Physiological and anatomical development of glycinergic inhibition in the mouse superior paraolivary nucleus following hearing onset

Rajaram, Ezhilarasan; Pagella, Sara; Grothe, Benedikt; Kopp‐Scheinpflug, Conny

doi:10.1152/jn.00053.2020

Cited by 3 publications

(3 citation statements)

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“…What effect will the more negative reversal potential have in SPN neurons? Remarkably, SPN neurons show very stable, strongly hyperpolarized IPSC reversal potentials after the D/H shift has taken place, without further changes after hearing onset around P12 92 . This suggests that the crucial window for adjusting the strength of inhibition is indeed around the D/H shift.…”

Section: Discussionmentioning

confidence: 97%

Serine 937 phosphorylation enhances KCC2 activity and strengthens synaptic inhibition

Radulovic,

Rajaram,

Ebbers

et al. 2023

Sci Rep

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The potassium chloride cotransporter KCC2 is crucial for Cl- extrusion from mature neurons and thus key to hyperpolarizing inhibition. Auditory brainstem circuits contain well-understood inhibitory projections and provide a potent model to study the regulation of synaptic inhibition. Two peculiarities of the auditory brainstem are (i) posttranslational activation of KCC2 during development and (ii) extremely negative reversal potentials in specific circuits. To investigate the role of the potent phospho-site serine 937 therein, we generated a KCC2 Thr934Ala/Ser937Asp double mutation, in which Ser937 is replaced by aspartate mimicking the phosphorylated state, and the neighbouring Thr934 arrested in the dephosphorylated state. This double mutant showed a twofold increased transport activity in HEK293 cells, raising the hypothesis that auditory brainstem neurons show lower [Cl−]i. and increased glycinergic inhibition. This was tested in a mouse model carrying the same KCC2 Thr934Ala/Ser937Asp mutation by the use of the CRISPR/Cas9 technology. Homozygous KCC2 Thr934Ala/Ser937Asp mice showed an earlier developmental onset of hyperpolarisation in the auditory brainstem. Mature neurons displayed stronger glycinergic inhibition due to hyperpolarized ECl−. These data demonstrate that phospho-regulation of KCC2 Ser937 is a potent way to interfere with the excitation-inhibition balance in neural circuits.

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Section: Discussionmentioning

confidence: 97%

Serine 937 phosphorylation enhances KCC2 activity and strengthens synaptic inhibition

Radulovic,

Rajaram,

Ebbers

et al. 2023

Sci Rep

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“…The establishment of the mature calyx of Held in MNTB requires the elimination of multiple small inputs until exactly one calyx remains, strengthens, and forms a highly reticulated encapsulation of a principal cell soma by the onset of hearing at about P12 ( Held, 1893 ; Kuwabara and Zook, 1991 ; Kuwabara et al, 1991 ; Hoffpauir et al, 2006 ; Holcomb et al, 2013 ). As calyces mature, MNTB neurons exhibit faster IPSC depression following hearing onset ( Rajaram et al, 2020 ). MNTB-LSO connections also strengthen as they decrease in IPSC amplitude leading up to hearing onset while MNTB-MSO synapse amplitudes continue to decrease following hearing onset ( Kim and Kandler, 2003 ; Magnusson et al, 2005 ; Walcher et al, 2011 ; Pilati et al, 2016 ; Rajaram et al, 2020 ).…”

Section: Medial Nucleus Of the Trapezoid Body: Development And Effect...mentioning

confidence: 99%

“…As calyces mature, MNTB neurons exhibit faster IPSC depression following hearing onset ( Rajaram et al, 2020 ). MNTB-LSO connections also strengthen as they decrease in IPSC amplitude leading up to hearing onset while MNTB-MSO synapse amplitudes continue to decrease following hearing onset ( Kim and Kandler, 2003 ; Magnusson et al, 2005 ; Walcher et al, 2011 ; Pilati et al, 2016 ; Rajaram et al, 2020 ). In the gerbil, MNTB-LSO synapse strengthening is largely completed by the third postnatal week, and studies using cochlear ablations suggest that synaptic pruning and topographic establishment during the postnatal period are activity-dependent ( Sanes et al, 1992 ; Sanes and Takács, 1993 ; Kandler and Gillespie, 2005 ).…”

Section: Medial Nucleus Of the Trapezoid Body: Development And Effect...mentioning

confidence: 99%

Synapse Maturation and Developmental Impairment in the Medial Nucleus of the Trapezoid Body

Chokr

Milinkeviciute

Cramer

2022

Front. Integr. Neurosci.

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Sound localization requires rapid interpretation of signal speed, intensity, and frequency. Precise neurotransmission of auditory signals relies on specialized auditory brainstem synapses including the calyx of Held, the large encapsulating input to principal neurons in the medial nucleus of the trapezoid body (MNTB). During development, synapses in the MNTB are established, eliminated, and strengthened, thereby forming an excitatory/inhibitory (E/I) synapse profile. However, in neurodevelopmental disorders such as autism spectrum disorder (ASD), E/I neurotransmission is altered, and auditory phenotypes emerge anatomically, molecularly, and functionally. Here we review factors required for normal synapse development in this auditory brainstem pathway and discuss how it is affected by mutations in ASD-linked genes.

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

Lee,

Clause,

Kandler

2023

J. Neurosci.

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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. In this study, we investigated the development of MNTB-SPON connections in mice of both sexes from shortly after birth to three weeks of age, which encompasses the time before and after hearing onset. Individual axon reconstructions and electrophysiological analysis of MNTB-SPON connectivity demonstrate a dramatic increase in the number of MNTB axonal boutons in the SPON before hearing onset. However, this proliferation was not accompanied by changes in the strength of MNTB-SPON connections or by changes in the structural or functional topographic precision. However, following hearing onset, the spread of single-axon boutons along the tonotopic axis increased, indicating an unexpected decrease in the tonotopic precision of the MNTB-SPON pathway. These results provide new insight into the development and organization of inhibition to SPON neurons and the regulation of developmental plasticity in diverging inhibitory pathways.Significance StatementThe superior paraolivary nucleus (SPON) is a prominent auditory brainstem nucleus involved in the early detection of sound gaps and rhythmic oscillations. The ability of SPON neurons to fire at the offset of sound depends on strong and precise synaptic inhibition provided by glycinergic neurons in the medial nucleus of the trapezoid body (MNTB). Here, we investigated the anatomical and physiological maturation of MNTB-LSO connectivity in mice before and after the onset of hearing. We observed a period of bouton proliferation without accompanying changes in topographic precision before hearing onset. This was followed by bouton elimination and an unexpected decrease in the tonotopic precision after hearing onset. These results provide new insight into the development of inhibition to the SPON.

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Physiological and anatomical development of glycinergic inhibition in the mouse superior paraolivary nucleus following hearing onset

Cited by 3 publications

References 73 publications

Serine 937 phosphorylation enhances KCC2 activity and strengthens synaptic inhibition

Serine 937 phosphorylation enhances KCC2 activity and strengthens synaptic inhibition

Synapse Maturation and Developmental Impairment in the Medial Nucleus of the Trapezoid Body

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

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