Structural and Functional Development of Inhibitory Connections from the Medial Nucleus of the Trapezoid Body to the Superior Paraolivary Nucleus.

The medial nucleus of the trapezoid body (MNTB) in the auditory brainstem is the principal source of synaptic inhibition to several functionally distinct auditory nuclei. Prominent projections of individual MNTB neurons comprise the major binaural nuclei that are involved in the early processing stages of sound localization as well as the superior paraolivary nucleus (SPON), which contains monaural neurons that extract rapid changes in sound intensity to detect sound gaps and rhythmic oscillations that commonly occur in animal calls and human speech. While the processes that guide the development and refinement of MNTB axon collaterals to the binaural nuclei have become increasingly understood, little is known about the development of MNTB collaterals to the monaural SPON.

Embryonic medial ganglionic eminence cells survive and integrate into the inferior colliculus of adult mice.

Acoustic overexposure can lead to decreased inhibition in auditory centers, including the inferior colliculus (IC), and has been implicated in the development of central auditory pathologies. While systemic drugs that increase GABAergic transmission have been shown to provide symptomatic relief, their side effect profiles impose an upper-limit on the dose and duration of use. A treatment that locally increases inhibition in auditory nuclei could mitigate these side effects.

Long-term potentiation of glycinergic synapses by semi-natural stimulation patterns during tonotopic map refinement.

Before the onset of hearing, cochlea-generated patterns of spontaneous spike activity drive the maturation of central auditory circuits. In the glycinergic sound localization pathway from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) this spontaneous activity guides the strengthening and silencing of synapses which underlies tonotopic map refinement. However, the mechanisms by which patterned activity regulates synaptic refinement in the MNTB-LSO pathway are still poorly understood.

Role of GluA3 AMPA Receptor Subunits in the Presynaptic and Postsynaptic Maturation of Synaptic Transmission and Plasticity of Endbulb-Bushy Cell Synapses in the Cochlear Nucleus.

The AMPA receptor (AMPAR) subunit GluA3 has been suggested to shape synaptic transmission and activity-dependent plasticity in endbulb-bushy cell synapses (endbulb synapses) in the anteroventral cochlear nucleus, yet the specific roles of GluA3 in the synaptic transmission at endbulb synapses remains unexplored. Here, we compared WT and GluA3 KO mice of both sexes and identified several important roles of GluA3 in the maturation of synaptic transmission and short-term plasticity in endbulb synapses. We show that GluA3 largely determines the ultrafast kinetics of endbulb synapses glutamatergic currents by promoting the insertion of postsynaptic AMPARs that contain fast desensitizing flop subunits.

And the Band Keeps Marching On.

Before the onset of hearing, activity in the developing auditory system is dominated by periodic bursts of action potentials that originate in the cochlea from where they propagate up the central auditory pathway. In this issue of Neuron, Babola et al. (2018) provide new insight into the spatiotemporal organization of prehearing activity in vivo and its homeostatic control.

Mice Lacking the Alpha9 Subunit of the Nicotinic Acetylcholine Receptor Exhibit Deficits in Frequency Difference Limens and Sound Localization.

Sound processing in the cochlea is modulated by cholinergic efferent axons arising from medial olivocochlear neurons in the brainstem. These axons contact outer hair cells in the mature cochlea and inner hair cells during development and activate nicotinic acetylcholine receptors composed of α9 and α10 subunits. The α9 subunit is necessary for mediating the effects of acetylcholine on hair cells as genetic deletion of the α9 subunit results in functional cholinergic de-efferentation of the cochlea.

Noise Trauma-Induced Behavioral Gap Detection Deficits Correlate with Reorganization of Excitatory and Inhibitory Local Circuits in the Inferior Colliculus and Are Prevented by Acoustic Enrichment.

Hearing loss leads to a host of cellular and synaptic changes in auditory brain areas that are thought to give rise to auditory perception deficits such as temporal processing impairments, hyperacusis, and tinnitus. However, little is known about possible changes in synaptic circuit connectivity that may underlie these hearing deficits. Here, we show that mild hearing loss as a result of brief noise exposure leads to a pronounced reorganization of local excitatory and inhibitory circuits in the mouse inferior colliculus.

Mapping Auditory Synaptic Circuits with Photostimulation of Caged Glutamate.

Photostimulation of neurons with caged glutamate is a viable tool for mapping the strength and spatial distribution of synaptic networks in living brain slices. In photostimulation experiments, synaptic connectivity is assessed by eliciting action potentials in putative presynaptic neurons via focal photolysis of caged glutamate, while measuring postsynaptic responses via intracellular recordings. Two approaches are commonly used for delivering light to small, defined areas in the slice preparation; an optical fiber-based method and a laser-scanning-based method.

Excitation by Axon Terminal GABA Spillover in a Sound Localization Circuit.

Synapses from neurons of the medial nucleus of the trapezoid body (MNTB) onto neurons of the lateral superior olive (LSO) in the auditory brainstem are glycinergic in maturity, but also GABAergic and glutamatergic in development. The role for this neurotransmitter cotransmission is poorly understood. Here we use electrophysiological recordings in brainstem slices from P3-P21 mice to demonstrate that GABA release evoked from MNTB axons can spill over to neighboring MNTB axons and cause excitation by activating GABAAR.

Hyperpolarization-independent maturation and refinement of GABA/glycinergic connections in the auditory brain stem.

During development GABA and glycine synapses are initially excitatory before they gradually become inhibitory. This transition is due to a developmental increase in the activity of neuronal potassium-chloride cotransporter 2 (KCC2), which shifts the chloride equilibrium potential (ECl) to values more negative than the resting membrane potential. While the role of early GABA and glycine depolarizations in neuronal development has become increasingly clear, the role of the transition to hyperpolarization in synapse maturation and circuit refinement has remained an open question.

Development of intrinsic connectivity in the central nucleus of the mouse inferior colliculus.

The inferior colliculus (IC) in the mammalian midbrain is the major subcortical auditory integration center receiving ascending inputs from almost all auditory brainstem nuclei as well as descending inputs from the thalamus and cortex. In addition to these extrinsic inputs, the IC also contains a dense network of local, intracollicular connections, which are thought to provide gain control and contribute to the selectivity for complex acoustic features. However, in contrast to the organization of extrinsic IC afferents, the development and functional organization of intrinsic connections in the IC has remained poorly understood.

The precise temporal pattern of prehearing spontaneous activity is necessary for tonotopic map refinement.

Patterned spontaneous activity is a hallmark of developing sensory systems. In the auditory system, rhythmic bursts of spontaneous activity are generated in cochlear hair cells and propagated along central auditory pathways. The role of these activity patterns in the development of central auditory circuits has remained speculative.

An optical fiber-based uncaging system.

This article describes the assembly and performance of a simple and inexpensive ultraviolet-flash system suitable for rapid focal photolysis of caged compounds in cultured neurons and brain slices. Advantages and limitations of this system are discussed. Examples are provided illustrating how this system can be used for stimulating neurons and mapping their functional inputs in brain slices.

Targeted single-neuron infection with rabies virus for transneuronal multisynaptic tracing.

The transynaptic and retrograde spread of rabies virus make it an efficient and robust transneuronal tracer, capable of revealing connectivity patterns of multisynaptic, neuronal circuits with great detail. Current techniques begin by infecting many neurons simultaneously, from which higher-order neurons are then labeled sequentially in time. Here we report on a method that can initially infect a single neuron-of-choice, allowing for greater precision and specificity of labeled circuits.

Cannabinoid receptor expression at the MNTB-LSO synapse in developing rats.

The organization of developing auditory circuits depends on the elimination of aberrant connections and strengthening of appropriate ones. Endocannabinoid mediated plasticity is a proposed mechanism for this refinement. Here we investigated for the anatomical presence of cannabinoid receptors (CB1R) in the lateral superior olive (LSO) and medial nucleus of the trapezoid body (MNTB) of developing rats.

Paired recordings from distant inhibitory neuron pairs by a sequential scanning approach.

Simultaneous recordings from connected neuron pairs have brought important insights into synaptic communication between neurons. However, patch clamp recordings from neuron pairs have been largely restricted to brain areas in which connections among nearby neurons exist at a relatively high probability. In the case of more distant connections or in areas in which neurons are connected with low probability, recordings from synaptically connected neuron pairs have remained scarce.

An acoustic startle-based method of assessing frequency discrimination in mice.

The acoustic startle response (ASR) is a reflexive contraction of skeletal muscles in response to a loud, abrupt acoustic stimulus. ASR magnitude is reduced if the startle stimulus is preceded by a weaker acoustic or non-acoustic stimulus, a phenomenon known as prepulse inhibition (PPI). PPI has been used to test various aspects of sensory discrimination in both animals and humans.

Changing tune in auditory cortex.

Investigating the organization of tone representation in the rodent auditory cortex at high resolution, two new studies in this issue find that the arrangement of relative frequency responsiveness is not preserved at a fine-scale cortical level.

Glutamate co-release at GABA/glycinergic synapses is crucial for the refinement of an inhibitory map.

Many nonglutamatergic synaptic terminals in the mammalian brain contain the vesicular glutamate transporter 3 (VGLUT3), indicating that they co-release the excitatory neurotransmitter glutamate. However, the functional role of glutamate co-transmission at these synapses is poorly understood. In the auditory system, VGLUT3 expression and glutamate co-transmission are prominent in a developing GABA/glycinergic sound-localization pathway.

NMDAR-Mediated Calcium Transients Elicited by Glutamate Co-Release at Developing Inhibitory Synapses.

Before hearing onset, the topographic organization of the inhibitory sound localization pathway from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) is refined by means of synaptic silencing and strengthening. During this refinement period MNTB-LSO synapses not only release GABA and glycine but also release glutamate. This co-released glutamate can elicit postsynaptic currents that are predominantly mediated by NMDA receptors (NMDARs).

Competing pathways in the photo-Favorskii rearrangement and release of esters: studies on fluorinated p-hydroxyphenacyl-caged GABA and glutamate phototriggers.

Three new trifluoromethylated p-hydroxyphenacyl (pHP)-caged gamma-aminobutyric acid (GABA) and glutamate (Glu) derivatives have been examined for their efficacy as photoremovable protecting groups in aqueous solution. Through the replacement of hydrogen with fluorine, e.g.

Tonotopic reorganization of developing auditory brainstem circuits.

A fundamental organizing principle of auditory brain circuits is tonotopy, the orderly representation of the sound frequency to which neurons are most sensitive. Tonotopy arises from the coding of frequency along the cochlea and the topographic organization of auditory pathways. The mechanisms that underlie the establishment of tonotopy are poorly understood.

Protein kinase C regulation of neuronal zinc signaling mediates survival during preconditioning.

Sub-lethal activation of cell death processes initiate pro-survival signaling cascades. As intracellular Zn(2+) liberation mediates neuronal death pathways, we tested whether a sub-lethal increase in free Zn(2+) could also trigger neuroprotection. Neuronal free Zn(2+) transiently increased following preconditioning, and was both necessary and sufficient for conferring excitotoxic tolerance.