Histamine reduces flash sensitivity of on ganglion cells in the primate retina

Abstract

PURPOSE. In Old World primates, the retina receives input from histaminergic neurons in the posterior hypothalamus. They are a subset of the neurons that project throughout the central nervous system and fire maximally during the day. The contribution of these neurons to vision, was examined by applying histamine to a dark-adapted, superfused baboon eye cup preparation while making extracellular recordings from peripheral retinal ganglion cells. METHODS. The stimuli were 5-ms, 560-nm, weak, full-field flashes in the low scotopic range. Ganglion cells with sustained and transient ON responses and two cell types with OFF responses were distinguished; their responses were recorded with a 16-channel microelectrode array. RESULTS. Low micromolar doses of histamine decreased the rate of maintained firing and the light sensitivity of ON ganglion cells. Both sustained and transient ON cells responded similarly to histamine. There were no statistically significant effects of histamine in a more limited study of OFF ganglion cells. The response latencies of ON cells were approximately 5 ms slower, on average, when histamine was present. Histamine also reduced the signal-to-noise ratio of ON cells, particularly in those cells with a histamine-induced increase in maintained activity. CONCLUSIONS. A major action of histamine released from retinopetal axons under dark-adapted conditions, when rod signals dominate the response, is to reduce the sensitivity of ON ganglion cells to light flashes. These findings may relate to reports that humans are less sensitive to light stimuli in the scotopic range during the day, when histamine release in the retina is expected to be at its maximum.

Figure 1.

Experimental protocol. A piece of baboon eye cup was placed in the chamber and dark adapted for 30 minutes. Then, in complete darkness, the electrode array was positioned to obtain strong signals on at least three electrodes. The retina was stimulated with LED flashes of 5-ms duration. At each recording site, the threshold for one of the best-isolated cells was found and used as the first stimulus. The flashes were grouped into trials, each containing five flashes with strength increased by a factor of two on successive presentations. There were 2 seconds between flashes and 2 seconds between trials. The main experiment consisted of three intervals—control, histamine application, and washout—each with 18 to 24 trials. The intervals are not drawn to scale.

Figure 2.

Intensity–response curves. Each point is the averaged firing rate for 200 ms after beginning the 5-ms flashes. The light response of the cell was isolated by subtracting the average maintained firing rate recorded in the 500 ms before the start of the flashes. Intensity response data were fitted with the original Naka-Rushton equation (i.e., equation 2). The initial slope of the fitted function was used to characterize light flash sensitivity (S_f) under control conditions (circles) and during histamine application (squares). (A) A representative slow sustained cell. The control S_f was 167 imp/s per Rh*, and the S_f during histamine was 40 imp/s per Rh*. (B) A representative slow transient cell. The S_f under control conditions was 906 imp/s per Rh*, and the S_f during histamine application was 713 imp/s per Rh*.

Figure 3.

Four types of ON light responses. Standardized, averaged peristimulus time histograms for four types of light responses. The flash stimulus (5-ms duration) began at time 0 and was the fourth in the intensity series. Error bars, standard deviations. (A) Fast sustained cells (n = 17) had relatively long response latencies and gradually returned to baseline levels. (B) Slow sustained cells had even longer response latencies and times to peak response (n = 16). (C) Fast transient cells (n = 13) had responses that returned to baseline levels after 150 ms, followed by oscillations in the firing rate. (D) Slow transient cells showed small plateaus in the firing rate after 150 ms and returned to baseline 50 ms later (n = 68). The transient cell types had shorter response latencies than did the sustained types. Some of the amplitudes in the PSTHs have negative values because of the standardization procedure, in which the mean amplitude of the entire histogram was subtracted from the amplitude of each time point in the histogram. Repeated ANOVA tests, with the cell type as the factor, were used to compare the fast and slow transient types, to ensure that they were significantly different. (C, D) Responses compared at times ranging from 123 to 225 ms after the flash, when the responses of the slow transient cells remained elevated. The responses of the two types of ganglion cell were found to be significantly different in this range (F = 5.662, P = 0.02), justifying the subdivision into two separate groups.

Figure 4.

Two types of OFF light responses. OFF cells were subdivided into two groups, sustained and transient, on the basis of the kinetics of their responses to 500-ms steps of light presented after completion of the tests with 5-ms flashes. (A) Peristimulus time histogram of the response of a representative OFF transient cell to a 5-ms flash. (B) Peristimulus time histogram of the response of a representative OFF sustained cell to a 5-ms flash. The 5-ms flash stimulus began at time 0 and was the fourth in the series of increasing stimulus strengths. Error bars, standard deviations. (C, D) Standardized, averaged peristimulus time histograms for both types of light responses to 500-ms steps of light. (C) Transient OFF cells (n = 4) had no maintained activity in the dark but increased their firing rates in response to the offset of the light stimulus. (D) Sustained OFF cells (n = 21) decreased their rate of maintained firing in response to the light.

Figure 5.

Effects of histamine on maintained firing of ON ganglion cells in darkness. The maintained firing rate was averaged from 500-ms intervals recorded before each flash. For each ON cell with detectable maintained activity, the ratio of the maintained rate during histamine application, to the control rate before, is plotted versus the control rate. Note that both scales are logarithmic. In 75% of ON cells, histamine decreased the maintained rate. In the entire sample, histamine decreased the maintained rate to 81% of the baseline value (P < 0 0.0001 paired t-test). Although the four subtypes of ON cells differed in their rates of maintained firing under control conditions, there were no statistically significant differences in the effect of histamine among the subtypes.

Figure 6.

Effects of histamine on the flash sensitivity of ON ganglion cells. The intensity response curves were fitted with the Naka-Rushton equation (equation 2), and the flash sensitivity (imp/s per Rh*) was calculated from the initial slopes (Fig. 2). Under control conditions, the flash sensitivity of ON transient cells was higher than that of ON sustained cells. For all ON cells, the flash sensitivity was decreased to 73.4% of the control value with histamine, although there were no statistically significant differences in the effects of histamine among the four subtypes.