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.

Ribbon synapses of vertebrate photoreceptors constantly release glutamate in darkness. Transmitter release is maintained by a steady influx of calcium through voltage-dependent calcium channels, implying the presence of a mechanism that is able to extrude calcium at an equal rate. The two predominant mechanisms of intracellular calcium extrusion are the plasma membrane calcium ATPase (PMCA) and the Na+/Ca2+-exchanger. Immunohistochemical staining of retina sections revealed strong immunoreactivity for the PMCA in rod and cone terminals, whereas staining for the Na+/Ca2+-exchanger was very weak. The PMCA was localized to the plasma membrane along the sides of the photoreceptor terminals and was excluded from the base of the terminals where the active zones are located. The amplitude of a calcium-activated chloride current was used to monitor the intracellular calcium concentration. An upper limit for the time required to remove intracellular free calcium is obtained from two time constants measured for the calcium-activated chloride current tail currents: one of 50 msec and a second of 190 msec. Calcium extrusion was inhibited in the absence of intracellular ATP or in the presence of the PMCA inhibitor orthovanadate, but was unaffected by replacement of external Na+ with Li+. The data indicate that the PMCA, rather than the Na+/Ca2+-exchanger, is the predominant mechanism for calcium extrusion from photoreceptor synaptic terminals.

Voltage‐clamp and current‐clamp recordings were made from bipolar cells in dark‐adapted mouse retinal slices. Light‐evoked responses fell into three groups corresponding to the rod bipolar cells, on‐cone bipolar cells and off‐cone bipolar cells. The morphology of the recorded cells confirmed this classification. Intensity‐response relations were well fitted by a Michaelis saturation function with Hill coefficients of 1.15 ± 0.11 (n= 6) for rod bipolar cells and 2.33 ± 0.06 (n= 4) for cone inputs onto on‐cone bipolar cells. In the absence of antagonists for GABA or glycine receptors, light‐evoked synaptic currents for all cells displayed linear current‐voltage relations that reversed near 0 mV, indicating that very little inhibition was activated under dark‐adapted recording conditions. Saturating light stimuli evoked conductances of 0.81 ± 0.56 nS (n= 4) in rod bipolar cells and 1.1 ± 0.8 nS (n= 4) in on‐cone bipolar cells. Receptive field widths were estimated by flashing a vertical light bar at various locations along the slice. Rod and on‐cone bipolar cells had receptive field widths of 67 ± 16 μm (n= 6) and 43 ± 7 μm (n= 5), respectively. The maximum spatial resolution of an array of such cone bipolar cells was estimated to be 0.3 cycles deg−1, compared with a maximum resolution of 0.5 cycles deg−1 obtained from behavioural studies in mice. Our results suggest that this limit to spatial resolution could be imposed early in the visual system by the size of the bipolar cell receptive fields.

At very low light levels the sensitivity of the visual system is determined by the efficiency with which single photons are captured, and the resulting signal transmitted from the rod photoreceptors through the retinal circuitry to the ganglion cells and on to the brain. Although the tiny electrical signals due to single photons have been observed in rod photoreceptors, little is known about how these signals are preserved during subsequent transmission to the optic nerve. We find that the synaptic currents elicited by single photons in mouse rod bipolar cells have a peak amplitude of 5-6 pA, and that about 20 rod photoreceptors converge upon each rod bipolar cell. The data indicates that the first synapse, between rod photoreceptors and rod bipolar cells, signals a binary event: the detection, or not, of a photon or photons in the connected rod photoreceptors. We present a simple model that demonstrates how a threshold nonlinearity during synaptic transfer allows transmission of the single photon signal, while rejecting the convergent neural noise from the 20 other rod photoreceptors feeding into this first synapse.

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.

Bipolar cells convey information through the retina via graded changes in their membrane potential and modulate transmitter release through the influx of calcium via L-type calcium channels. However, the molecular identity of the alpha(1) subunit has not been confirmed. We report the presence of the newly cloned alpha(1F) subunit in mouse bipolar cell synaptic terminals. The alpha(1F) subunits are localized to hot spots, possibly corresponding to active zones. We also report the physiological properties of two calcium currents present in mouse bipolar cells, a low-voltage-activated L-type current and a low-voltage-activated T-type calcium current. The physiological properties of the T-type current suggest that it is completely inactivated under physiological conditions. The L-type current may be mediated by the alpha(1F) subunit, and influx of calcium through the alpha(1F) channel may control neurotransmitter release from the bipolar cell terminal.

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 (I h ) channels to the membrane properties of MNTB and AVCN neurons. Our results show that I h is larger in MNTB neurons from deaf mice than in normal mice. In contrast, no significant differences were found in I h 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 I h helps to reduce temporal summation of synaptic potentials. A larger I h 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.

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.