Neuromodulation mediated by metabotropic glutamate receptors (mGluRs) regulates many brain functions. However, the functions of mGluRs in the auditory system under normal and diseased states are not well understood. The medial nucleus of the trapezoid body (MNTB) is a critical nucleus in the auditory brainstem nuclei involved in sound localization. In addition to the classical calyx excitatory inputs, MNTB neurons also receive synaptic inhibition and it remains entirely unknown how this inhibition is regulated. Here, using whole-cell voltage clamp in brain slices, we investigated group I mGluR (mGluR I)-mediated modulation of the glycinergic and GABAergic inputs to MNTB neurons in both WT mice and a fragile X syndrome (FXS) mouse model (both sexes) in which the fragile X mental retardation gene 1 is knocked out ( KO), causing exaggerated activity of mGluR I and behavioral phenotypes. Activation of mGluR I by (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG) increased the frequency and amplitude of glycinergic spontaneous IPSCs (sIPSCs) in both WT and KO neurons in a voltage-gated sodium channel-dependent fashion, but did not modulate glycinergic evoked IPSCs (eIPSCs). In contrast, 3,5-DHPG did not affect GABAergic sIPSCs, but did suppress eIPSCs in WT neurons via endocannabinoid signaling. In the KO, the effect of 3,5-DHPG on GABAergic eIPSCs was highly variable, which supports the notion of impaired GABAergic signaling in the FXS model. The differential modulation of sIPSC and eIPSC and differential modulation of glycinergic and GABAergic transmission suggest distinct mechanisms responsible for spontaneous and evoked release of inhibitory transmitters and their modulation through the mGluR I signaling pathway. Neurons communicate with each other through the release of neurotransmitters, which assumes two basic modes, spontaneous and evoked release. These two release modes are believed to function using the same vesicle pool and machinery. Recent works have challenged this dogma, pointing to distinct vesicle release mechanisms underlying the two release modes. Here, we provide the first evidence in the central auditory system supporting this novel concept. We discovered neural-transmitter- and release-mode-specific neuromodulation of inhibitory transmission by metabotropic glutamate receptors and revealed part of the signaling pathways underlying this differential modulation. The results establish the foundation for a multitude of directions to study physiological significance of different release modes in auditory processing.
One emerging concept in neuroscience states that synaptic vesicles and the molecular machinery underlying spontaneous transmitter release are different from those underlying action potential-driven synchronized transmitter release. Differential neuromodulation of these two distinct release modes by metabotropic glutamate receptors (mGluRs) constitutes critical supporting evidence. However, the mechanisms underlying such a differential modulation are not understood. Here, we investigated the mechanisms of the modulation by group I mGluRs (mGluR Is) on spontaneous glutamate release in the medial nucleus of the trapezoid body (MNTB), an auditory brainstem nucleus critically involved in sound localization. Whole-cell patch recordings from brainstem slices of mice of both sexes were performed. Activation of mGluR I by 3,5-dihydroxyphenylglycine (3,5-DHPG; 200 lM) produced an inward current at 260 mV and increased spontaneous glutamate release in MNTB neurons. Pharmacological evidence indicated involvement of both mGluR1 and mGluR5, which was further supported for mGluR5 by immunolabeling results. The modulation was eliminated by blocking Na V channels (tetrodotoxin, 1 lM), persistent Na 1 current (I NaP ; riluzole, 10 lM), or Ca V channels (CdCl 2 , 100 lM). Presynaptic calyx recordings revealed that 3,5-DHPG shifted the activation of I NaP to more hyperpolarized voltages and increased I NaP at resting membrane potential. Our data indicate that mGluR I enhances spontaneous glutamate release via regulation of I NaP and subsequent Ca 21 -dependent processes under resting condition.
The ability of humans and animals to localize the source of a sound in a complex acoustic environment facilitates communication and survival. Two cues are used for sound localization at horizontal planes, interaural time and level differences (ITD and ILD), which are analyzed by distinct neural circuits in the brainstem. Here, we review the studies on metabotropic glutamate receptor (mGluR)-mediated neuromodulation of both intrinsic and synaptic properties of brainstem neurons in these circuits. Both mammalian and avian animal models have been used, with each having their advantages that are not present in the other. For the mammalian model, we discuss mGluR neuromodulation in the ILD circuit, with an emphasis on the recent discovery of differential modulation of synaptic transmission of different transmitter release modes. For the avian model, we focus on reviewing mGluR neuromodulation in the ITD pathway, with an emphasis on tonotopic distribution and synaptic plasticity of mGluR modulation in coincidence detector neurons. Future works are proposed to further investigate the functions and mechanisms of mGluRs in the sound localization circuits.
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