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Bruce Walmsley

Publications and source records attributed to Bruce Walmsley.

12 recordsLinked to original sources
PubMed2006

Hyperpolarization-activated currents are differentially expressed in mice brainstem auditory nuclei.

The hyperpolarization-activated cation current (I(h)) may influence precise auditory processing by modulating resting membrane potential and cell excitability. We used electrophysiology and immunohistochemistry to investigate the properties of I(h) in three auditory brainstem nuclei in mice: the anteroventral cochlear nucleus (AVCN), the medial nucleus of the trapezoid body (MNTB) and the lateral superior olive (LSO). I(h) amplitude varied considerably between these cell types, with the order of magnitude LSO > AVCN > MNTB. Kinetically, I(h) is faster in LSO neurons, and more active at rest, compared with AVCN and MNTB cells. The half-activation voltage is -10 mV more hyperpolarized for AVCN and MNTB cells compared with LSO neurons. HCN1 immunoreactivity strongly labelled AVCN and LSO neurons, while HCN2 staining was more diffuse in all nuclei. The HCN4 subunit displayed robust membrane staining in AVCN and MNTB cells but weak labelling of the LSO. We used a dynamic clamp, after blocking I(h), to reinsert I(h) to the different cell types. Our results indicate that the native I(h) for each cell type influences the resting membrane potential and can delay the generation of action potentials in response to injected current. Native I(h) increases rebound depolarizations following hyperpolarizations in all cell types, and increases the likelihood of rebound action potentials (particularly in multiple-firing LSO neurons). This systematic comparison shows that I(h) characteristics vary considerably between different brainstem nuclei, and that these differences significantly affect the response properties of cells within these nuclei.

Action Potentials↗
PubMed2006

Activity-dependent regulation of synaptic strength and neuronal excitability in central auditory pathways.

Neural activity plays an important role in regulating synaptic strength and neuronal membrane properties. Attempts to establish guiding rules for activity-dependent neuronal changes have led to such concepts as homeostasis of cellular activity and Hebbian reinforcement of synaptic strength. However, it is clear that there are diverse effects resulting from activity changes, and that these changes depend on the experimental preparation, and the developmental stage of the neural circuits under study. In addition, most experimental evidence on activity-dependent regulation comes from reduced preparations such as neuronal cultures. This review highlights recent results from studies of the intact mammalian auditory system, where changes in activity have been shown to produce alterations in synaptic and membrane properties at the level of individual neurons, and changes in network properties, including the formation of tonotopic maps.

Animals↗
PubMed2006

Altered sodium currents in auditory neurons of congenitally deaf mice.

Sodium currents are essential for action potential generation and propagation in most excitable cells. Appropriate tuning of these currents can be modulated both developmentally and in response to activity. Here we use a mouse model of congenital deafness (dn/dn- asymptomatic deafness associated with hair cell degeneration) to investigate the effect of lack of activity in the expression of Na(+) currents in neurons from the medial nucleus of the trapezoid body (MNTB). Patch-clamp recordings show that at postnatal day (P) 14, both normal and deaf mice display a significant amount of persistent and resurgent Na(+) currents. However, the persistent current is greater in deaf mice than in normal mice, and resurgent current kinetics are slower in deaf mice. At P7, resurgent currents are not present in either group. MNTB immunohistochemistry demonstrates that Nav1.1 subunits are expressed postsynaptically in both P14 normal and deaf mice, while postsynaptic Nav1.6 staining was only observed in deaf mice. Labelling of Nav1.6 subunits in different age groups revealed that at younger ages (P7), both normal and deaf mice express this protein. Nav1.6 staining was not observed in MNTB neurons of P28 normal mice, whereas it is maintained in deaf mice cells until much later (P28). At P7, none of the groups displayed resurgent currents (despite the detection of Nav1.6 subunits at this age group); this suggests that factors other than alpha subunits are important for modulating these currents in MNTB cells. Our results emphasize the importance of activity during development in regulating Na(+) channels.

Action Potentials↗
PubMed2005

Topographic organization in the auditory brainstem of juvenile mice is disrupted in congenital deafness.

There is an orderly topographic arrangement of neurones within auditory brainstem nuclei based on sound frequency. Previous immunolabelling studies in the medial nucleus of the trapezoid body (MNTB) have suggested that there may be gradients of voltage-gated currents underlying this tonotopic arrangement. Here, our electrophysiological and immunolabelling results demonstrate that underlying the tonotopic organization of the MNTB is a combination of medio-lateral gradients of low-and high-threshold potassium currents and hyperpolarization-activated cation currents. Our results also show that the intrinsic membrane properties of MNTB neurones produce a topographic gradient of time delays, which may be relevant to sound localization, following previous demonstrations of the importance of the timing of inhibitory input from the MNTB to the medial superior olive (MSO). Most importantly, we demonstrate that, in the MNTB of congenitally deaf mice, which exhibit no spontaneous auditory nerve activity, the normal tonotopic gradients of neuronal properties are absent. Our results suggest an underlying mechanism for the observed topographic gradient of neuronal firing properties in the MNTB, show that an intrinsic neuronal mechanism is responsible for generating a topographic gradient of time-delays, and provide direct evidence that these gradients rely on spontaneous auditory nerve activity during development.

Action Potentials↗
PubMed2005

Non-random nature of spontaneous mIPSCs in mouse auditory brainstem neurons revealed by recurrence quantification analysis.

A change in the spontaneous release of neurotransmitter is a useful indicator of processes occurring within presynaptic terminals. Linear techniques (e.g. Fourier transform) have been used to analyse spontaneous synaptic events in previous studies, but such methods are inappropriate if the timing pattern is complex. We have investigated spontaneous glycinergic miniature synaptic currents (mIPSCs) in principal cells of the medial nucleus of the trapezoid body. The random versus deterministic (or periodic) nature of mIPSCs was assessed using recurrence quantification analysis. Nonlinear methods were then used to quantify any detected determinism in spontaneous release, and to test for chaotic or fractal patterns. Modelling demonstrated that this procedure is much more sensitive in detecting periodicities than conventional techniques. mIPSCs were found to exhibit periodicities that were abolished by blockade of internal calcium stores with ryanodine, suggesting calcium oscillations in the presynaptic inhibitory terminals. Analysis indicated that mIPSC occurrences were chaotic in nature. Furthermore, periodicities were less evident in congenitally deaf mice than in normal mice, indicating that appropriate neural activity during development is necessary for the expression of deterministic chaos in mIPSC patterns. We suggest that chaotic oscillations of mIPSC occurrences play a physiological role in signal processing in the auditory brainstem.

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PubMed2005

Hyperpolarization-activated (I) currents in auditory brainstem neurons of normal and congenitally deaf mice.

We have investigated the membrane properties of brainstem auditory neurons in a mouse model of congenital deafness (dn/dn). Whole-cell recordings were made from visualized neurons in slices of the medial nucleus of the trapezoid body (MNTB) and anteroventral cochlear nucleus (AVCN). We have recently demonstrated that MNTB neurons in deaf mice are more excitable than in normal mice, due in part to a reduced expression of low-threshold potassium currents. In this study, we have examined the contribution of hyperpolarization-activated (Ih) channels to the membrane properties of MNTB and AVCN neurons. Our results show that Ih is larger in MNTB neurons from deaf mice than in normal mice. In contrast, no significant differences were found in Ih or excitability between AVCN bushy cells from dn/dn and normal mice. Experimental evidence and neuronal modelling suggests that, in the MNTB of normal mice, a small contribution of Ih helps to reduce temporal summation of synaptic potentials. A larger Ih in neurons from deaf mice has a much greater effect in reducing temporal summation of synaptic potentials, counteracting to some extent the greater excitability of these cells. Our results provide further insight into the role of activity during development in regulating the membrane and firing properties of central neurons.

Action Potentials↗
PubMed2004

Reduced low-voltage activated K+ conductances and enhanced central excitability in a congenitally deaf (dn/dn) mouse.

We have investigated changes in the neuronal excitability of the auditory brainstem in a congenitally deaf mouse (deafness dn/dn). Whole cell patch recordings from principal neurones of the medial nucleus of the trapezoid body (MNTB) showed strikingly enhanced excitability in the deaf mice when compared to control CBA mice at 12-14 days postnatal. MNTB neurones in normal CBA mice showed the phenotypic single action potential response on depolarization in current clamp; however, recordings from CBA mice carrying the homozygous deafness mutation fired trains of action potentials on depolarization. We show here that these changes are associated with reduced functional expression of dendrotoxin-sensitive Kv1 potassium channels. In contrast, no differences were found in voltage-gated calcium currents between control and deaf mice. These results reveal that loss of hair cell function in the cochlea leads to changes in ion channel expression in the central nervous system and suggests that this deafness model will be an important tool in understanding central changes occurring in human congenital deafness and in exploring activity-dependent regulation of ion channel expression.

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PubMed2003

Differences in glycinergic mIPSCs in the auditory brain stem of normal and congenitally deaf neonatal mice.

We have investigated the fundamental properties of central auditory glycinergic synapses in early postnatal development in normal and congenitally deaf (dn/dn) mice. Glycinergic miniature inhibitory postsynaptic currents (mIPSCs) were recorded using patch-clamp methods in neurons from a brain slice preparation of the medial nucleus of the trapezoid body (MNTB), at 12-14 days postnatal age. Our results show a number of significant differences between normal and deaf mice. The frequency of mIPSCs is greater (50%) in deaf versus normal mice. Mean mIPSC amplitude is smaller in deaf mice than in normal mice (mean mIPSC amplitude: deaf, 64 pA; normal, 106 pA). Peak-scaled fluctuation analysis of mIPSCs showed that mean single channel conductance is greater in the deaf mice (deaf, 64 pS; normal, 45 pS). The mean decay time course of mIPSCs is slower in MNTB neurons from deaf mice (mean half-width: deaf, 2.9 ms; normal, 2.3 ms). Light- and electron-microscopic immunolabeling results showed that MNTB neurons from deaf mice have more (30%) inhibitory synaptic sites (postsynaptic gephyrin clusters) than MNTB neurons in normal mice. Our results demonstrate substantial differences in glycinergic transmission in normal and congenitally deaf mice, supporting a role for activity during development in regulating both synaptic structure (connectivity) and the fundamental (quantal) properties of mIPSCs at central glycinergic synapses.

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PubMed2003

Glycinergic mIPSCs in mouse and rat brainstem auditory nuclei: modulation by ruthenium red and the role of calcium stores.

Spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded in central neurons are usually highly variable in amplitude due to many factors such as intrinsic postsynaptic channel fluctuations at each release site, site-to-site variability between release sites, electrotonic attenuation due to variable dendritic locations of synapses, and the possibility of synchronous multivesicular release. A detailed knowledge of these factors is essential for the interpretation of mIPSC amplitude distributions and mean quantal size. We have studied glycinergic mIPSCs in two auditory brainstem nuclei, the rat anteroventral cochlear nucleus (AVCN) and the mouse medial nucleus of the trapezoid body (MNTB). Our previous results have demonstrated the location of glycinergic synapses on these neurons to be somatic, thus avoiding electrotonic complications. Spontaneous glycinergic mIPSCs were recorded from AVCN and MNTB neurons in brainstem slices, in the presence of TTX to block action potentials, and 6-cyano-7-nitroquinoxaline-2, 3-dione, (+/-)-2-amino-5-phosphonopentanoic acid and bicuculline to block glutamatergic and GABAergic synaptic currents. Ruthenium red (RuR), which was used to increase the frequency of mIPSCs, significantly changed the shape of most (90 %) mIPSC amplitude distributions by increasing the proportion of large-amplitude mIPSCs. The possibility was investigated (following previous evidence at GABAergic synapses) that large-amplitude glycinergic mIPSCs are due to synchronous multivesicular release initiated by presynaptic calcium sparks from ryanodine-sensitive calcium stores. Interval analysis of mIPSCs indicated that the number of potentially undetected (asynchrony < 0.5 ms) multivesicular mIPSCs was low in comparison with the number of large-amplitude mIPSCs. Ryanodine, thapsigargin and calcium-free perfusate did not reduce the frequency of large-amplitude mIPSCs (> 150 pA), arguing against a significant role for presynaptic calcium stores. Our results support previous evidence suggesting that RuR increases miniature postsynaptic current (mSC) frequency by a mechanism that does not involve presynaptic calcium stores. Our results also indicate that at glycinergic synapses in the AVCN and MNTB, site-to-site variability in mIPSC amplitude, rather than multivesicular release, is a major factor underlying the large range of amplitudes of glycinergic mIPSCs.

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PubMed2002

Synaptic transmission in the auditory brainstem of normal and congenitally deaf mice.

The deafness (dn/dn) mutant mouse provides a valuable model of human congenital deafness. We investigated the properties of synaptic transmission in the anteroventral cochlear nucleus (AVCN) of normal and congenitally deaf dn/dn mice. Excitatory postsynaptic currents (EPSCs) were evoked by focal stimulation of single auditory nerve fibres, and measured by whole-cell recordings from neurones in AVCN slices (mean postnatal age = P13). Absolute amplitudes of both AMPA- and NMDA-mediated components of evoked EPSCs were greater (170 %) in deaf versus control animals. Enhanced transmission in deaf mice was due to a presynaptic mechanism. Variance-mean analysis revealed that the probability of transmitter release was significantly greater in deaf (P(r) = 0.8) versus control animals (P(r) = 0.5). Following high frequency stimulation, deaf mice showed a greater depression of evoked EPSCs, and a significant increase in the frequency of delayed-release (asynchronous) miniature EPSCs (aEPSCs) (deaf 100 Hz vs. control 7 Hz). The acetoxymethyl ester of EGTA (EGTA-AM) blocked the increase in miniature aEPSCs and returned tetanic depression to control values. In deaf mice, reduction of mean P(r) using cadmium caused an expected increase in paired-pulse ratio (PPR). However, in the same cells, a similar reduction in release by EGTA-AM did not result in a change in PPR, demonstrating that a change may occur in P(r) without a concomitant change in PPR. In many respects, transmission in deaf mice was found to be remarkably similar to control mice, implying that many parameters of synaptic transmission develop normally in these animals. The two significant differences (higher P(r) and asynchronous release in deaf mice) could both be reversed by the addition of EGTA-AM, suggesting that endogenous calcium buffering may be impaired or undeveloped in the presynaptic terminals of the auditory nerve in deaf mice.

Animals↗
PubMed2002

Ultrastructural basis of synaptic transmission between endbulbs of Held and bushy cells in the rat cochlear nucleus.

Auditory nerve fibres make large excitatory synaptic contacts, the endbulbs of Held, with bushy cells in the anteroventral cochlear nucleus (AVCN). We have used serial-section electron microscopy to reconstruct seven endbulbs of Held in contact with three different AVCN bushy cells from a 25-day-old rat, as a basis for interpreting our previous physiological results at this connection. Four endbulbs of Held contacting the same bushy cell were completely reconstructed. The number of separate synaptic specializations within these endbulbs varied from 85 to 217, with a mean of 155. Detailed measurements were obtained from high magnification segments of four endbulbs contacting three different bushy cells. Large variability was found in the size of synaptic specializations within an individual endbulb. The size of postsynaptic densities (PSDs) varied between endbulbs (mean PSD area 0.03, 0.07, 0.07 and 0.18 microm(2); n = 4 endbulbs). The number of morphologically docked vesicles at individual specializations within the same endbulb varied considerably (between 1 and 102). The mean number of morphologically docked vesicles per specialization differed between endbulbs (mean numbers of docked vesicles per specialization = 2.1, 3.7, 5.3, 14.8; n = 4 endbulbs). Despite these large differences, the density of docked vesicles per square micron of PSD was similar between endbulbs (54, 80, 81, 83 docked vesicles per microm(2); n = 4 endbulbs). Within an endbulb, a linear relationship was found between the number of docked vesicles and PSD area, and between PSD area and the number of undocked vesicles within 150 nm of the active zone. The ratio of undocked vesicles (< 150 nm) to docked vesicles ranged from 2 to 5 in different endbulbs (n = 4 endbulbs). These structural observations are discussed in relation to the functional properties of synaptic transmission between endbulbs of Held and bushy cells in the AVCN.

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