A Developmental Shift from GABAergic to Glycinergic Transmission in the Central Auditory System

Abstract

GABAergic and glycinergic circuits are found throughout the auditory brainstem, and it is generally assumed that transmitter phenotype is established early in development. The present study documents a profound transition from GABAergic to glycinergic transmission in the gerbil lateral superior olive (LSO) during the first 2 postnatal weeks. Whole-cell voltage-clamp recordings were obtained from LSO neurons in a brain slice preparation, and IPSCs were evoked by electrical stimulation of the medial nucleus of the trapezoid body (MNTB), a known glycinergic projection in adult animals. GABAergic and glycinergic components were identified by blocking transmission with bicuculline and strychnine (SN), respectively. In the medial limb of LSO, there was a dramatic change in the GABAergic IPSC component, decreasing from 78% at postnatal day 3 (P3)-P5 to 12% at P12-P16. There was an equal and opposite increase in the glycinergic component during this same period. Direct application of GABA also elicited significantly larger amplitude and longer duration responses in P3-P5 neurons compared with glycine-evoked responses. In contrast, MNTB-evoked IPSCs in lateral limb neurons were more sensitive to SN throughout development. Consistent with the electrophysiological observations, there was a reduction in staining for the beta2,3-GABAA receptor subunit from P4 to P14, whereas staining for the glycine receptor-associated protein gephyrin increased. Brief exposure to baclofen depressed transmission at excitatory and inhibitory synapses for approximately 15 min, suggesting a GABAB-mediated metabotropic signal. Collectively, these data demonstrate a striking switch from GABAergic to glycinergic transmission during postnatal development. Although GABA and glycine elicit similar postsynaptic ionotropic responses, our results raise the possibility that GABAergic transmission in neonates may play a developmental role distinct from that of glycine.

Reciprocal developmental regulation of presynaptic ionotropic receptors

“…This increase parallels the presynaptic glycine receptor localization that we have observed and coincides with an increase in glycine immunoreactivity of the glycinergic MNTB neurons themselves (35). During this time, striking changes take place in the pharmacology of inhibition in targets of the MNTB, lateral superior olive, and medial superior olive, in which slow GABAergic transmission abates and glycinergic transmission is strengthened (11,13,35). Thus, the change in expression of presynaptic receptors takes place in the context of other shifts in receptors and transmitters mediating synaptic transmission.…”

“…Other studies have described several major changes in inhibitory transmission in nuclei of the superior olivary complex. In the lateral superior olive, inhibitory transmission shifts from depolarizing to hyperpolarizing in the first week after birth (11,12). Moreover, IPSCs generated by MNTB neurons in the lateral superior olive and the medial superior olive initially are mediated in part by GABA and, later, become exclusively glycinergic in the 2 weeks after birth (11,13).…”

Mixed Inhibitory Synaptic Balance Correlates with Glutamatergic Synaptic Phenotype in Cerebellar Unipolar Brush Cells

“…In other structures, GABAergic inhibition may predominate in young synapses of mixed inhibitory networks, whereas glycinergic components prevail at more mature stages (Kotak et al, 1998;Keller et al, 2001;Nabekura et al, 2004). This is unlikely to be the source of the heterogeneity reported here, because experiments were performed in 17-to 22-d-old rats, when the morphological maturation of the UBC brush is almost finished (Morin et al, 2001), and GABAergic transmission persists in adults (C.V.R., S.D., M.A.D., unpublished results).…”

Glycinergic/GABAergic synapses in the lateral superior olive are excitatory in neonatal C57Bl/6J mice

“…These data indicate that MNTB-evoked PSPs are primarily depolarizing up to P3 and hyperpolarizing thereafter. Thus, compared to rats [11] or gerbils [12] MNTB-evoked PSPs in mice become hyperpolarizing 5-7 days earlier, consistent with the somewhat faster maturation of the mouse auditory system [5].…”

“…Information from the contralateral ear reaches the LSO via a highly tonotopically organized, inhibitory pathway that arises in the medial nucleus of the trapezoid body (MNTB). This MNTB-LSO pathway uses the neurotransmitter glycine and, in neonatal animals, also uses GABA [12]. During early postnatal development, the spatial connectivity pattern of this inhibitory MNTB-LSO pathway is sharpened by activity-dependent mechanisms resulting in the precise tonotopic organization seen in adult animals (for review see [15,16]).…”