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SUMMARY1. A statistical analysis has been made of the transmitter release at the hair cell afferent fibre synapse in the sacculus of the goldfish, using the amplitude of the excitatory post-synaptic potentials (e.p.s.p.s) in response to stimulus tone as a measure of the transmitter release under application of tetrodotoxin.2. Application of binomial statistics allowed a direct calculation of the mean probability of release (p) and the readily available store (n), and the X2-test showed that the binomial predictions fitted fairly well with the observed distribution of the responses.3. Adaptive rundown of e.p.s.p.s during sound stimulation, i.e. the successive rundown in the size of the mean quantal content (m), was found to be associated with a reduction in the size of parameter n, but not of p.4. A marked negative correlation was demonstrated between the amplitude of two consecutive e.p.s.p.s, supporting the depletion hypothesis of the adaptive rundown of e.p.s.p.s.5. The increase in the e.p.s.p. amplitude and the increase in the mean quantal content, m, brought about by an increase in the tone intensity were found mostly explicable in terms of an increase in the statistical parameter n. The probability parameter p was found largely invariable, although in certain instances the increase in m was also accompanied by a slight increase in the parameter p.

The spike output of neural pathways can be regulated by modulating output neuron excitability and/or their synaptic inputs. Dopaminergic interneurons synapse onto cells that route signals to mammalian retinal ganglion cells, but it is unknown whether dopamine can activate receptors in these ganglion cells and, if it does, how this affects their excitability. Here, we show D1a-receptor-like immunoreactivity in ganglion cells identified in adult rats by retrogradely transported dextran, and that dopamine, D1-type receptor agonists, and cAMP analogs inhibit spiking in ganglion cells dissociated from adult rats. These ligands curtailed repetitive spiking during constant current injections, and reduced the number and rate of rise of spikes elicited by fluctuating current injections without significantly altering the timing of the remaining spikes. Consistent with mediation by D1-type receptors, SCH-23390 reversed the effects of dopamine on spikes. Contrary to a recent report, spike inhibition by dopamine was not precluded by blocking Ih. Consistent with the reduced rate of spike rise, dopamine reduced voltage-gated Na+ current (INa) amplitude and tetrodotoxin, at doses that reduced INa as moderately as dopamine, also inhibited spiking. These results provide the first direct evidence that D1-type dopamine receptor activation can alter mammalian retinal ganglion cell excitability, and demonstrate that dopamine can modulate spikes in these cells by a mechanism different from the pre- and postsynaptic means proposed by previous studies. To our knowledge, our results also provide the first evidence that dopamine receptor activation can reduce excitability without altering the temporal precision of spike firing.

Spiking in central neurons depends on the availability of inward and outward currents activated by depolarization and on the activation and priming of currents by hyperpolarization. Of these processes, priming by hyperpolarization is the least described. In the case of T-type Ca2+ current availability, the interplay of hyperpolarization and depolarization has been studied most completely in expression systems, in part because of the difficulty of pharmacologically separating the Ca2+ currents of native neurons. To facilitate understanding of this current under physiological conditions, we measured T-type current of isolated goldfish retinal ganglion cells with perforated-patch voltage-clamp methods in solutions containing a normal extracellular Ca2+ concentration. The voltage sensitivities and rates of current activation, inactivation, deactivation, and recovery from inactivation were similar to those of expressed alpha1G (CaV3.1) Ca2+ channel clones, except that the rate of deactivation was significantly faster. We reproduced the amplitude and kinetics of measured T currents with a numerical simulation based on a kinetic model developed for an alpha1G Ca2+ channel. Finally, we show that this model predicts the increase of T-type current made available between resting potential and spike threshold by repetitive hyperpolarizations presented at rates that are within the bandwidth of signals processed in situ by these neurons.