In this review we take a physiological perspective on the role of voltage-gated potassium channels in an identified neuron in the auditory brainstem. The large number of KCN genes for potassium channel subunits and the heterogeneity of the subunit combination into K + channels make identification of native conductances especially difficult. We provide a general pharmacological and biophysical profile to help identify the common voltage-gated K + channel families in a neuron. Then we consider the physiological role of each of these conductances from the perspective of the principal neuron in the medial nucleus of the trapezoid body (MNTB). The MNTB is an inverting relay, converting excitation generated by sound from one cochlea into inhibition of brainstem nuclei on the opposite side of the brain; this information is crucial for binaural comparisons and sound localization. The important features of MNTB action potential (AP) firing are inferred from its inhibitory projections to four key target nuclei involved in sound localization (which is the foundation of auditory scene analysis in higher brain centres). These are: the medial superior olive (MSO), the lateral superior olive (LSO), the superior paraolivary nucleus (SPN) and the nuclei of the lateral lemniscus (NLL). The Kv families represented in the MNTB each have a distinct role: Kv1 raises AP firing threshold; Kv2 influences AP repolarization and hyperpolarizes the inter-AP membrane potential during high frequency firing; and Kv3 accelerates AP repolarization. These actions are considered in terms of fidelity of transmission, AP duration, firing rates and temporal jitter. An emerging theme is activity-dependent phosphorylation of Kv channel activity and suggests that intracellular signalling has a dynamic role in refining neuronal excitability and homeostasis.

The medial nucleus of the trapezoid body (MNTB) is specialized for high frequency firing by expression of Kv3 channels, which minimize action potential (AP) duration, and Kv1 channels, which suppress multiple AP firing, during each calyceal giant EPSC. However, the outward K + current in MNTB neurons is dominated by another unidentified delayed rectifier. It has slow kinetics and a peak conductance of ∼37 nS; it is half-activated at −9.2 ± 2.1 mV and half-inactivated at −35.9 ± 1.5 mV. It is blocked by several non-specific potassium channel antagonists including quinine (100 μm) and high concentrations of extracellular tetraethylammonium (TEA; IC 50 = 11.8 mm), but no specific antagonists were found. These characteristics are similar to recombinant Kv2-mediated currents. Quantitative RT-PCR showed that Kv2.2 mRNA was much more prevalent than Kv2.1 in the MNTB. A Kv2.2 antibody showed specific staining and Western blots confirmed that it recognized a protein ∼110 kDa which was absent in brainstem tissue from a Kv2.2 knockout mouse. Confocal imaging showed that Kv2.2 was highly expressed in axon initial segments of MNTB neurons. In the absence of a specific antagonist, Hodgkin-Huxley modelling of voltage-gated conductances showed that Kv2.2 has a minor role during single APs (due to its slow activation) but assists recovery of voltage-gated sodium channels (Nav) from inactivation by hyperpolarizing interspike potentials during repetitive AP firing. Current-clamp recordings during high frequency firing and characterization of Nav inactivation confirmed this hypothesis. We conclude that Kv2.2-containing channels have a distinctive initial segment location and crucial function in maintaining AP amplitude by regulating the interspike potential during high frequency firing. Potassium currents have multiple and diverse roles in shaping electrical signalling, with different suites of voltage-gated and rectifying non-gated channels setting neuronal membrane potentials, firing threshold, action potential waveform and firing patterns. Identification of the channel family and subunits contributing to these functions in native neurons is complicated by their heterogeneous subunit composition, their particular functional localization to the plasma membrane and by the absence of specific antagonists for some families. For these reasons the full complement of the K + channels and subunits underlying native K + currents are still not known for any identified central neuron. We have focused on studying the potassium currents of a 'simple' neuron This paper has online supplemental material.within the medial nucleus of the trapezoid body (MNTB), which serves as a relay in the binaural circuits involved in sound source localization. These neurons receive the glutamatergic calyx of Held giant synapse, which reliably triggers postsynaptic APs with large, well-timed EPSCs which have a magnitude of around 30 times firing threshold. In vivo recordings show the calyceal input fires spontaneously at frequencies ranging between 0 and 100 Hz ...

The relationship between microRNA regulation and the specification of behaviour is only beginning to be explored. Here we find that mutation of a single microRNA locus (miR-iab4/8) in Drosophila larvae affects the animal' s capacity to correct its orientation if turned upside-down (self-righting). One of the microRNA targets involved in this behaviour is the Hox gene Ultrabithorax whose derepression in two metameric neurons leads to self-righting defects. In vivo neural activity analysis reveals that these neurons, the self-righting node (SRN), have different activity patterns in wild type and miRNA mutants whilst thermogenetic manipulation of SRN activity results in changes in self-righting behaviour. Our work thus reveals a microRNA-encoded behaviour and suggests that other microRNAs might also be involved in behavioural control in Drosophila and other species.The regulation of RNA expression and function is emerging as a hub for gene expression control across a variety of cellular and physiological contexts including neural development and specification. Small RNAs such as microRNAs (miRNAs) have been shown to affect neural differentiation (1, 2) but their roles in the control of behaviour are only beginning to be explored.Previous work in our laboratory focused on the mechanisms and impact of RNA regulation on the expression and neural function of the Drosophila Hox genes (3-6). These genes encode a family of evolutionarily conserved transcription factors that control specific programs of neural differentiation along the body axis (7-9) offering an opportunity to investigate how RNA regulation relates to the formation of complex tissues such as the nervous system.Here we use the Hox gene system to investigate the roles played by a single miRNA locus (miR-iab4/8) (3,(10)(11)(12)(13)(14)30) on the specification of the nervous system during early Drosophila development. This miRNA locus controls the embryonic expression of posterior Hox genes (3,(10)(11)(12)(13)(14). Given that we found no detectable differences in the morphological layout of the main components of the nervous system in late Drosophila embryos of wild + This manuscript has been accepted for publication in Science. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencemag.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS. * Correspondence to: Claudio R. Alonso c.alonso@sussex.ac.uk. (13)) (Fig S3B-F) we analysed early larval behaviour as a stratagem to probe the functional integrity of the late embryonic nervous system. Europe PMC Funders GroupMost behaviours in early larva were unaffected by the miRNA mutation ( Fig. S1, movie S1 and S2) except self-righting (SR) behaviour ( Fig. 1A-C, movies S3-S4): miRNA mutant larvae were unable to return to their normal orientation at the same speed as their wild type counterparts.By means of selective target ...

Motion anticipation allows the visual system to compensate for the slow speed of phototransduction so that a moving object can be accurately located. This correction is already present in the signal that ganglion cells send from the retina but the biophysical mechanisms underlying this computation are not known. Here we demonstrate that motion anticipation is computed autonomously within the dendritic tree of each ganglion cell and relies on feedforward inhibition. The passive and non-linear interaction of excitatory and inhibitory synapses enables the somatic voltage to encode the actual position of a moving object instead of its delayed representation. General rather than specific features of the retinal connectome govern this computation: an excess of inhibitory inputs over excitatory, with both being randomly distributed, allows tracking of all directions of motion, while the average distance between inputs determines the object velocities that can be compensated for.DOI: http://dx.doi.org/10.7554/eLife.06250.001