Modulation of synaptic depression of the calyx of Held synapse by GABA_B receptors and spontaneous activity

Abstract

Key points• Spontaneous activity contributes to low synaptic depression of the calyx of Held synapse in vivo.• Application of a reversible blocker in combination with juxtacellular recordings allows a relatively good estimate of local drug concentrations reached during microiontophoresis.• Activation of the GABA B receptor on the young-adult calyx of Held can reduce short-term depression, both in vivo and in slices.• The ambient concentration of GABA in the auditory brainstem is low. AbstractThe calyx of Held synapse of the medial nucleus of the trapezoid body is a giant axosomatic synapse in the auditory brainstem, which acts as a relay synapse showing little dependence of its synaptic strength on firing frequency. The main mechanism that is responsible for its resistance to synaptic depression is its large number of release sites with low release probability. Here, we investigated the contribution of presynaptic GABA B receptors and spontaneous activity to release probability both in vivo and in vitro in young-adult mice. Maximal activation of presynaptic GABA B receptors by baclofen reduced synaptic output by about 45% in whole-cell voltage clamp slice recordings, which was accompanied by a reduction in short-term depression. A similar reduction in transmission was observed when baclofen was applied in vivo by microiontophoresis during juxtacellular recordings using piggyback electrodes. No significant change in synaptic transmission was observed during application of the GABA B receptor antagonist CGP54626 both during in vivo and slice recordings, suggesting a low ambient GABA concentration. Interestingly, we observed that synapses with a high spontaneous frequency showed almost no synaptic depression during auditory stimulation, whereas synapses with a low spontaneous frequency did depress during noise bursts. Our data thus suggest that spontaneous firing can tonically reduce release probability in vivo. In addition, our data show that the ambient GABA concentration in the auditory brainstem is too low to activate the GABA B receptor at the calyx of Held significantly, but that activation of GABA B receptors can reduce sound-evoked synaptic depression.

In vivo synaptic transmission and morphology in mouse models of Tuberous sclerosis, Fragile X syndrome, Neurofibromatosis type 1, and Costello syndrome

“…Spontaneous firing rates in this study were lower than in our earlier study in the C57BL/6 background ( Lorteije et al, 2009 ), but similar as in other studies in both mice and other species ( Kopp-Scheinpflug et al, 2008 ; Wang et al, 2013 ). Synaptic transmission along the calyx of Held synapse in the WT animals generally matched our previous in vivo experiments as well, including the observation that STD during a tone was lower in the studies in which spontaneous frequency was higher, presumably because of larger tonic depression ( Lorteije et al, 2009 ; Wang et al, 2013 ).…”

“…Similarly, the peak of the eAP, which typically coincides with the maximum rate of rise of the postsynaptic AP, provides a measure for the postsynaptic excitability. Because of the difficulty of delineating the amplitude of the eEPSP from the eAP, we used the eEPSP’ as a measure for the strength of transmission, as previously described ( Wang et al, 2013 ). The absolute size of the eEPSP’ depends on experimental parameters such as seal resistance; on average it was about 10 V/s; this value did not differ significantly between mutant and its WT control for any of the four lines (Supplementary Figure S5 ).…”

GABAB receptor‐mediated tonic inhibition regulates the spontaneous firing of locus coeruleus neurons in developing rats and in citalopram‐treated rats

“…2011; Wang et al . ), perhaps including the LC neurons, as our EM study showed presynaptic location of GABA B Rs in the LC. As GABA B R signalling and the activity of GABA transporters in many physiological and pathological processes can be regulated by various transmitter/receptor systems, such as the activation of 5‐HT 1A receptors during chronic exposure to SSRIs, our results suggest that tonic inhibition and presynaptic regulation of transmitter release mediated by peri/extrasynaptic GABA B Rs on LC neurons could be important players in the development of normal and abnormal behaviours/brain functions that are associated with the LC–NA system.…”

“…For example, since ambient GABA levels in the LC are significantly higher during REM/non-REM sleep than during wakefulness (Nitz & Siegel, 1997;Nelson et al 2002), our results suggest that GABA B R-mediated tonic inhibition may play an important role in regulating the SFR of LC neurons, and thus the wakefulness/arousal level of the brain. In addition to postsynaptic regulation, GABA B Rs at presynaptic sites have been shown to regulate glutamate and GABA release in many brain areas (Wu et al 2011;Wang et al 2013), perhaps including the LC neurons, as our EM study showed presynaptic location of GABA B Rs in the LC. As GABA B R signalling and the activity of GABA transporters in many physiological and pathological processes can be regulated by various transmitter/receptor systems, such as the activation of 5-HT 1A receptors during chronic exposure to SSRIs, our results suggest that tonic inhibition and presynaptic regulation of transmitter release mediated by peri/extrasynaptic GABA B Rs on LC neurons could be important players in the development of normal and abnormal behaviours/brain functions that are associated with the LC-NA system.…”

Merits and Limitations of Vesicle Pool Models in View of Heterogeneous Populations of Synaptic Vesicles

“…At the same time, these authors found that release probability time is not assumed to be constant any longer (assumption 2, above) but is calculated as the product of a fixed rate-constant and the number of empty release sites. In other words: pool refilling is assumed to start only after some delay, when sites have been vacated (Hosoi et al, 2007;Thanawala and Regehr, 2013;Wang et al, 2013;Wesseling and Lo, 2002). Thanawala and Regehr (2013) simulated this type of model and concluded that the simple back-extrapolation (SMN plot) underestimates the real pool, because it assigns too much of the early release to newly recruited vesicles.…”