)

References 75 publications

(149 reference statements)

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“…Cerebellar mossy fiber boutons were identified based upon morphology and 5 passive membrane parameters as described previously (35,45,82). Recordings were performed in lobules III-VI of the cerebellar vermis.…”

Section: Presynaptic Recordingsmentioning

confidence: 99%

“…Presynaptic series resistance was typically <30 MΩ (median 20 22.9, range 12-50) and compensated online by 40-60% with 10 µs delay. We pharmacologically isolated presynaptic Ca 2+ currents as previously described (35,45,82). Ca 2+ currents were elicited by square pulses of varying duration, and were corrected for leak and capacitance currents using the P/4 method.…”

Section: Presynaptic Recordingsmentioning

confidence: 99%

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Rapid and Sustained Homeostatic Control of Presynaptic Exocytosis at a Central Synapse

Delvendahl

Kita

Mueller

2019

Preprint

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Animal behavior is remarkably robust despite constant changes in neural activity. Homeostatic plasticity stabilizes central nervous system (CNS) function on time scales of hours to days. If and how CNS function is stabilized on more rapid time 15 scales remains unknown. Here we discovered that mossy fiber synapses in the mouse cerebellum homeostatically control synaptic efficacy within minutes after pharmacological glutamate receptor impairment. This rapid form of homeostatic plasticity is expressed presynaptically. We show that modulations of readilyreleasable vesicle pool size and release probability normalize synaptic strength in a 20 hierarchical fashion upon acute pharmacological and prolonged genetic receptor perturbation. Presynaptic membrane capacitance measurements directly demonstrate regulation of vesicle pool size upon receptor impairment. Moreover, presynaptic voltage-clamp analysis revealed increased calcium-current density under specific experimental conditions. Thus, homeostatic modulation of presynaptic 25 exocytosis through specific mechanisms stabilizes synaptic transmission in a CNS circuit on time scales ranging from minutes to months. Rapid presynaptic homeostatic plasticity may ensure stable neural circuit function in light of rapid activity-dependent plasticity.30

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Section: Presynaptic Recordingsmentioning

confidence: 99%

Section: Presynaptic Recordingsmentioning

confidence: 99%

Rapid and Sustained Homeostatic Control of Presynaptic Exocytosis at a Central Synapse

Delvendahl

Kita

Mueller

2019

Preprint

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“…2,33 In SCMs, endogenous calcium buffers can be substituted with exogenous calcium chelators by dialysis of intracellular contents during ≥15 minutes in the whole-cell configuration. This is why the addition of exogenous calcium buffers, such as EGTA or BAPTA to the cytoplasm, is used to investigate the coupling of VGCCs to synaptic vesicles.…”

Section: The Interaction Of Pregabalin With Synaptic α2δ-1 Subunitsmentioning

confidence: 99%

“…This is why the addition of exogenous calcium buffers, such as EGTA or BAPTA to the cytoplasm, is used to investigate the coupling of VGCCs to synaptic vesicles. 2,33 In SCMs, endogenous calcium buffers can be substituted with exogenous calcium chelators by dialysis of intracellular contents during ≥15 minutes in the whole-cell configuration. 20 The RRP size remained constant when the cytoplasm contained 1 mmol/L EGTA, suggesting the presence of an equivalent concentration of endogenous calcium buffers ( Figure 4A).…”

Section: The Interaction Of Pregabalin With Synaptic α2δ-1 Subunitsmentioning

confidence: 99%

Outside‐in regulation of the readily releasable pool of synaptic vesicles by α2δ‐1

et al. 2019

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The readily releasable pool (RRP) of synaptic vesicles is a key determinant of phasic neurotransmission. Although the size of the RRP is tightly regulated by intracellular factors, there is little evidence for its modification by extracellular signals. By studying the homogeneous population of synapses present in autaptic microcultures, we show that pregabalin, a prototypical gabapentinoid, decreases the effective RRP size. Simultaneous imaging of presynaptic calcium influx and recording of postsynaptic responses shows that the effect is not related to a reduction of calcium entry. The main cause is the impairment of the functional coupling among N‐type calcium channels and the RRP, resembling an increase of intracellular mobile calcium buffers. The ectodomain of neurexin‐1α shows a similar action to pregabalin, acting as an endogenous ligand of α2δ‐1 that reduces the RRP size without affecting presynaptic calcium influx. The regulatory actions described for pregabalin and the ectodomain of neurexin‐1α are mutually exclusive. The overexpression of α2δ‐1 enhances the effect of pregabalin and the ectodomain of neurexin‐1α on neurotransmission by decreasing their effective concentration. In contrast, knockdown of α2δ‐1 causes a profound inhibition of synaptic transmission. These observations prompt to consider α2δ‐1 as an outside‐in signaling platform that binds exogenous and endogenous cues for regulating the coupling of voltage‐gated calcium channels to synaptic vesicles.

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“…78 79 Here, we demonstrate a decrease or increase in conduction velocity in central axons 80 through the application of HCN blockers or neuromodulators. To gain mechanistic 81 insights into the modulation of conduction velocity by HCN channels, we performed 82 recordings from en passant cerebellar mossy fiber boutons (cMFB; Ritzau-Jost et al, 83 2014; Delvendahl et al, 2015). We found that HCN channels in cMFBs mainly consist 84 of the HCN2 subunit, are ~7% activated at resting membrane potential, ensure high-85 frequency firing, and control the passive membrane properties.…”

mentioning

confidence: 99%

HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons

Byczkowicz

Eshra

Montanaro

et al. 2019

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18Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels control electrical 19 rhythmicity and excitability in the heart and brain, but the function of HCN channels at 20 subcellular level in axons remains poorly understood. Here, we show that the action 21 potential conduction velocity in both myelinated and unmyelinated central axons can 22 bidirectionally be modulated by HCN channel blockers, cyclic adenosine 23 monophosphate (cAMP), and neuromodulators. Recordings from mice cerebellar mossy 24 fiber boutons show that HCN channels ensure reliable high-frequency firing and are 25 strongly modulated by cAMP (EC 50 40 µM; estimated endogenous cAMP concentration 26 13 µM). In accord, immunogold-electron microscopy revealed HCN2 as the dominating 27 subunit in cerebellar mossy fibers. Computational modeling indicated that HCN2 28 channels control conduction velocity primarily via altering the resting membrane 29 potential and was associated with significant metabolic costs. These results suggest that 30 the cAMP-HCN pathway provides neuromodulators an opportunity to finely tune 31 energy consumption and temporal delays across axons in the brain. 32 33 for statistical testing). Since some studies implied that ZD7288 might have some 102 unspecific side effects, such as blocking voltage-dependent Na + channels (Chevaleyre 103 and Castillo, 2002;Wu et al., 2012), we recorded Na + currents from 53 cMFBs and 104 found no change in amplitude or kinetics of voltage-dependent Na + currents after 105 ZD7288 application (Supplemental Fig. 1), suggesting that under our conditions and at 106 a concentration of 30 µM, ZD7288 did not affect the Na + currents. Because of the 107 modulation of HCN channels by intracellular cAMP, we measured conduction velocity 108 during application of 8-bromoadenosine 3′,5′-cyclic monophosphate (8-Br-cAMP; 109 500 µM), a membrane-permeable cAMP-analogue. The conduction velocity increased 110 by 5.9 ± 2.8% in cerebellar mossy fibers (n = 17), by 3.7 ± 1.4% in parallel fibers (n = 111 10), and by 4.6 ± 0.6% in optic nerves (n = 5; see Fig. 1 and legend for statistical 112 testing). These results indicate that HCN channels control the conduction velocity both 113 Schweighofer et al., 2004), which decrease the cAMP concentration. Although we used 129 rather high concentrations of the agonists and off-target effects cannot be excluded (e.g., 130 NE activating dopamine receptors; Sánchez-Soto et al., 2016), these data nevertheless 131 indicate that physiological neuromodulators can both increase or decrease action 132 potential conduction velocity, depending on the type of neuromodulator and receptor. 133

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Reduced endogenous Ca ²⁺ buffering speeds active zone Ca ²⁺ signaling

Cited by 53 publications

References 75 publications

Rapid and Sustained Homeostatic Control of Presynaptic Exocytosis at a Central Synapse

Rapid and Sustained Homeostatic Control of Presynaptic Exocytosis at a Central Synapse

Outside‐in regulation of the readily releasable pool of synaptic vesicles by α2δ‐1

HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons

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Reduced endogenous Ca 2+ buffering speeds active zone Ca 2+ signaling

Cited by 53 publications

References 75 publications

Rapid and Sustained Homeostatic Control of Presynaptic Exocytosis at a Central Synapse

Rapid and Sustained Homeostatic Control of Presynaptic Exocytosis at a Central Synapse

Outside‐in regulation of the readily releasable pool of synaptic vesicles by α2δ‐1

HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons

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Reduced endogenous Ca ²⁺ buffering speeds active zone Ca ²⁺ signaling