A depolarizing inhibitory response to GABA in brainstem auditory neurons of the chick

doi:10.1016/0006-8993(95)00130-I

Brain Research

Volume 677, Issue 1, 17 April 1995, Pages 117-126

https://doi.org/10.1016/0006-8993(95)00130-I Get rights and content

Abstract

Neurons in the brainstem auditory nuclei, n. magnocellularis and n. laminaris, of the chick are contacted by terminals containing the inhibitory neurotransmitter γ-aminobutyric acid (GABA). In this report we describe the physiological response of these neurons to GABA using an in vitro slice preparation. In brainstem auditory neurons, GABA produced a depolarization of up to 20 mV and an associated decrease in input resistance. This depolarization was inhibitory; action potentials generated by orthodromic synaptic drive, antidromic stimulation and intracellular current injection were prevented by GABA application. The GABA response still occurred when synaptic transmission was prevented by perfusing the slice with a medium containing low Ca²⁺ and high Mg²⁺ concentrations. Thus, the effects of GABA were directly on the postsynaptic neuron and not via an interneuron. Whole-cell voltage clamp of neurons revealed that the reversal potential of the inward current was approximately −45 mV, suggesting that the channel responsible for this response is not selective for Cl⁻ or K⁺. Pharmacological analyses suggest that this GABA receptor has properties distinct from those typical of either GABA_a or GABA_b receptors. Although a similar response was observed with the GABA_a agonist, muscimol, it was not blocked by the GABA_a antagonist, bicuculline. The response was not evoked by the GABA_b agonist, baclofen, and was not blocked by the GABA_b antagonist phaclofen. This unusual depolarizing response is not a common feature of all brainstem neurons. Neurons located in the neighboring medial vestibular nucleus show a more traditional response to GABA application. At resting potential, these neurons show a hyperpolarizing or biphasic response associated with a decrease in input resistance and inhibition of their spontaneous activity. GABA-induced responses in the medial vestibular nucleus are blocked by bicuculline. These results suggest that an unusual form of the GABA receptor is present in the brainstem auditory system of the chick. It is possible that this form of GABA receptor provides an efficient mechanism for inhibiting the relatively powerful EPSPs received by brainstem auditory neurons, or it may play a trophic role in the afferent regulation of neuronal integrity in this system.

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We were puzzled by our observation that both transporters, the inward NKCC1 as well as the outward KCC2 transporter increased their expression levels during development with highest expression occurring at P1 (last age analyzed). Several studies in the auditory brainstem report the chloride reversal potential to remain more positive than the resting potential even at post-hatch stages (Hyson et al., 1995; Monsivais et al., 2000; Monsivais and Rubel, 2001). Based on this, our initial hypothesis was a higher expression of NKCC1 at all developmental ages and a low or absent expression of KCC2 in later ages.
GABAergic transmission changes from depolarization to hyperpolarization in most vertebrate brain regions during development. By contrast, in the auditory brainstem of chicken a depolarizing effect of GABA persists after hatching. Since auditory brainstem neurons that receive GABAergic input have a Cl⁻ reversal potential above resting membrane potential, a specifically tuned activity of Cl⁻ transporters is likely. We here present a developmental study of the expression patterns of several members of the SLC12 family (NKCC1, NKCC2, KCC1, KCC2, KCC4, CCC6, CCC9) and of AE3 at developmental ages E7, E10, E12, E15, E17, and P1 with quantitative RT-PCR. NKCC2 and CCC9 were not detected in auditory brainstem (positive control: kidney). KCC1, CCC6 and AE3 were expressed, but not regulated, while NKCC1, KCC2 and KCC4 were regulated. The expression of the latter transporters increased, with KCC2 exhibiting the strongest expression at all time points. Biochemical analysis of the protein expression of NKCC1, KCC2 and KCC4 corroborated the findings on the mRNA level. All three transporters showed a localization at the outer rim of the cells, with NKCC1 and KCC2 expressed in neurons, and KCC4 predominantly in glia. The comparison of the published chloride reversal potential and expression of transporter proteins suggest strong differences in the efficiency of the three transporters. Further, the strong KCC2 expression could reflect a role in the structural development of auditory brainstem synapses that might lead to changes in the physiological properties.
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Tonotopic differentiations of ion channels ensure sound processing across frequencies. Afferent input plays a critical role in differentiations. We demonstrate here in organotypic culture of chicken cochlear nucleus that expression of Kv1.1 was coupled with Ca²⁺ to a different degree depending on tonotopic regions, thereby differentiating the level of expression within the nucleus. In the culture, Kv1.1 was down-regulated and not differentiated tonotopically. Chronic depolarization increased Kv1.1 expression in a level-dependent manner. Moreover, the dependence was steeper at higher-frequency regions, which restored the differentiation. The depolarization increased Kv1.1 via activation of Cav1 channels, whereas basal Ca²⁺ level elevated similarly irrespective of tonotopic regions. Thus, the efficiency of Ca²⁺-dependent Kv1.1 expression would be fine-tuned in a tonotopic-region-specific manner, emphasizing the importance of neuronal tonotopic identity as well as pattern of afferent input in the tonotopic differentiation of the channel in the auditory circuit.
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This proposed mechanism has clear parallels to what may be happening in the chick NM following deafness. Unlike the mammalian system in which GABAA activation typically induces depolarization only during development, NM neurons continue to show a depolarizing response to GABA in maturity (Hyson et al., 1995). This depolarization may be sufficient to activate voltage-gated Ca2+ channels and thus increase intracellular Ca2+concentrations.
To better understand the effects of deafness on the brain, these experiments examine how disrupted balance between excitatory and inhibitory neurotransmission following the loss of excitatory input from the auditory nerve alters the central auditory system. In the avian cochlear nucleus, nucleus magnocellularis (NM), deprivation of excitatory input induced by deafness triggers neuronal death. While this neuronal death was previously accredited to the loss of excitatory drive, the present experiments examine an alternative hypothesis: that inhibitory input to NM, which may also be affected by deafness, contributes to neuronal death in NM. Using an in vitro slice preparation in which excitatory input from the auditory nerve is absent, we pharmacologically altered GABA receptor activation in NM, and assayed an early marker of neuronal health, antigenicity for the ribosomal antibody Y10B (Y10B-ir). We found that GABA decreases Y10B-ir, and that GABA_A activation is necessary for the GABA-induced effect. We further found that endogenous GABA_A activation similarly decreases Y10B-ir and this decrease requires extracellular Ca²⁺. Our results suggest that, in the absence of excitatory input, endogenous activation of ionotropic GABA_A receptors is detrimental to NM neurons.
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On the physiological level, a notable difference is observed between the mammalian MSO and the nucleus laminaris, its avian counterpart. Both are involved in azimuthal sound localization, but the MSO receives phasic glycinergic input that causes hyperpolarization (Grothe and Sanes, 1993, 1994), whereas the nucleus laminaris receives tonic GABAergic inhibition that causes depolarization (Hyson et al., 1995; Monsivais et al., 2000). Current evidence indicates that the nucleus laminaris processes ITDs according to the Jeffress model with the use of delay lines (Jeffress, 1948), whereas in mammals, they might be computed from the overall discharge rate within the broadly tuned MSO (Lesica et al., 2010).
Localization of sound sources is a central aspect of auditory processing. A unique feature of mammals is the smooth, tonotopically organized extension of the hearing range to high frequencies (HF) above 10 kHz, which likely induced positive selection for novel mechanisms of sound localization. How this change in the auditory periphery is accompanied by changes in the central auditory system is unresolved. I will argue that the major VGlut2⁺ excitatory projection neurons of sound localization circuits (dorsal cochlear nucleus (DCN), lateral and medial superior olive (LSO and MSO)) represent serial homologs with modifications, thus being paramorphs. This assumption is based on common embryonic origin from an Atoh1⁺/Wnt1⁺ cell lineage in the rhombic lip of r5, same cell birth, a fusiform cell morphology, shared genetic components such as Lhx2 and Lhx9 transcription factors, and similar projection patterns. Such a parsimonious evolutionary mechanism likely accelerated the emergence of neurons for sound localization in all three dimensions. Genetic analyses indicate that auditory nuclei in fish, birds, and mammals receive contributions from the same progenitor lineages. Anatomical and physiological differences and the independent evolution of tympanic ears in vertebrate groups, however, argue for convergent evolution of sound localization circuits in tetrapods (amphibians, reptiles, birds, and mammals). These disparate findings are discussed in the context of the genetic architecture of the developing hindbrain, which facilitates convergent evolution. Yet, it will be critical to decipher the gene regulatory networks underlying development of auditory neurons across vertebrates to explore the possibility of homologous neuronal populations.
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As the major excitatory neurotransmitter used in the vertebrate brain, glutamate activates ionotropic and metabotropic glutamate receptors (mGluRs), which mediate fast and slow neuronal actions, respectively. Important modulatory roles of mGluRs have been shown in many brain areas, and drugs targeting mGluRs have been developed for the treatment of brain disorders. Here, I review studies on mGluRs in the auditory system. Anatomical expression of mGluRs in the cochlear nucleus has been well characterized, while data for other auditory nuclei await more systematic investigations at both the light and electron microscopy levels. The physiology of mGluRs has been extensively studied using in vitro brain slice preparations, with a focus on the lower auditory brainstem in both mammals and birds. These in vitro physiological studies have revealed that mGluRs participate in neurotransmission, regulate ionic homeostasis, induce synaptic plasticity, and maintain the balance between excitation and inhibition in a variety of auditory structures. However, very few in vivo physiological studies on mGluRs in auditory processing have been undertaken at the systems level. Many questions regarding the essential roles of mGluRs in auditory processing still remain unanswered and more rigorous basic research is warranted.
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A depolarizing inhibitory response to GABA in brainstem auditory neurons of the chick

Abstract

Trends Neurosci.

Hearing Res.

Neurosci. Lett.

Neuroscience

Brain Res.

Neuroscience

Hearing Res.

Neurosci. Lett.

Eur. J. Pharmacol.

Brain Res.

Prog. Neurobiol.

Neuron

Dev. Brain Res.

Dev. Brain Res.

GABAa receptor-mediated increase in membrane chloride conductance in rat paratracheal neurones

Br. J. Pharmacol.

Two different responses of hippocampal pyramidal cells to application of γ-aminobutyric acid

J. Physiol.

Ascending projections of the primary cochlear nuclei and nucleus laminaris in the pigeon

J. Comp. Neurol.

Projection of the cochlear and lagenar nerves on the cochlear nuclei of the pigeon

J. Comp. Neurol.

Mechanism of anion permeation through channels gated by glycine and γ-aminobutyric acid in mouse cultured spinal neurones

J. Physiol.

The distribution of GABAergic neurons and terminals is correlated with funcional inhibition in the auditory system of the barn owl

J. Comp. Neurol.

Development of GABA-immunoreactivity in brainstem auditory nuclei of the chick: Ontogeny of gradients in terminal staining

J. Comp. Neurol.

Pharmacology of GABA receptor Cl- channels in rat retinal bipolar cells

Nature

The role of GABAergic inhibition in processing of interaural time difference in the owl's auditory system

J. Neurosci.

GABA_a receptor-mediated increase in membrane chloride conductance in rat paratracheal neurones