Autifony Srl Laboratories

Verona, Italy

Autifony Srl Laboratories

Verona, Italy

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Weatherstone J.H.,University of Washington | Kopp-Scheinpflug C.,University of Leicester | Kopp-Scheinpflug C.,Ludwig Maximilians University of Munich | Pilati N.,University of Leicester | And 6 more authors.
Journal of Neurophysiology | Year: 2017

The medial nucleus of the trapezoid body (MNTB) is an important source of inhibition during the computation of sound location. It transmits fast and precisely timed action potentials at high frequencies; this requires an efficient calcium clearance mechanism, in which plasma membrane calcium ATPase 2 (PMCA2) is a key component. Deafwaddler (dfw2J) mutant mice have a null mutation in PMCA2 causing deafness in homozygotes (dfw2J/ dfw2J) and high-frequency hearing loss in heterozygotes (+/dfw2J). Despite the deafness phenotype, no significant differences in MNTB volume or cell number were observed in dfw2J homozygous mutants, suggesting that PMCA2 is not required for MNTB neuron survival. The MNTB tonotopic axis encodes high to low sound frequencies across the medial to lateral dimension. We discovered a cell size gradient along this axis: lateral neuronal somata are significantly larger than medially located somata. This size gradient is decreased in +/dfw2J and absent in dfw2J/dfw2J. The lack of acoustically driven input suggests that sound-evoked activity is required for maintenance of the cell size gradient. This hypothesis was corroborated by selective elimination of auditory hair cell activity with either hair cell elimination in Pou4f3 DTR mice or inner ear tetrodotoxin (TTX) treatment. The change in soma size was reversible and recovered within 7 days of TTX treatment, suggesting that regulation of the gradient is dependent on synaptic activity and that these changes are plastic rather than permanent. NEW & NOTEWORTHY Neurons of the medial nucleus of the trapezoid body (MNTB) act as fast-spiking inhibitory interneurons within the auditory brain stem. The MNTB is topographically organized, with low sound frequencies encoded laterally and high frequencies medially. We discovered a cell size gradient along this axis: lateral neurons are larger than medial neurons. The absence of this gradient in deaf mice lacking plasma membrane calcium ATPase 2 suggests an activity-dependent, calcium-mediated mechanism that controls neuronal soma size. © 2017, American Physiological Society. All rights reserved.


Pilati N.,Autifony Srl Laboratories | Pilati N.,University of Leicester | Linley D.M.,University of Leicester | Selvaskandan H.,University of Leicester | And 5 more authors.
Journal of Physiology | Year: 2016

Key points: Lateral superior olive (LSO) principal neurons receive AMPA receptor (AMPAR) - and NMDA receptor (NMDAR)-mediated EPSCs and glycinergic IPSCs. Both EPSCs and IPSCs have slow kinetics in prehearing animals, which during developmental maturation accelerate to sub-millisecond decay time-constants. This correlates with a change in glutamate and glycine receptor subunit composition quantified via mRNA levels. The NMDAR-EPSCs accelerate over development to achieve decay time-constants of 2.5 ms. This is the fastest NMDAR-mediated EPSC reported. Acoustic trauma (AT, loud sounds) slow AMPAR-EPSC decay times, increasing GluA1 and decreasing GluA4 mRNA. Modelling of interaural intensity difference suggests that the increased EPSC duration after AT shifts interaural level difference to the right and compensates for hearing loss. Two months after AT the EPSC decay times recovered to control values. Synaptic transmission in the LSO matures by postnatal day 20, with EPSCs and IPSCs having fast kinetics. AT changes the AMPAR subunits expressed and slows the EPSC time-course at synapses in the central auditory system. Abstract: Damaging levels of sound (acoustic trauma, AT) diminish peripheral synapses, but what is the impact on the central auditory pathway? Developmental maturation of synaptic function and hearing were characterized in the mouse lateral superior olive (LSO) from postnatal day 7 (P7) to P96 using voltage-clamp and auditory brainstem responses. IPSCs and EPSCs show rapid acceleration during development, so that decay kinetics converge to similar sub-millisecond time-constants (τ, 0.87 ± 0.11 and 0.77 ± 0.08 ms, respectively) in adult mice. This correlated with LSO mRNA levels for glycinergic and glutamatergic ionotropic receptor subunits, confirming a switch from Glyα2 to Glyα1 for IPSCs and increased expression of GluA3 and GluA4 subunits for EPSCs. The NMDA receptor (NMDAR)-EPSC decay τ accelerated from >40 ms in prehearing animals to 2.6 ± 0.4 ms in adults, as GluN2C expression increased. In vivo induction of AT at around P20 disrupted IPSC and EPSC integration in the LSO, so that 1 week later the AMPA receptor (AMPAR)-EPSC decay was slowed and mRNA for GluA1 increased while GluA4 decreased. In contrast, GlyR IPSC and NMDAR-EPSC decay times were unchanged. Computational modelling confirmed that matched IPSC and EPSC kinetics are required to generate mature interaural level difference functions, and that longer-lasting EPSCs compensate to maintain binaural function with raised auditory thresholds after AT. We conclude that LSO excitatory and inhibitory synaptic drive matures to identical time-courses, that AT changes synaptic AMPARs by expression of subunits with slow kinetics (which recover over 2 months) and that loud sounds reversibly modify excitatory synapses in the brain, changing synaptic function for several weeks after exposure. © 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society


PubMed | University of Leicester, University of Buenos Aires, University of Edinburgh and Autifony Srl Laboratories
Type: Journal Article | Journal: The Journal of physiology | Year: 2016

Lateral superior olive (LSO) principal neurons receive AMPA receptor (AMPAR) - and NMDA receptor (NMDAR)-mediated EPSCs and glycinergic IPSCs. Both EPSCs and IPSCs have slow kinetics in prehearing animals, which during developmental maturation accelerate to sub-millisecond decay time-constants. This correlates with a change in glutamate and glycine receptor subunit composition quantified via mRNA levels. The NMDAR-EPSCs accelerate over development to achieve decay time-constants of 2.5ms. This is the fastest NMDAR-mediated EPSC reported. Acoustic trauma (AT, loud sounds) slow AMPAR-EPSC decay times, increasing GluA1 and decreasing GluA4 mRNA. Modelling of interaural intensity difference suggests that the increased EPSC duration after AT shifts interaural level difference to the right and compensates for hearing loss. Two months after AT the EPSC decay times recovered to control values. Synaptic transmission in the LSO matures by postnatal day 20, with EPSCs and IPSCs having fast kinetics. AT changes the AMPAR subunits expressed and slows the EPSC time-course at synapses in the central auditory system.Damaging levels of sound (acoustic trauma, AT) diminish peripheral synapses, but what is the impact on the central auditory pathway? Developmental maturation of synaptic function and hearing were characterized in the mouse lateral superior olive (LSO) from postnatal day 7 (P7) to P96 using voltage-clamp and auditory brainstem responses. IPSCs and EPSCs show rapid acceleration during development, so that decay kinetics converge to similar sub-millisecond time-constants (, 0.870.11and 0.770.08ms, respectively) in adult mice. This correlated with LSO mRNA levels for glycinergic and glutamatergic ionotropic receptor subunits, confirming a switch from Gly2 to Gly1 for IPSCs and increased expression of GluA3 and GluA4 subunits for EPSCs. The NMDA receptor (NMDAR)-EPSC decay accelerated from >40ms in prehearing animals to 2.60.4ms in adults, as GluN2C expression increased. In vivo induction of AT at around P20 disrupted IPSC and EPSC integration in the LSO, so that 1week later the AMPA receptor (AMPAR)-EPSC decay was slowed and mRNA for GluA1 increased while GluA4 decreased. In contrast, GlyR IPSC and NMDAR-EPSC decay times were unchanged. Computational modelling confirmed that matched IPSC and EPSC kinetics are required to generate mature interaural level difference functions, and that longer-lasting EPSCs compensate to maintain binaural function with raised auditory thresholds after AT. We conclude that LSO excitatory and inhibitory synaptic drive matures to identical time-courses, that AT changes synaptic AMPARs by expression of subunits with slow kinetics (which recover over 2months) and that loud sounds reversibly modify excitatory synapses in the brain, changing synaptic function for several weeks after exposure.

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