Activity-dependent, homeostatic regulation of neurotransmitter release from auditory nerve fibers

Abstract

Information processing in the brain requires reliable synaptic transmission. High reliability at specialized auditory nerve synapses in the cochlear nucleus results from many release sites (N), high probability of neurotransmitter release (P r ), and large quantal size (Q). However, high P r also causes auditory nerve synapses to depress strongly when activated at normal rates for a prolonged period, which reduces fidelity. We studied how synapses are influenced by prolonged activity by exposing mice to constant, nondamaging noise and found that auditory nerve synapses changed to facilitating, reflecting low P r . For mice returned to quiet, synapses recovered to normal depression, suggesting that these changes are a homeostatic response to activity. Two additional properties, Q and average excitatory postsynaptic current (EPSC) amplitude, were unaffected by noise rearing, suggesting that the number of release sites (N) must increase to compensate for decreased P r . These changes in N and P r were confirmed physiologically using the integration method. Furthermore, consistent with increased N, endbulbs in noise-reared animals had larger VGlut1-positive puncta, larger profiles in electron micrographs, and more release sites per profile. In current-clamp recordings, noise-reared BCs had greater spike fidelity even during high rates of synaptic activity. Thus, auditory nerve synapses regulate excitability through an activitydependent, homeostatic mechanism, which could have major effects on all downstream processing. Our results also suggest that noise-exposed bushy cells would remain hyperexcitable for a period after returning to normal quiet conditions, which could have perceptual consequences.homeostasis | release probability | cochlear nucleus S ynapses must be able to transmit information reliably over a range of activity levels. A critical factor in regulating this fidelity is the probability of neurotransmitter release (P r ). If P r is too high, synapses may have high fidelity at low rates of activity, but they would strongly depress at high rates, which could reduce postsynaptic spiking. If P r is too low, failure to release neurotransmitter could reduce fidelity.Activity can influence synaptic properties through multiple mechanisms. One mechanism, homeostatic synaptic scaling, is an activity-dependent regulation of quantal size (Q) (1-3), which has recently been reported to occur in vivo (4, 5). One limitation is that changes in Q do not change the degree of synaptic depression. Furthermore, increases in Q could be limited by receptor number or density. In dissociated hippocampal cell cultures, activity-dependent changes in P r have been observed (6-8). However, it is not known whether such changes in P r occur in vivo in the intact brain. In addition, it is not clear how modulation of P r could prevent depression without also causing large changes in the magnitude of the excitatory postsynaptic current (EPSC).Fidelity is critical for auditory nerve (AN) synapses onto bushy cells (BCs) in the anteroventr...

Gαi Proteins are Indispensable for Hearing

“…9B, green). As previously described reduced vGLUT1 expression goes along with reduced activity [61], we suggest differences in vGLUT1 activity of auditory nerves between both Gnai3 mutants.…”

“…Interestingly, following noise exposure elevated firing rates in the cochlear nucleus (CN) are accompanied by a modification of GABA B R [88,89]. In this context preliminary findings of lower vGLUT1 immunoreactivity in Gnai3 gKO than Gnai3 cKO mice may be indicative for less active transmitter release sites, as previously suggested [61]. Additionally, the absence of Gα i3 expression in satellite cells of the cochlea in global but not conditional Gnai3 mutants (Fig.…”

“…the bushy cells in the ventral cochlear nucleus, VCN), which are identified through vGLUT1 positive presynaptic contacts (Fig. 9, green) [61], Gα i3 antibody staining was detected in Gnai3 cKO (Fig. 9B, red) but not in Gnai3 gKO mice (Fig.…”

Plastic changes along auditory pathway during salicylate-induced ototoxicity: Hyperactivity and CF shifts

“…These changes were interpreted as evidence of increased excitatory synapses in the VCN designed to compensate for the reduced neural response from the cochlea. Homeostatic plasticity has been observed in bushy cells in the anteroventral cochlear nucleus following chronic, non-damaging sound stimulation (Ngodup et al, 2015). In measurements of excitatory postsynaptic currents in brain slices, prolonged noise stimulation decreased the probability of release and an increased in number of release sites.…”

Control of lung ventilation following overwintering conditions in bullfrogs,Lithobates catesbeianus

“…From the neural perspective, a wealth of information exists regarding how neurons and circuits maintain target levels of activity despite removing or enhancing activity inputs (termed homeostatic plasticity). However, models to study these processes use pharmacological or pathological paradigms to manipulate neuronal activity in vivo and in vitro primarily at early developmental stages (Hengen et al, 2013;Knogler et al, 2010;Ngodup et al, 2015;Schacher and Hu, 2014;Turrigiano, 2012;Wilhelm and Wenner, 2008). Thus, the bullfrog respiratory control system following overwintering offers a powerful ability to uncover mechanisms leading to and resulting in the preservation (respiratory motor output and hypoxia sensitivity) and deterioration (CO 2 sensitivity) of sensorimotor function in the same species, individual and neural control system after ecologically relevant inactivity.…”