Developmental Shift of Inhibitory Transmitter Content at a Central Auditory Synapse

Abstract

Synaptic inhibition in the CNS is mostly mediated by GABA or glycine. Generally, the use of the two transmitters is spatially segregated, but there are central synapses employing both, which allows for spatial and temporal variability of inhibitory mechanisms. Spherical bushy cells (SBCs) in the mammalian cochlear nucleus receive primary excitatory inputs through auditory nerve fibers arising from the organ of Corti and non-primary inhibition mediated by a dual glycine-GABA transmission. Slow kinetics IPSCs enable activity dependent tonic-like conductance build up, functioning as a gain control by filtering out small or temporally imprecise EPSPs. However, it remained elusive whether GABA and glycine are released as content of the same vesicle or from distinct presynaptic terminals. The developmental profile of quantal release was investigated with whole cell recordings of miniature inhibitory postsynaptic currents (mIPSCs) from P1–P25 SBCs of Mongolian gerbils. GABA is the initial transmitter eliciting slow-rising and -decaying events of relatively small amplitudes, occurring only during early postnatal life. Around and after hearing onset, the inhibitory quanta are predominantly containing glycine that—with maturity—triggers progressively larger and longer mIPSC. In addition, GABA corelease with glycine evokes mIPSCs of particularly large amplitudes consistently occurring across all ages, but with low probability. Together, these results suggest that GABA, as the primary transmitter released from immature inhibitory terminals, initially plays a developmental role. In maturity, GABA is contained in synaptic vesicles only in addition to glycine to increase the inhibitory potency, thereby fulfilling solely a modulatory function.

GABA-Glycine Cotransmitting Neurons in the Ventrolateral Medulla: Development and Functional Relevance for Breathing

“…The occurrence of GGCN has been associated with immature neuronal networks, since in many instances the number of GGCN is reduced during maturation of synapses, neurons and neuronal networks (Aubrey and Supplisson, 2018). Consistently, GGCN were often detected in young animals (Jonas et al, 1998; O’Brien and Berger, 1999; Russier et al, 2002; Rahman et al, 2013) and developmental shifts from GGCN to an either GABAergic or glycinergic phenotype have been described in a number of neuronal networks (Gao et al, 2001; Keller et al, 2001; Nerlich et al, 2017). Similarly, in the preBötC almost 70% of inhibitory neurons show a GGCN phenotype during late embryonic development, and their number appears to decrease just around birth (Rahman et al, 2015).…”

“…The two major inhibitory neurotransmitters are GABA and glycine. However, in addition to GABAergic and glycinergic neurons, also GABA-glycine cotransmitting neurons (GGCN) were identified in the ventral respiratory column (Koizumi et al, 2013; Rahman et al, 2013, 2015), as well as in other brain areas (Triller et al, 1987; Spike et al, 1993; Jonas et al, 1998; Wu et al, 2002; Nerlich et al, 2014, 2017). The functional relevance of this cotransmission is still unclear (Burnstock, 2004).…”

Functional Development of Principal Neurons in the Anteroventral Cochlear Nucleus Extends Beyond Hearing Onset

“…The gross inhibitory inputs on BCs and SCs apparently originate from the same sources (Wickesberg and Oertel, 1990; Saint Marie et al, 1991; Campagnola and Manis, 2014), thus providing broadly tuned inhibition also to BCs (Kuenzel et al, 2011; Keine et al, 2016). Synaptogenesis of glycinergic terminals and the development of the release machinery continue after hearing onset, while the number of postsynaptic GABA A R seemingly decreases (Luján et al, 2008; Nerlich et al, 2017). Thus, mature IPSCs are predominantly mediated by glycine receptors, having slower kinetics compared to SCs (Xie and Manis, 2013; Nerlich et al, 2014a,b).…”

“…To date, the in vivo functional development of BCs and SCs in mice is still not well understood. Our knowledge about the cochlear nucleus development is based on data from acute slice preparations from both low-frequency hearing animals (chick: Lawrence and Trussell, 2000; Brenowitz and Trussell, 2001; Lu and Trussell, 2007; Tang et al, 2013; Goyer et al, 2015; Sanchez et al, 2015; Hong et al, 2016; Oline et al, 2016; gerbil: Milenković et al, 2007; Witte et al, 2014; Jovanovic et al, 2017; Nerlich et al, 2017) and high-frequency hearing animals (rat: Bellingham et al, 1998; mouse: Wu and Oertel, 1987; Lu et al, 2007; Yang and Xu-Friedman, 2010; Campagnola and Manis, 2014). Respective in vivo developmental data were collected more than 30 years ago from the cochlear nucleus of chicken (Saunders et al, 1973; Rubel and Parks, 1975), gerbil (Woolf and Ryan, 1985), and cat (Pujol, 1972; Romand and Marty, 1975; Brugge et al, 1978).…”

GABA is a modulator, rather than a classical transmitter, in the medial nucleus of the trapezoid body–lateral superior olive sound localization circuit

“…In several neural systems, glycine and GABA coexist in presynaptic axon terminals and in synaptic vesicles from which they can be released together (Ottersen et al 1988;Todd et al 1996;Jonas et al 1998;O'Brien & Berger, 1999;Keller et al 2001;Dugué et al 2005;Crook et al 2006;Dufour et al 2010;Hirtz et al 2012;Rahman et al 2013;Nerlich et al 2014;Ramakrishnan et al 2014;Vaaga et al 2014;Moore & Trussell, 2017). Therefore, mixed GABA-glycine inhibition has been implicated (Kotak et al 1998;Dumoulin et al 2001;Keller et al 2001;Muller et al 2006;Dufour et al 2010;Apostolides & Trussell, 2013;Ishibashi et al 2013;Nerlich et al 2017; but see Hnasko & Edwards, 2012).…”