An essential feature of the first synapse in the retina is a negative feedback pathway from horizontal cells to cones. Here we show that at this synapse, connexin26 forms hemichannels on horizontal cell dendrites near the glutamate release site of the cones. Blocking these hemichannels hyperpolarizes horizontal cells, modulates the Ca2+ channels of the cones, and abolishes all feedback-mediated responses. We propose a feedback mechanism in which the activity of the Ca2+ channels and the subsequent glutamate release of the cones are modulated by a current through these hemichannels. Because the current through the hemichannels depends on the polarization of the horizontal cells, their activity modulates the output of the cones.

We studied feedback from horizontal cells to cones in isolated goldfish retinae and found that surround stimuli evoke an inward current and a slowly developing outward current. The surround-evoked currents are blocked by the glutamate antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) and are, like horizontal cell responses, most effectively evoked by large stimuli. This indicates that the currents are caused by feedback from horizontal cells. The surround-evoked inward current is neither blocked by picrotoxin nor carried by chloride. Instead, it is carried by calcium, and it triggers a slowly developing calcium-dependent chloride current. We were unable to mimick the surround-evoked currents by modulating the extracellular GABA concentration. We conclude that when horizontal cells hyperpolarize they feed back to the cones by shifting the cone calcium-current activation range to more negative potentials. This type of feedback, directly targeted at the calcium current, scarcely influences the membrane potential of the receiving neuron, but effectively modulates its synaptic output.

No abstract

On bipolar cells are connected to photoreceptors via a sign-inverting synapse. At this synapse, glutamate binds to a metabotropic receptor which couples to the closure of a cation-selective transduction channel. The molecular identity of both the receptor and the G protein are known, but the identity of the transduction channel has remained elusive. Here, we show that the transduction channel in mouse rod bipolar cells, a subtype of On bipolar cell, is likely to be a member of the TRP family of channels. To evoke a transduction current, the metabotropic receptor antagonist LY341495 was applied to the dendrites of cells that were bathed in a solution containing the mGluR6 agonists L-AP4 or glutamate. The transduction current was suppressed by ruthenium red and the TRPV1 antagonists capsazepine and SB-366791. Furthermore, focal application of the TRPV1 agonists capsaicin and anandamide evoked a transduction-like current. The capsaicin-evoked and endogenous transduction current displayed prominent outward rectification, a property of the TRPV1 channel. To test the possibility that the transduction channel is TRPV1, we measured rod bipolar cell function in the TRPV1 Ϫ/Ϫ mouse. The ERG b-wave, a measure of On bipolar cell function, as well as the transduction current and the response to TRPV1 agonists were normal, arguing against a role for TRPV1. However, ERG measurements from mice lacking TRPM1 receptors, another TRP channel implicated in retinal function, revealed the absence of a b-wave. Our results suggest that a TRP-like channel, possibly TRPM1, is essential for synaptic function in On bipolar cells.

SummaryBackground Mutant mouse models suggest that the chloride channel ClC-2 has functions in ion and water homoeostasis, but this has not been confi rmed in human beings. We aimed to defi ne novel disorders characterised by distinct patterns of MRI abnormalities in patients with leukoencephalopathies of unknown origin, and to identify the genes mutated in these disorders. We were specifi cally interested in leukoencephalopathies characterised by white matter oedema, suggesting a defect in ion and water homoeostasis.