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1.
iScience ; 27(5): 109691, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38736549

RESUMEN

Salicylate is commonly used to induce tinnitus in animals, but its underlying mechanism of action is still debated. We therefore tested its effects on the firing properties of neurons in the mouse inferior colliculus (IC). Salicylate induced a large decrease in the spontaneous activity and an increase of ∼20 dB SPL in the minimum threshold of single units. In response to sinusoidally modulated noise (SAM noise) single units showed both an increase in phase locking and improved rate coding. Mice also became better at detecting amplitude modulations, and a simple threshold model based on the IC population response could reproduce this improvement. The responses to dynamic random chords (DRCs) suggested that the improved AM encoding was due to a linearization of the cochlear output, resulting in larger contrasts during SAM noise. These effects of salicylate are not consistent with the presence of tinnitus, but should be taken into account when studying hyperacusis.

2.
PLoS Biol ; 22(4): e3002586, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38683852

RESUMEN

Having two ears enables us to localize sound sources by exploiting interaural time differences (ITDs) in sound arrival. Principal neurons of the medial superior olive (MSO) are sensitive to ITD, and each MSO neuron responds optimally to a best ITD (bITD). In many cells, especially those tuned to low sound frequencies, these bITDs correspond to ITDs for which the contralateral ear leads, and are often larger than the ecologically relevant range, defined by the ratio of the interaural distance and the speed of sound. Using in vivo recordings in gerbils, we found that shortly after hearing onset the bITDs were even more contralaterally leading than found in adult gerbils, and travel latencies for contralateral sound-evoked activity clearly exceeded those for ipsilateral sounds. During the following weeks, both these latencies and their interaural difference decreased. A computational model indicated that spike timing-dependent plasticity can underlie this fine-tuning. Our results suggest that MSO neurons start out with a strong predisposition toward contralateral sounds due to their longer neural travel latencies, but that, especially in high-frequency neurons, this predisposition is subsequently mitigated by differential developmental fine-tuning of the travel latencies.


Asunto(s)
Estimulación Acústica , Gerbillinae , Neuronas , Complejo Olivar Superior , Animales , Neuronas/fisiología , Complejo Olivar Superior/fisiología , Localización de Sonidos/fisiología , Masculino , Núcleo Olivar/fisiología , Sonido , Femenino
3.
Bio Protoc ; 13(24): e4902, 2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-38156034

RESUMEN

The inferior colliculus (IC) is an important processing center in the auditory system, which also receives non-auditory sensory input. The IC consists of several subnuclei whose functional role in (non-) auditory processing and plastic response properties are best approached by studying awake animals, preferably in a longitudinal fashion. The increasing use of mice in auditory research, the availability of genetic models, and the superficial location of the IC in the mouse have made it an attractive species for studying IC function. Here, we describe a protocol for exposing the mouse IC for up to a few weeks for in vivo imaging or electrophysiology in a stable manner. This method allows for a broader sampling of the IC while maintaining the brain surface in good quality and without reopening the craniotomy. Moreover, as it is adaptable for both electrophysiological recordings of the entire IC and imaging of the dorsal IC surface, it can be applied to answer a multitude of questions. Key features • A surgical protocol for long-term physiological recordings from the same or separate neuronal populations in the inferior colliculus. • Optimized for awake in vivo experiments in the house mouse (Mus musculus).

4.
J Neurophysiol ; 130(3): 524-546, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37465872

RESUMEN

Amplitude modulation (AM) is a common feature of natural sounds, including speech and animal vocalizations. Here, we used operant conditioning and in vivo electrophysiology to determine the AM detection threshold of mice as well as its underlying neuronal encoding. Mice were trained in a Go-NoGo task to detect the transition to AM within a noise stimulus designed to prevent the use of spectral side-bands or a change in intensity as alternative cues. Our results indicate that mice, compared with other species, detect high modulation frequencies up to 512 Hz well, but show much poorer performance at low frequencies. Our in vivo multielectrode recordings in the inferior colliculus (IC) of both anesthetized and awake mice revealed a few single units with remarkable phase-locking ability to 512 Hz modulation, but not sufficient to explain the good behavioral detection at that frequency. Using a model of the population response that combined dimensionality reduction with threshold detection, we reproduced the general band-pass characteristics of behavioral detection based on a subset of neurons showing the largest firing rate change (both increase and decrease) in response to AM, suggesting that these neurons are instrumental in the behavioral detection of AM stimuli by the mice.NEW & NOTEWORTHY The amplitude of natural sounds, including speech and animal vocalizations, often shows characteristic modulations. We examined the relationship between neuronal responses in the mouse inferior colliculus and the behavioral detection of amplitude modulation (AM) in sound and modeled how the former can give rise to the latter. Our model suggests that behavioral detection can be well explained by the activity of a subset of neurons showing the largest firing rate changes in response to AM.


Asunto(s)
Colículos Inferiores , Animales , Ratones , Colículos Inferiores/fisiología , Estimulación Acústica , Sonido , Ruido , Neuronas/fisiología
5.
J Neurosci ; 43(22): 4093-4109, 2023 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-37130779

RESUMEN

The medial superior olive (MSO) is a binaural nucleus that is specialized in detecting the relative arrival times of sounds at both ears. Excitatory inputs to its neurons originating from either ear are segregated to different dendrites. To study the integration of synaptic inputs both within and between dendrites, we made juxtacellular and whole-cell recordings from the MSO in anesthetized female gerbils, while presenting a "double zwuis" stimulus, in which each ear received its own set of tones, which were chosen in a way that all second-order distortion products (DP2s) could be uniquely identified. MSO neurons phase-locked to multiple tones within the multitone stimulus, and vector strength, a measure for spike phase-locking, generally depended linearly on the size of the average subthreshold response to a tone. Subthreshold responses to tones in one ear depended little on the presence of sound in the other ear, suggesting that inputs from different ears sum linearly without a substantial role for somatic inhibition. The "double zwuis" stimulus also evoked response components in the MSO neuron that were phase-locked to DP2s. Bidendritic subthreshold DP2s were quite rare compared with bidendritic suprathreshold DP2s. We observed that in a small subset of cells, the ability to trigger spikes differed substantially between both ears, which might be explained by a dendritic axonal origin. Some neurons that were driven monaurally by only one of the two ears nevertheless showed decent binaural tuning. We conclude that MSO neurons are remarkably good in finding binaural coincidences even among uncorrelated inputs.SIGNIFICANCE STATEMENT Neurons in the medial superior olive are essential for precisely localizing low-frequency sounds in the horizontal plane. From their soma, only two dendrites emerge, which are innervated by inputs originating from different ears. Using a new sound stimulus, we studied the integration of inputs both within and between these dendrites in unprecedented detail. We found evidence that inputs from different dendrites add linearly at the soma, but that small increases in somatic potentials could lead to large increases in the probability of generating a spike. This basic scheme allowed the MSO neurons to detect the relative arrival time of inputs at both dendrites remarkably efficient, although the relative size of these inputs could differ considerably.


Asunto(s)
Localización de Sonidos , Complejo Olivar Superior , Animales , Femenino , Complejo Olivar Superior/fisiología , Gerbillinae , Neuronas/fisiología , Estimulación Acústica , Localización de Sonidos/fisiología , Núcleo Olivar/fisiología , Vías Auditivas/fisiología
6.
PLoS Comput Biol ; 17(10): e1009527, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34699519

RESUMEN

At synapses, the pre- and postsynaptic cells get so close that currents entering the cleft do not flow exclusively along its conductance, gcl. A prominent example is found in the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB), where the presynaptic action potential can be recorded in the postsynaptic cell in the form of a prespike. Here, we developed a theoretical framework for ephaptic coupling via the synaptic cleft, and we tested its predictions using the MNTB prespike recorded in voltage-clamp. The shape of the prespike is predicted to resemble either the first or the second derivative of the inverted presynaptic action potential if cleft currents dissipate either mostly capacitively or resistively, respectively. We found that the resistive dissipation scenario provided a better description of the prespike shape. Its size is predicted to scale with the fourth power of the radius of the synapse, explaining why intracellularly recorded prespikes are uncommon in the central nervous system. We show that presynaptic calcium currents also contribute to the prespike shape. This calcium prespike resembled the first derivative of the inverted calcium current, again as predicted by the resistive dissipation scenario. Using this calcium prespike, we obtained an estimate for gcl of ~1 µS. We demonstrate that, for a circular synapse geometry, such as in conventional boutons or the immature calyx of Held, gcl is scale-invariant and only defined by extracellular resistivity, which was ~75 Ωcm, and by cleft height. During development the calyx of Held develops fenestrations. We show that these fenestrations effectively minimize the cleft potentials generated by the adult action potential, which might otherwise interfere with calcium channel opening. We thus provide a quantitative account of the dissipation of currents by the synaptic cleft, which can be readily extrapolated to conventional, bouton-like synapses.


Asunto(s)
Modelos Neurológicos , Sinapsis/fisiología , Cuerpo Trapezoide/fisiología , Potenciales de Acción/fisiología , Animales , Canales de Calcio/fisiología , Biología Computacional , Ratones , Ratones Endogámicos C57BL , Terminales Presinápticos/fisiología
7.
J Physiol ; 598(20): 4603-4619, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33439501

RESUMEN

KEY POINTS: During development the giant, auditory calyx of Held forms a one-to-one connection with a principal neuron of the medial nucleus of the trapezoid body. While anatomical studies described that most of the target cells are temporarily contacted by multiple calyces, multi-calyceal innervation was only sporadically observed in in vivo recordings, suggesting a structure-function discrepancy. We correlated synaptic strength of inputs, identified in in vivo recordings, with post hoc labelling of the recorded neuron and synaptic terminals containing vesicular glutamate transporters (VGluT). During development only one input increased to the level of the calyx of Held synapse, and its strength correlated with the large VGluT cluster contacting the postsynaptic soma. As neither competing strong inputs nor multiple large VGluT clusters on a single cell were observed, our findings did not indicate a structure-function discrepancy. ABSTRACT: In adult rodents, a principal neuron in the medial nucleus of the trapezoid (MNTB) is generally contacted by a single, giant axosomatic terminal called the calyx of Held. How this one-on-one relation is established is still unknown, but anatomical evidence suggests that during development principal neurons are innervated by multiple calyces, which may indicate calyceal competition. However, in vivo electrophysiological recordings from principal neurons indicated that only a single strong synaptic connection forms per cell. To test whether a mismatch exists between synaptic strength and terminal size, we compared the strength of synaptic inputs with the morphology of the synaptic terminals. In vivo whole-cell recordings of the MNTB neurons from newborn Wistar rats of either sex were made while stimulating their afferent axons, allowing us to identify multiple inputs. The strength of the strongest input increased to calyceal levels in a few days across cells, while the strength of the second strongest input was stable. The recorded cells were subsequently immunolabelled for vesicular glutamate transporters (VGluT) to reveal axosomatic terminals with structured-illumination microscopy. Synaptic strength of the strongest input was correlated with the contact area of the largest VGluT cluster at the soma (r = 0.8), and no indication of a mismatch between structure and strength was observed. Together, our data agree with a developmental scheme in which one input strengthens and becomes the calyx of Held, but not with multi-calyceal competition.


Asunto(s)
Tronco Encefálico , Cuerpo Trapezoide , Animales , Vías Auditivas , Neuronas , Ratas , Ratas Wistar , Sinapsis
8.
Elife ; 82019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31612853

RESUMEN

The dorsal (DCIC) and lateral cortices (LCIC) of the inferior colliculus are major targets of the auditory and non-auditory cortical areas, suggesting a role in complex multimodal information processing. However, relatively little is known about their functional organization. We utilized in vivo two-photon Ca2+ imaging in awake mice expressing GCaMP6s in GABAergic or non-GABAergic neurons in the IC to investigate their spatial organization. We found different classes of temporal responses, which we confirmed with simultaneous juxtacellular electrophysiology. Both GABAergic and non-GABAergic neurons showed spatial microheterogeneity in their temporal responses. In contrast, a robust, double rostromedial-caudolateral gradient of frequency tuning was conserved between the two groups, and even among the subclasses. This, together with the existence of a subset of neurons sensitive to spontaneous movements, provides functional evidence for redefining the border between DCIC and LCIC.


Asunto(s)
Vías Auditivas/anatomía & histología , Mapeo Encefálico , Colículos Inferiores/anatomía & histología , Neuronas/fisiología , Estimulación Acústica , Potenciales de Acción , Animales , Vías Auditivas/fisiología , Colículos Inferiores/fisiología , Ratones Endogámicos C57BL , Imagen Óptica , Vigilia
9.
J Neurosci ; 38(8): 2057-2068, 2018 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-29358364

RESUMEN

A single whisker stimulus elicits action potentials in a sparse subset of neurons in somatosensory cortex. The precise contribution of these neurons to the animal's perception of a whisker stimulus is unknown. Here we show that single-cell stimulation in rat barrel cortex of both sexes influences the psychophysical detection of a near-threshold whisker stimulus in a cell type-dependent manner, without affecting false alarm rate. Counterintuitively, stimulation of single fast-spiking putative inhibitory neurons increased detection performance. Single-cell stimulation of putative excitatory neurons failed to change detection performance, except for a small subset of deep-layer neurons that were highly sensitive to whisker stimulation and that had an unexpectedly strong impact on detection performance. These findings indicate that the perceptual impact of excitatory barrel cortical neurons relates to their firing response to whisker stimulation and that strong activity in a single highly sensitive neuron in barrel cortex can already enhance sensory detection. Our data suggest that sensory detection is based on a decoding mechanism that lends a disproportionally large weight to interneurons and to deep-layer neurons showing a strong response to sensory stimulation.SIGNIFICANCE STATEMENT Rat whisker somatosensory cortex contains a variety of neuronal cell types with distinct anatomical and physiological characteristics. How each of these different cell types contribute to the animal's perception of whisker stimuli is unknown. We explored this question by using a powerful electrophysiological stimulation technique that allowed us to target and stimulate single neurons with different sensory response types in whisker cortex. In awake, behaving animals, trained to detect whisker stimulation, only costimulation of single fast-spiking inhibitory neurons or single deep-layer excitatory neurons with strong responses to whisker stimulation enhanced detection performance. Our data demonstrate that single cortical neurons can have measurable impact on the detection of sensory stimuli and suggest a decoding mechanism based on select cell types.


Asunto(s)
Neuronas/citología , Neuronas/fisiología , Corteza Somatosensorial/citología , Corteza Somatosensorial/fisiología , Vibrisas/inervación , Potenciales de Acción/fisiología , Animales , Femenino , Masculino , Ratas , Ratas Wistar
10.
J Neurosci ; 37(30): 7278-7289, 2017 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-28659280

RESUMEN

The relative arrival times of sounds at both ears constitute an important cue for localization of low-frequency sounds in the horizontal plane. The binaural neurons of the medial superior olive (MSO) act as coincidence detectors that fire when inputs from both ears arrive near simultaneously. Each principal neuron in the MSO is tuned to its own best interaural time difference (ITD), indicating the presence of an internal delay, a difference in the travel times from either ear to the MSO. According to the stereausis hypothesis, differences in wave propagation along the cochlea could provide the delays necessary for coincidence detection if the ipsilateral and contralateral inputs originated from different cochlear positions, with different frequency tuning. We therefore investigated the relation between interaural mismatches in frequency tuning and ITD tuning during in vivo loose-patch (juxtacellular) recordings from principal neurons of the MSO of anesthetized female gerbils. Cochlear delays can be bypassed by directly stimulating the auditory nerve; in agreement with the stereausis hypothesis, tuning for timing differences during bilateral electrical stimulation of the round windows differed markedly from ITD tuning in the same cells. Moreover, some neurons showed a frequency tuning mismatch that was sufficiently large to have a potential impact on ITD tuning. However, we did not find a correlation between frequency tuning mismatches and best ITDs. Our data thus suggest that axonal delays dominate ITD tuning.SIGNIFICANCE STATEMENT Neurons in the medial superior olive (MSO) play a unique role in sound localization because of their ability to compare the relative arrival time of low-frequency sounds at both ears. They fire maximally when the difference in sound arrival time exactly compensates for the internal delay: the difference in travel time from either ear to the MSO neuron. We tested whether differences in cochlear delay systematically contribute to the total travel time by comparing for individual MSO neurons the best difference in arrival times, as predicted from the frequency tuning for either ear, and the actual best difference. No systematic relation was observed, emphasizing the dominant contribution of axonal delays to the internal delay.


Asunto(s)
Vías Auditivas/fisiología , Cóclea/fisiología , Modelos Neurológicos , Conducción Nerviosa/fisiología , Células Receptoras Sensoriales/fisiología , Localización de Sonidos/fisiología , Complejo Olivar Superior/fisiología , Animales , Simulación por Computador , Femenino , Gerbillinae , Percepción del Tiempo/fisiología
11.
Proc Natl Acad Sci U S A ; 114(16): 4249-4254, 2017 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-28373550

RESUMEN

The shape of the presynaptic action potential (AP) has a strong impact on neurotransmitter release. Because of the small size of most terminals in the central nervous system, little is known about the regulation of their AP shape during natural firing patterns in vivo. The calyx of Held is a giant axosomatic terminal in the auditory brainstem, whose biophysical properties have been well studied in slices. Here, we made whole-cell recordings from calyceal terminals in newborn rat pups. The calyx showed a characteristic burst firing pattern, which has previously been shown to originate from the cochlea. Surprisingly, even for frequencies over 200 Hz, the AP showed little or no depression. Current injections showed that the rate of rise of the AP depended strongly on its onset potential, and that the membrane potential after the AP (Vafter) was close to the value at which no depression would occur during high-frequency activity. Immunolabeling revealed that Nav1.6 is already present at the calyx shortly after its formation, which was in line with the fast recovery from AP depression that we observed in slice recordings. Our findings thus indicate that fast recovery from depression and an inter-AP membrane potential that minimizes changes on the next AP in vivo, together enable high timing precision of the calyx of Held already shortly after its formation.


Asunto(s)
Axones/fisiología , Tronco Encefálico/fisiología , Potenciales de la Membrana/fisiología , Terminales Presinápticos/fisiología , Transmisión Sináptica/fisiología , Potenciales de Acción , Animales , Animales Recién Nacidos , Técnicas de Placa-Clamp , Ratas , Ratas Wistar
12.
Front Cell Neurosci ; 11: 418, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29354033

RESUMEN

The neurodevelopmental disorder Angelman syndrome (AS) is characterized by intellectual disability, motor dysfunction, distinct behavioral aspects, and epilepsy. AS is caused by a loss of the maternally expressed UBE3A gene, and many of the symptoms are recapitulated in a Ube3a mouse model of this syndrome. At the cellular level, changes in the axon initial segment (AIS) have been reported, and changes in vesicle cycling have indicated the presence of presynaptic deficits. Here we studied the role of UBE3A in the auditory system by recording synaptic transmission at the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) through in vivo whole cell and juxtacellular recordings. We show that MNTB principal neurons in Ube3a mice exhibit a hyperpolarized resting membrane potential, an increased action potential (AP) amplitude and a decreased AP half width. Moreover, both the pre- and postsynaptic AP in the calyx of Held synapse of Ube3a mice showed significantly faster recovery from spike depression. An increase in AIS length was observed in the principal MNTB neurons of Ube3a mice, providing a possible substrate for these gain-of-function changes. Apart from the effect on APs, we also observed that EPSPs showed decreased short-term synaptic depression (STD) during long sound stimulations in AS mice, and faster recovery from STD following these tones, which is suggestive of a presynaptic gain-of-function. Our findings thus provide in vivo evidence that UBE3A plays a critical role in controlling synaptic transmission and excitability at excitatory synapses.

13.
J Physiol ; 595(1): 207-231, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-27426483

RESUMEN

KEY POINTS: Neurons in the medial nucleus of the trapezoid body of anaesthetized rats of postnatal day (P)2-6 showed burst firing with a preferred interval of about 100 ms, which was stable, and a second preferred interval of 5-30 ms, which shortened during development. In 3 out of 132 cases, evidence for the presence of two large inputs was found. In vivo whole-cell recordings revealed that the excitability of the principal neuron and the size of its largest synaptic inputs were developmentally matched. At P2-4, action potentials were triggered by barrages of small synaptic events that summated to plateau potentials, while at later stages firing depended on a single, large and often prespike-associated input, which is probably the nascent calyx of Held. Simulations with a Hodgkin-Huxley-like model, which was based on fits of the intrinsic postsynaptic properties, suggested an essential role for the low-threshold potassium conductance in this transition. ABSTRACT: In the adult, principal neurons of the medial nucleus of the trapezoid body (MNTB) are typically contacted by a single, giant terminal called the calyx of Held, whereas during early development a principal neuron receives inputs from many axons. How these changes in innervation impact the postsynaptic activity has not yet been studied in vivo. We therefore recorded spontaneous inputs and intrinsic properties of principal neurons in anaesthetized rat pups during the developmental period in which the calyx forms. A characteristic bursting pattern could already be observed at postnatal day (P)2, before formation of the calyx. At this age, action potentials (APs) were triggered by barrages of summating EPSPs causing plateau depolarizations. In contrast, at P5, a single EPSP reliably triggered APs, resulting in a close match between pre- and postsynaptic firing. Postsynaptic excitability and the size of the largest synaptic events were developmentally matched. The developmental changes in intrinsic properties were estimated by fitting in vivo current injections to a Hodgkin-Huxley-type model of the principal neuron. Our simulations indicated that the developmental increases in Ih , low-threshold K+ channels and leak currents contributed to the reduction in postsynaptic excitability, but that low-threshold K+ channels specifically functioned as a dampening influence in the near-threshold range, thus precluding small inputs from triggering APs. Together, these coincident changes help to propagate bursting activity along the auditory brainstem, and are essential steps towards establishing the relay function of the calyx of Held synapse.


Asunto(s)
Tronco Encefálico/fisiología , Sinapsis/fisiología , Potenciales de Acción , Animales , Animales Recién Nacidos , Potenciales Postsinápticos Excitadores , Femenino , Masculino , Modelos Neurológicos , Neuronas/fisiología , Ratas Wistar
14.
Front Cell Neurosci ; 9: 234, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26190969

RESUMEN

Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1(+/-) and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1 (+/) (-) mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission.

15.
J Neurosci ; 35(10): 4280-6, 2015 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-25762674

RESUMEN

Sensory hair cells in the cochlea, like most neuronal populations that are postmitotic, terminally differentiated, and non-regenerating, depend on robust mechanisms of self-renewal for lifelong survival. We report that hair cell homeostasis requires a specific sub-branch of the DNA damage nucleotide excision repair pathway, termed transcription-coupled repair (TCR). Cockayne syndrome (CS), caused by defects in TCR, is a rare DNA repair disorder with a broad clinical spectrum that includes sensorineural hearing loss. We tested hearing and analyzed the cellular integrity of the organ of Corti in two mouse models of this disease with mutations in the Csb gene (CSB(m/m) mice) and Csa gene (Csa(-/-) mice), respectively. Csb(m/m) and Csa(-/-) mice manifested progressive hearing loss, as measured by an increase in auditory brainstem response thresholds. In contrast to wild-type mice, mutant mice showed reduced or absent otoacoustic emissions, suggesting cochlear outer hair cell impairment. Hearing loss in Csb(m/m) and Csa(-/-) mice correlated with progressive hair cell loss in the base of the organ of Corti, starting between 6 and 13 weeks of age, which increased by 16 weeks of age in a basal-to-apical gradient, with outer hair cells more severely affected than inner hair cells. Our data indicate that the hearing loss observed in CS patients is reproduced in mouse models of this disease. We hypothesize that accumulating DNA damage, secondary to the loss of TCR, contributes to susceptibility to hearing loss.


Asunto(s)
Cóclea/patología , Enzimas Reparadoras del ADN/genética , Predisposición Genética a la Enfermedad/genética , Células Ciliadas Auditivas Internas/patología , Pérdida Auditiva/genética , Degeneración Nerviosa/genética , Proteínas/genética , Estimulación Acústica , Factores de Edad , Animales , Muerte Celular/genética , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico/genética , Pérdida Auditiva/complicaciones , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Emisiones Otoacústicas Espontáneas/genética , Proteínas de Unión a Poli-ADP-Ribosa , Proteínas/metabolismo
16.
J Neurosci ; 34(21): 7047-58, 2014 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-24849341

RESUMEN

Specific missense mutations in the CACNA1A gene, which encodes a subunit of voltage-gated CaV2.1 channels, are associated with familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of common migraine with aura. We used transgenic knock-in (KI) mice harboring the human pathogenic FHM1 mutation S218L to study presynaptic Ca(2+) currents, EPSCs, and in vivo activity at the calyx of Held synapse. Whole-cell patch-clamp recordings of presynaptic terminals from S218L KI mice showed a strong shift of the calcium current I-V curve to more negative potentials, leading to an increase in basal [Ca(2+)]i, increased levels of spontaneous transmitter release, faster recovery from synaptic depression, and enhanced synaptic strength despite smaller action-potential-elicited Ca(2+) currents. The gain-of-function of transmitter release of the S218L mutant was reproduced in vivo, including evidence for an increased release probability, demonstrating its relevance for glutamatergic transmission. This synaptic phenotype may explain the misbalance between excitation and inhibition in neuronal circuits resulting in a persistent hyperexcitability state and other migraine-relevant mechanisms such as an increased susceptibility to cortical spreading depression.


Asunto(s)
Tronco Encefálico/fisiología , Canales de Calcio Tipo N/genética , Calcio/metabolismo , Migraña con Aura/genética , Migraña con Aura/metabolismo , Mutación/genética , Sinapsis/fisiología , Agatoxinas/farmacología , Animales , Tronco Encefálico/citología , Modelos Animales de Enfermedad , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Migraña con Aura/patología , Migraña con Aura/fisiopatología , Neurotoxinas/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Sinapsis/efectos de los fármacos , Sinapsis/genética , Tetrodotoxina/farmacología , Factores de Tiempo
17.
J Physiol ; 591(19): 4877-94, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-23940376

RESUMEN

The calyx of Held synapse of the medial nucleus of the trapezoid body is a giant axosomatic synapse in the auditory brainstem, which acts as a relay synapse showing little dependence of its synaptic strength on firing frequency. The main mechanism that is responsible for its resistance to synaptic depression is its large number of release sites with low release probability. Here, we investigated the contribution of presynaptic GABA(B) receptors and spontaneous activity to release probability both in vivo and in vitro in young-adult mice. Maximal activation of presynaptic GABA(B) receptors by baclofen reduced synaptic output by about 45% in whole-cell voltage clamp slice recordings, which was accompanied by a reduction in short-term depression. A similar reduction in transmission was observed when baclofen was applied in vivo by microiontophoresis during juxtacellular recordings using piggyback electrodes. No significant change in synaptic transmission was observed during application of the GABA(B) receptor antagonist CGP54626 both during in vivo and slice recordings, suggesting a low ambient GABA concentration. Interestingly, we observed that synapses with a high spontaneous frequency showed almost no synaptic depression during auditory stimulation, whereas synapses with a low spontaneous frequency did depress during noise bursts. Our data thus suggest that spontaneous firing can tonically reduce release probability in vivo. In addition, our data show that the ambient GABA concentration in the auditory brainstem is too low to activate the GABA(B) receptor at the calyx of Held significantly, but that activation of GABA(B) receptors can reduce sound-evoked synaptic depression.


Asunto(s)
Potenciales de Acción , Depresión Sináptica a Largo Plazo , Receptores de GABA-B/metabolismo , Sinapsis/fisiología , Estimulación Acústica , Factores de Edad , Animales , Baclofeno/farmacología , Agonistas de Receptores GABA-B/farmacología , Antagonistas de Receptores de GABA-B/farmacología , Ratones , Ratones Endogámicos C57BL , Compuestos Organofosforados/farmacología , Sinapsis/metabolismo , Potenciales Sinápticos , Tegmento Mesencefálico/citología , Tegmento Mesencefálico/metabolismo , Tegmento Mesencefálico/fisiología
19.
Neuron ; 78(5): 936-48, 2013 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-23764292

RESUMEN

Neurons in the medial superior olive (MSO) enable sound localization by their remarkable sensitivity to submillisecond interaural time differences (ITDs). Each MSO neuron has its own "best ITD" to which it responds optimally. A difference in physical path length of the excitatory inputs from both ears cannot fully account for the ITD tuning of MSO neurons. As a result, it is still debated how these inputs interact and whether the segregation of inputs to opposite dendrites, well-timed synaptic inhibition, or asymmetries in synaptic potentials or cellular morphology further optimize coincidence detection or ITD tuning. Using in vivo whole-cell and juxtacellular recordings, we show here that ITD tuning of MSO neurons is determined by the timing of their excitatory inputs. The inputs from both ears sum linearly, whereas spike probability depends nonlinearly on the size of synaptic inputs. This simple coincidence detection scheme thus makes accurate sound localization possible.


Asunto(s)
Lateralidad Funcional/fisiología , Audición , Modelos Lineales , Neuronas/fisiología , Núcleo Olivar/fisiología , Localización de Sonidos/fisiología , Estimulación Acústica , Potenciales de Acción , Animales , Animales Recién Nacidos , Vías Auditivas/fisiología , Fenómenos Biofísicos , Mapeo Encefálico , Estimulación Eléctrica , Gerbillinae , Técnicas In Vitro , Potenciales Postsinápticos Inhibidores/fisiología , Modelos Neurológicos , Inhibición Neural/fisiología , Núcleo Olivar/citología , Técnicas de Placa-Clamp , Tiempo de Reacción
20.
Artículo en Inglés | MEDLINE | ID: mdl-23386812

RESUMEN

Frequency modulations occur in many natural sounds, including vocalizations. The neuronal response to frequency modulated (FM) stimuli has been studied extensively in different brain areas, with an emphasis on the auditory cortex and the central nucleus of the inferior colliculus. Here, we measured the responses to FM sweeps in whole-cell recordings from neurons in the dorsal cortex of the mouse inferior colliculus. Both up- and downward logarithmic FM sweeps were presented at two different speeds to both the ipsi- and the contralateral ear. Based on the number of action potentials that were fired, between 10 and 24% of cells were selective for rate or direction of the FM sweeps. A somewhat lower percentage of cells, 6-21%, showed selectivity based on EPSP size. To study the mechanisms underlying the generation of FM selectivity, we compared FM responses with responses to simple tones in the same cells. We found that if pairs of neurons responded in a similar way to simple tones, they generally also responded in a similar way to FM sweeps. Further evidence that FM selectivity can be generated within the dorsal cortex was obtained by reconstructing FM sweeps from the response to simple tones using three different models. In about half of the direction selective neurons the selectivity was generated by spectrally asymmetric synaptic inhibition. In addition, evidence for direction selectivity based on the timing of excitatory responses was also obtained in some cells. No clear evidence for the local generation of rate selectivity was obtained. We conclude that FM direction selectivity can be generated within the dorsal cortex of the mouse inferior colliculus by multiple mechanisms.


Asunto(s)
Estimulación Acústica/métodos , Corteza Auditiva/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Colículos Inferiores/fisiología , Membranas Intracelulares/fisiología , Animales , Corteza Auditiva/citología , Colículos Inferiores/citología , Ratones , Ratones Endogámicos C57BL , Potenciales Sinápticos/fisiología
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