European Journal of Neuroscience, Vol. 41, pp. 17–30, 2015

doi:10.1111/ejn.12783

DEVELOPMENTAL NEUROSCIENCE

Dopamine D2 receptors preferentially regulate the development of light responses of the inner retina Ning Tian,1 Hong-ping Xu2 and Ping Wang1 1 2

Department of Ophthalmology and Visual Science, University of Utah School of Medicine, Salt Lake City, UT 84132, USA Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA

Keywords: activity-dependent plasticity, dopamine D2 receptor, electroretinogram, light deprivation, retinal development

Abstract Retinal light responsiveness measured via electroretinography undergoes developmental modulation, and is thought to be critically regulated by both visual experience and dopamine. The primary goal of this study was to determine whether dopamine D2 receptors regulate the visual experience-dependent functional development of the retina. Accordingly, we recorded electroretinograms from wild-type mice and mice with a genetic deletion of the gene that encodes the D2 receptor raised under normal cyclic light conditions and constant darkness. Our results demonstrate that D2 receptor mutation preferentially increases the amplitude of the inner retinal light responses evoked by high-intensity light measured as oscillatory potentials in adult mice. During postnatal development, all three major components of electroretinograms, i.e. a-waves, b-waves, and oscillatory potentials, increase with age. Comparatively, D2 receptor mutation preferentially reduces the age-dependent increase in b-waves evoked by low-intensity light. Light deprivation from birth reduces b-wave amplitudes and completely abolishes the increased amplitude of oscillatory potentials of D2 receptor mutants. Taken together, these results demonstrate that D2 receptors play an important role in the activity-dependent functional development of the mouse retina.

Introduction The synaptic circuitry in the retina undergoes developmental modification in mammals, including humans. Visual experience affects many aspects of the functional and morphological development of the retina, including synaptic density, bipolar cell structure, expression of neurotransmitter receptors, retinal ganglion cell (RGC) synapses, and dendrites (Xu & Tian, 2004; Tian, 2008, 2011). However, little is known about the mechanisms by which activity regulates the development of the retina. Dopamine receptors have been thought to play important roles in the activity-dependent synaptic plasticity in the central nervous system (Smith et al., 2005; Sun et al., 2005; Surmeier et al., 2007, 2010, 2011; Wolf, 2010; Xing et al., 2010; Xu & Yao, 2010; Chergui, 2011; Herwerth et al., 2012; Zhu et al., 2012; Edelmann & Lessmann, 2013). In the retina, dopamine receptors are expressed by all types of neurons, and are thought to regulate retinal development, synapse formation, synaptic transmission, and light adaptation (Nguyen-Legros et al., 1999; Dowling, 2012). For instance, dopamine D1 receptors are expressed by horizontal cells and AII amacrine cells to regulate gap junction connections between these cells (Mills & Massey, 1995; Urschel et al., 2006; Mills et al., 2007; Kothmann et al., 2009; Zhang et al., 2011). D1 receptors also regulate GABA release from horizontal cells (Herrmann et al., 2011), acetylcholine release from amacrine cells (Hensler & Dubocovich, 1986; Hensler et al., 1987), and light adaptation and sensitivity

Correspondence: Ning Tian, as above. E-mail: [email protected] Received 29 May 2014, revised 25 September 2014, accepted 13 October 2014

of RGCs (Vaquero et al., 2001; Van Hook et al., 2012), and are thought to regulate neurite outgrowth (Lankford et al., 1987) and activity-dependent ocular growth (Stone et al., 1990). Recently, we found that D1 receptors regulate the activity-dependent development of the mouse retina (He et al., 2013). On the other hand, dopamine D2 receptors are expressed by photoreceptors (Witkovsky et al., 1988; Ribelayga et al., 2008), RGCs (Mills et al., 2007) and amacrine cells (Derouiche & Asan, 1999; Nguyen-Legros et al., 1999; Weber et al., 2001). Activation of D2 receptors regulates gap junction couplings between rods and cones, gap junction couplings between RGCs (Mills et al., 2007; Ribelayga & Mangel, 2010), transmembrane currents in rods (Kawai et al., 2011), the amplitudes of electroretinogram (ERG) b-waves (MirandaAnaya et al., 2002) and oscillatory potentials (OPs) (Perry & George, 2007), and the light responses of RGCs (Bodis-Wollner & Tzelepi, 1998). In addition, development and visual activity regulates the expression of dopamine receptors, the number of dopaminergic cells (Melamed et al., 1986; Klitten et al., 2008), and the storage and release of dopamine (Melamed et al., 1986; Spira & Parkinson, 1991; Shelke et al., 1997; Lorenc-Duda et al., 2009). Therefore, it is highly likely that D2 receptors might also regulate the activity-dependent development of the retina. To test this possibility, we examined the ERGs of wild-type (WT) mice and mice with mutation of the gene encoding the D2 receptor (D2
/
mice) raised under normal cyclic light/dark conditions and constant darkness. Our results demonstrate that D2 receptors play an important role in the activity-dependent functional development of the mouse retina.

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

18 N. Tian et al.

Materials and methods

R ¼ Rmin þ

Ethics statement All procedures for handling, maintenance and preparation of animals met the NIH guidelines for care and use of animals in research, and were approved by the Animal Care and Use Committee of Yale University. Animals and dark rearing The procedures for animal handling and preparation in this study have been described previously (Vistamehr & Tian, 2004; He et al., 2013). ERGs were recorded from both the left and right eyes simultaneously of C57BL/6 (WT), D2
/
and D3
/
mice (The Jackson Laboratory, Bar Harbor, ME, USA). These mice were either raised under cyclic light/dark conditions as controls or raised under constant darkness. The control mice were fed and housed under 12 : 12-h cyclic light/dark conditions in regular mouse rooms located in the Animal Care Facility. The average light intensity illuminating the cages during the subjective day was 40 lux for control mice. Dark-reared mice were housed in conventional mouse cages, which were placed in a continuously ventilated light-tight box. The temperature and humidity inside the box were continuously monitored, and balanced by adjusting the speed of the ventilating fan. The box was placed in a light-tight room located in the same facility as control mice. All procedures of daily monitoring and routine maintenance of dark-reared mice were conducted under infrared illumination by trained personal with the use of a pair of infrared-sensitive goggles (B.E. Meyers, Redmond, WA, USA). ERG recordings and data analysis The procedures for ERG recordings have also been described previously (Vistamehr & Tian, 2004; He et al., 2013), and were in accordance with the recommendations of the International Society for Clinical Electrophysiology of Vision (Marmor et al., 2009). Briefly, mice reared under cyclic light/dark conditions were dark-adapted for at least 30 min before experiments. Dark-reared mice were transferred from the dark room to the ERG recording room in a lighttight transfer box. Prior to the recordings, mice were anesthetised with xylazine (13 mg/kg) and ketamine (87 mg/kg), and the pupils were dilated with atropine (1%; Bausch & Lomb Pharmaceuticals, Tampa, FL, USA) and phenylephrine-HCl (Mydfrin 2.5%; Alcon, Humacao, Puerto Rico). A topical anesthetic agent, proparacarine (0.5%; Alcon), was used before the contact electrodes were applied to the corneas. ERGs were evoked with 100-ms white flashes generated by light-emitting diode arrays built into a pair of miniature Ganzfield stimulators for both the left and right eyes of each mouse (EPIC-3000; LKC Technologies, Gaithersburg, MD, USA) and recorded simultaneously for both eyes. Signals were bandpass-filtered between 0.3 and 500 Hz. For each of the intensities between 0.008 cd*s/m2 and 0.8 cd*s/m2, ERGs were averaged from five single flashes. The inter-stimulus interval was 30 s. ERGs were averaged from three single flashes for the intensities between 2.5 cd*s/ m2 and 25 cd*s/m2. The inter-stimulus interval was 60 s. All recordings were made at approximately the same time of the day (from 11:00 h to 15:00 h). Responses of ERG components were fitted to the following equation (a modified Naka–Rushton function) by the use of IGOR (WaveMetrics, Lake Oswego, OR, USA) with the Levenberg–Marquardt algorithm to determine the Rmax and I50:

Rmax
Rmin  n 1 þ I50I

Here, R is the ERG a-wave, b-wave or OP amplitude, Rmax is the amplitude of the saturated responses predicted from the recordings, Rmin is the amplitude of the minimum responses predicted from the recordings, I is the light intensity for each recorded data point (R), I50 is the light intensity at which the half-saturated response would be predicted from the recordings (semisaturation constant), and n is a variable that determines the steepness of the curves. ANOVA, post hoc (Bonferroni–Dunn) tests and ANCOVA were used to determine the significance of the difference between more than two means and the interaction between two independent factors. Student t-tests were used to examine the difference between two means. All of the statistical tests were performed with STATVIEW (Abacus Concepts, Berkeley, CA, USA).

Results The amplitude of inner retinal light responses is selectively enhanced in D2
/
mice D2 receptors have been found to be expressed in both the inner and outer retina (Witkovsky et al., 1988; Derouiche & Asan, 1999; Nguyen-Legros et al., 1999; Vaquero et al., 2001; Weber et al., 2001; Mills et al., 2007; Ribelayga et al., 2008; Kothmann et al., 2009; Zhang et al., 2011; Van Hook et al., 2012), but the effects of D2 receptors on the ERG are contradictory. Pharmacological blockade or genetic mutation of D2 receptors has been shown to increase b-wave amplitudes in goldfish and cats and OPs of mouse ERGs (Schneider & Zrenner, 1991; Kim & Jung, 2012; Lavoie et al., 2014), but decrease b-wave amplitudes in rabbits (Hupp
e-Gourgues et al., 2005). On the other hand, activation of D2 receptors enhances b-wave amplitudes of scotopic ERGs of the green iguana retina (Miranda-Anaya et al., 2002), but has no effect on rabbit ERGs (Hupp
e-Gourgues et al., 2005). We first determined the effects of genetic mutation of the D2 receptor on the ERG responses in young adult mice. ERGs at eight different light intensities were recorded from WT, D2
/
and D3
/
mice at postnatal day (P)30. WT mice were used as negative controls, as were D3
/
mice. Because the retina does not express dopamine D3 receptors (Jackson et al., 2009) and D3 receptor mutation has no detectable effect on b-waves (Herrmann et al., 2011), we could use D3
/
mice as controls for the effects of non-retinal dopamine signaling defects. The amplitudes of the three major components of the ERG, i.e. a-waves, bwaves, and OPs, were plotted as a function of stimulating light intensity. Figure 1A shows representative waveforms of ERGs (left) and OPs (right) recorded from a WT mouse and a D2
/
mouse. The initial portion of the a-wave is a measurement of photoreceptor function. The b-wave is mainly a measurement of ON bipolar cell function (Stockton & Slaughter, 1989; Tian & Slaughter, 1995). The OP, which reflects interactions among bipolar, amacrine and ganglion cells, is a measurement of inner retinal function (Wachtmeister, 1998). The OPs shown in Fig. 1A were isolated by bandpassfiltering (73–500 Hz) the waves of ERGs, and OP amplitudes were calculated from the sum of all peaks (Severns et al., 1994). The light intensities used to evoke ERG responses cover a wide range of luminosity, from 0.008 cd*s/m2 to 25 cd*s/m2. This will stimulate only rods at the lower intensities, and stimulate both rods and cones at the high intensities. Because no background light was used to

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 17–30

D2 receptor regulates retinal light responses 19 A

B

D

F

C

E

G

Fig. 1. The amplitudes of inner retinal light responses measured as ERG OPs have biphasic changes in D2
/
mice. ERGs were recorded from dark-adapted P30 WT, D2
/
and D3
/
mice at eight different intensities of light. The amplitudes of a-waves, b-waves and OPs were plotted as a function of intensity of light stimulus as intensity–response curves, and the a-wave, b-wave and OP amplitudes of D2
/
mice were also normalised to those of WT controls to reveal the relative changes in strength of the ERG of D2
/
mice. (A) Representative ERG (left) and OPs(right) waveforms recorded from a P30 WT mouse (upper) and a P30 D2
/
mouse (lower) evoked by eight different light intensities (from 0.008 cd*s/m2 at the bottom to 25 cd*s/m2 at the top). (B) Average intensity– response curves of a-wave amplitudes of WT (20 mice, 40 eyes), D2
/
(seven mice, 14 eyes) and D3
/
(10 mice, 20 eyes) mice. (C) Normalised a-waves of WT and D2
/
mice show that the a-wave amplitudes of D2
/
mice were not different from those of WT mice at all light intensities except for the lowest (0.008 cd*s/m2). The amplitude of a-waves of D2
/
mice evoked by 0.008 cd*s/m2 was more than two-fold higher than that of WT controls. (D) Average intensity–response curves of b-wave amplitudes of the same three groups of mice as shown in B. (E) Normalised b-waves of WT and D2
/
mice show that the b-wave amplitudes of D2
/
mice were not different from those of WT mice at all light intensities except for the lowest. The amplitude of b-waves of D2
/
mice evoked by 0.008 cd*s/m2 was ~30% lower than that of WT controls. (F) Average intensity–response curves of OP amplitudes of the same three groups of mice as shown in B. (G) Normalised OPs of WT and D2
/
mice show that OP amplitudes of D2
/
mice have biphasic changes, being reduced with low-intensity stimuli and enhanced to high-intensity stimuli. At the low light intensity (0.025 cd*s/m2), the OP amplitude of D2
/
mice was ~30% lower than that of WT controls, whereas at the high light intensities (2.5–25 cd*s/m2), the OP amplitude of D2
/
mice was approximately 30–35% higher than that of WT controls. In all panels and all following figures: *the difference is statistically significant, and the P-value is between 0.05 and 0.01; **P < 0.01; ***P < 0.001. Error bars indicate standard errors.

isolate cone-mediated light responses, the ERGs recorded in this study are either scotopic or mesopic responses. Figure 1B, D and F shows the average intensity–response curves of a-waves, b-waves and OPs recorded from WT, D2
/
and D3
/
mice. For a-waves and OPs, the average intensity–response curves of WT, D2
/
and D3
/
mice all had a sigmoid distribution, indicating that the light stimuli covered most of the dynamic range of photoreceptors and inner retinal light responses. On the other hand, the average intensity–response curves of b-waves of all three strains of mice had a somewhat linear distribution, indicating that the range of light intensity was probably only wide enough to cover the middle portion of the whole dynamic range of bipolar cell light responses. Comparison of the intensity–response curves of a-waves and b-waves in D2
/
mice with those of WT controls showed that a-wave and b-wave amplitudes were not affected by D2 receptor mutation at any light intensity except for the lowest (Fig. 1B and D). However, the amplitudes of OPs evoked by high-intensity light in D2
/
mice were significantly higher than those of WT controls (Fig. 1F). This is consistent with a recent report (Lavoie et al., 2014). As expected, D3 receptor mutation had no effect on any of the ERG components. To further reveal the relative extent of the alterations of ERG responses resulting from D2 receptor mutation, we quantified the differences in the intensity–response curves of a-waves, b-waves and OPs between D2
/
and WT mice by normalising the responses of D2
/
mice to those of the age-matched WT controls with the following equation:

Rnor ðiÞ ¼ RðiÞ=Rave ðiÞ  100 Here, Rnor(i) represents the normalised a-wave, b-wave or OP amplitude of D2
/
mice evoked by light intensity (i), R(i) represents the actual a-wave, b-wave or OP amplitude of D2
/
mice evoked by light stimulus (i), and Rave(i) is the average amplitude of a-waves, b-waves or OPs evoked by light stimulus (i) of WT controls. Therefore, the results for D2
/
mice are expressed as percentiles of the responses of WT mice. For the a-waves of D2
/
mice, only the normalised amplitude for the lowest light intensity (0.008 cd*s/m2) was increased, to 226  60.3% of that of WT controls (Fig. 1C). For b-waves, the normalised amplitude of the response to the lowest light intensity was reduced to 71  4.7% of that of WT controls (Fig. 1E). The amplitudes of a-waves and b-waves of D2
/
mice evoked by other light intensities were not different from those of WT controls. In contrast to the a-waves and b-waves, the normalised OP amplitudes of D2
/
mice had biphasic changes in comparison with WT controls. At light intensities of 0.008 cd*s/m2 and 0.025 cd*s/m2, the normalised OP amplitudes were reduced to 80  15.2% and 69  10.7% of those of WT controls, whereas the normalised OP amplitudes evoked by light intensities of 2.5 cd*s/m2, 8 cd*s/m2 and 25 cd*s/m2 were increased to 138  14.6%, 129  8.9%, and 125  8%, respectively, of those of WT controls (Fig. 1G). We further examined these data by fitting them to a modified Naka–Rushton function (see detailed description in Materials and

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 17–30

20 N. Tian et al. methods) to predict the maximal a-wave, b-wave and OP responses and the hemisaturation constant (I50) of D2
/
and WT mice. Consistent with the intensity–response curves, the predicted maximal a-wave and b-wave amplitudes of D2
/
mice were not significantly different from those of WT controls (Table 1). The average maximal a-wave amplitudes were
446.9  37.4 lV and
445.2  18 lV (mean  standard error for these and all following expressions; P = 0.8955) for D2
/
and WT mice, respectively, and the average maximal b-wave amplitudes were 1046.3  75.9 lV and 1108.1  44 lV (P = 0.7029), respectively. Although the average maximal OP amplitude of D2
/
mice was 17.7% higher than that of WT controls (1076.4  73.9 lV vs. 914.3  44.4 lV), the difference was not statistically significant (P = 0.0664; Table 1). The I50 values for a-waves, b-waves and OPs of D2
/
mice were not statistically different from those of age-matched WT controls (data not shown). The differences in the changes of a-wave, b-wave and OP amplitudes of D2
/
mice imply that D2 receptors might regulate the light response gain differently in the inner and outer retina. To further examine this possibility, we assessed the changes in response gains of the outer and inner retina resulting from D2 receptor mutation by comparing the b-wave/a-wave and OP/b-wave ratios of D2
/
and WT mice. When the average b-wave/a-wave ratios of WT mice were plotted as a function of light intensity (Fig. 2A), the curve was relatively flat, with the highest b-wave/a-wave ratio (–24.4  5.45) at a light intensity of 0.025 cd*s/m2, and the lowest b-wave/a-wave ratio (–2.14  0.13) at a light intensity of 25 cd*s/ m2. These results demonstrate that the strength of the light response gain at the outer retina depends upon the intensity of light stimulation and that the light responses evoked by weaker light stimuli have stronger synaptic gain. However, D2
/
mice seemed to have a highly elevated b-wave/a-wave ratio at a light intensity of 0.025 cd*s/m2. The average b-wave/a-wave ratios of WT and D2
/
mice at a light intensity of 0.025 cd*s/m2 were –24.41  5.45 and –67.45  23.2, respectively, but the difference was not statistically significant (P = 0.1692). To further reveal the relative extent of the alterations of ERG response gain resulting from D2 receptor mutation, we normalised the response gain of D2
/
mice to the age-matched WT controls by using the following equation: Gnor ðiÞ ¼ GðiÞ=Gave ðiÞ  100 Here, Gnor(i) represents the normalised response gain of D2
/
mice evoked by light intensity (i), G(i) represents the actual response gain of D2
/
mice evoked by a light stimulus (i), and

Gave(i) is the average response gain evoked by light stimulation of (i) of WT control mice. Therefore, the results for D2
/
mice are expressed as percentiles of the response gain of WT mice. Figure 2B shows that the b-wave/a-wave ratio of D2
/
mice at a light intensity of 0.025 cd*s/m2 was 276.3%  95% of that of WT controls. In contrast, the OP/b-wave ratios of D2
/
mice also had biphasic changes, with the OP/b-wave ratio at a light intensity of 0.025 cd*s/m2 being decreased to 75.9%  12.2% of that of WT controls (P = 0.0368), and the OP/b-wave ratios at light intensities of 0.8 cd*s/m2, 2.5 cd*s/m2, 8 cd*s/m2 and 25 cd*s/m2 being increased to 126.6%  16%, 131%  14.6%, 128.4%  11.3% and 124.8%  8.8% of those of WT controls (P = 0.0381, P = 0.0229, P = 0.0009, and P = 0.0022, respectively; Fig. 2D). These results support the notion that activation of D2 receptors preferentially decreases the transmission of visual signaling evoked by low-intensity light in the outer retina and inversely increases the transmission of visual signaling evoked by low-intensity light in the inner retina. In addition, activation of D2 receptors selectively decreases the transmission of visual signaling evoked by high-intensity light in the inner retina without affecting the outer retinal responses to high-intensity light. Furthermore, we examined the light response kinetics of ERGs by measuring the peak times of ERG awaves (Fig. 2E) and b-waves (Fig. 2F) of both D2
/
and WT mice. We found minimal differences between WT and D2
/
mice in the peak times for both a-waves and b-waves. Overall, the most significant effect of D2 receptor mutation on the retinal light responses is the increase in OP amplitudes with high-intensity light, which is opposite to the effect observed when the D1 receptor is mutated (He et al., 2013; Lavoie et al., 2014). On the other hand, D2 receptor mutation increases the light response gain of the outer retina and decreases the light response gain of the inner retina with low-intensity light, which is similar to the effect induced by D1 receptor mutation (He et al., 2013). Although the changes in the response gains of the inner retina and outer retina with low-intensity light occur in opposite directions, the magnitude of the changes in a-wave and OP amplitudes with low-intensity light is not as significant as the changes in OPs with high-intensity light. Despite this, the relative impact is still strong and significant. D2 receptor mutation reduces the developmental increase in ERG b-wave amplitudes It has been shown that ERG amplitudes undergo postnatal developmental enhancement in humans and other mammals (Reuter, 1976; Gorfinkel et al., 1988; el Azazi & Wachtmeister, 1991a,b; Rodriguez-Saez et al., 1993; Breton et al., 1995; Flores-Guevara et al.,

Table 1. Predicted maximal ERG responses P13

P30

a-wave

Mean (lV) SE (lV) n (eyes) P t

b-wave

OPs

a-wave

b-wave

OPs

WT

D2
/


WT

D2
/


WT

D2
/


WT

D2
/


WT

D2
/


WT

D2
/


–53.5 8.4 12 100% at most light intensities for both WT and D2
/
mice, except for a few intensities (from 38.9%  10% and 181.8%  41.3% at 0.008 cd*s/m2 to 718.4%  18.7% and 544.7%  34.3% at 25 cd*s/m2 for WT and D2
/
mice, respectively), indicating a developmental increase in a-wave amplitudes for most of the tested light intensities. In addition, the P30/P13 ratio increased with light intensity for both WT and D2
/
mice, indicating stronger developmental enhancement of light responsiveness mediated by cones. Furthermore, the P30/P13 ratios of a-wave amplitudes of WT and D2
/
mice had similar distribution patterns at most light intensities, and the distribution curves were not systematically different, except for a few sporadic points of light intensities where either WT or D2
/
mice had a higher ratio. These results demonstrate that a-wave amplitudes increase from P13 to P30 for both WT and D2
/
mice, and that D2 receptor mutation has a limited effect on the maturation of the photoreceptor light response. Similarly to those of a-waves, the P30/P13 ratios of b-waves were >100% at all light intensities for both WT and D2
/
mice (from 676.1%  21.2% and 396.3%  26.5% at 0.008 cd*s/m2 to 423.1%  10.6% and 376.4%  19.2% at 25 cd*s/m2 for WT and D2
/
mice, respectively) (Fig. 3D), demonstrating that b-wave amplitudes increased by approximately four-fold to seven-fold from P13 to P30 for both WT and D2
/
mice. As shown previously, the P30/P13 ratio of b-waves of WT mice decreases with the increase in light intensity (He et al., 2013), indicating stronger developmental enhancement of the response gain between rods to rod-bipolar cells than that of the response gain between cones and cone-bipolar cells. Interestingly, not only were the P30/P13 ratios of b-wave amplitudes of D2
/
mice significantly lower than those of WT controls at all light intensities, but the light intensity-dependent decrease in the P30/P13 ratios of b-wave amplitudes was also diminished in D2
/
mice. This is similar to the effects observed in D1
/
mice (He et al., 2013), and these results strongly suggest that both D1 and D2 receptors preferentially regulate the developmental increase in response gain between rods and rod-bipolar cells. Figure 3F shows the P30/P13 ratios of OP amplitudes of WT and D2
/
mice as a function of light intensity. Again, the P30/P13 ratios of OP amplitudes of WT and D2
/
mice were >100% at all light intensities (from 136.9%  7.9% and 125.6%  23.8% at 0.008 cd*s/m2 to 804%  32.9% and 661%  42.5% at 25 cd*s/ m2 for WT and D2
/
mice, respectively). The distributions of the P30/P13 ratios of OP amplitudes of both WT and D2
/
mice showed a biphasic pattern, in which the P30/P13 ratio of WT mice sharply increased with light intensities from 0.008 cd*s/m2 to 0.08 cd*s/m2, and reached a relatively flat phase at light intensities between 0.08 cd*s/m2 and 25 cd*s/m2. However, D2
/
mice had a clearly reduced sharpness of the light intensity-dependent increase in the P30/P13 ratios of OP amplitudes between 0.008 cd*s/m2 and 0.25 cd*s/m2. Comparison of the OP amplitudes of mice at P13 and P30 (Figs 1F and 3F) indicated that this seems to be the result of a slight enhancement of OP amplitudes with the low–intermediate light intensities in D2
/
mice. These results suggest that activation of D2 receptors suppresses the inner retinal light responses in both young and adult mice, but has more prominent effects in adult mice.

D2 receptors interact with visual activity to regulate the ERG The development of the mouse retinal light responses is sensitive to light deprivation (Tian & Copenhagen, 2003; Vistamehr & Tian, 2004; He et al., 2013), and D1 receptors have been shown to regulate the activity-dependent development of retinal light responses measured as ERGs (He et al., 2013). Therefore, we further investigated whether D2 receptors also participate in the activity-dependent development of retinal light responses by using ERG recordings. Accordingly, we dark-reared both D2
/
and WT mice from birth to P30, and compared the ERG responses of these dark-reared mice with those of age-matched controls raised under cyclic light conditions. As reported previously (Vistamehr & Tian, 2004; He et al., 2013), WT mice raised in constant darkness from birth to P30 had reduced amplitudes of all three major components of the ERG, especially the amplitudes of b-waves and OPs in response to high-intensity light (Fig. 4B and C). Similarly to what was found for WT mice, a-wave, b-wave and OP amplitudes of dark-reared D2
/
mice were reduced (Fig. 4E–G). Interestingly, although D2 receptor mutation significantly increased OP amplitudes (Fig. 4D) with high-intensity light, OP amplitudes of dark-reared D2
/
mice were not different from those of age-matched WT mice raised in constant darkness at all light intensities (Fig. 4H). These results suggest that the D2 receptor-dependent regulation of OP amplitude is sensitive to light deprivation. Because D1 receptor mutation differentially affects the response gain and kinetics of the inner and outer retina of dark-reared mice (He et al., 2013), we further analysed the b-wave/a-wave ratio and the OP/b-wave ratio of dark-reared WT and D2
/
mice, and compared the results with those of D2
/
and WT mice raised under cyclic light conditions. Figure 5A shows that light deprivation of WT mice significantly increased the b-wave/a-wave ratios with lowintensity light, whereas light deprivation of D2
/
mice caused this ratio to slightly decrease, but not in a statistically significant manner (Fig. 5C). This is similar to what occurs when the D1 receptor is mutated, but with a much weaker magnitude (He et al., 2013). Figure 5E compares the effects of dark rearing on the b-wave/a-wave ratios of WT and D2
/
mice by normalising the b-wave/a-wave ratios of dark-reared WT mice to those of age-matched WT controls, and the b-wave/a-wave ratios of dark-reared D2
/
mice to those of age-matched D2
/
control mice. It is evident that dark rearing preferentially affected the b-wave/a-wave ratio with low-intensity light in WT mice, but had very little effect on D2
/
mice, suggesting that the light-dependent change in the response gain of the outer retina is regulated by both D1and D2 receptors. In the inner retina, dark rearing had very little effect on the OP/b-wave ratio of WT mice (Fig. 5B) but significantly reduced the OP/b-wave ratio for high-intensity light in D2
/
mice (Fig. 5D). The data for normalised OP/b-wave ratios of dark-reared WT and D2
/
mice (Fig. 5F) confirm the notion that light deprivation preferentially decreases the OP/b-wave ratio of D2
/
mice with high-intensity light (Fig. 5F). This is opposite to the effect of D1 receptor mutation, in which light deprivation increases the OP/b-wave ratio with all light intensities (He et al., 2013). Finally, we examined the effects of dark rearing on the light response kinetics of the ERG by measuring the peak times of a-waves and b-waves of both WT and D2
/
mice raised in constant darkness and cyclic light conditions. In WT mice, dark rearing reduced the peak time of both a-waves and b-waves at most light intensities (Fig. 6A and B). In D2
/
mice, dark rearing had little effect on the peak times of both a-waves and b-waves (Fig. 6C and D). When we compared the effects of dark rearing on the a-wave

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 17–30

24 N. Tian et al. A

B

C

D

E

F

G

H

Fig. 4. Light deprivation suppresses the ERG amplitudes of both WT and D2
/
mice. To determine the effects of light deprivation on ERG amplitudes, WT and D2
/
mice were raised in constant darkness from birth, and the ERGs were recorded at P30. (A) Average intensity–response curves of a-wave amplitudes of WT mice raised in cyclic light/dark conditions (WT light, 20 mice, 40 eyes) and constant darkness (WT dark, seven mice, 14 eyes). (B) Average intensity– response curves of b-wave amplitudes of WT mice raised in cyclic light/dark conditions and constant darkness. (C) Average intensity–response curves of OPs of WT mice raised in cyclic light/dark conditions and constant darkness, showing significant decreases in OP amplitudes of dark-reared mice. (D) Average intensity–response curves of OP amplitudes of WT and D2
/
mice raised under cyclic light/dark conditions, showing significant increases in OP amplitudes evoked by high-intensity light of D2
/
mice. (E) Average intensity–response curves of a-wave amplitudes of D2
/
mice raised in cyclic light/dark conditions (D2
/
light, seven mice, 14 eyes) and constant darkness (D2
/
dark, nine mice, 18 eyes). (F) Average intensity–response curves of b-wave amplitudes of D2
/
mice raised in cyclic light/dark conditions and constant darkness. (G) Average intensity–response curves of OPs of D2
/
mice raised in cyclic light/dark conditions and constant darkness, showing significant decreases in OP amplitudes, especially the responses to high-intensity light, of D2
/
mice raised in constant darkness. (H) Average intensity–response curves of OP amplitudes of WT and D2
/
mice raised in constant darkness, showing that light deprivation suppressed OP amplitudes of WT and D2
/
mice to the same level.

and b-wave peak times of WT and D2
/
mice by normalising the a-wave and b-wave peak times of dark-reared mice to those of genetically matched and age-matched controls, it was evident that the dark rearing-induced effects on a-wave peak times of WT mice were light intensity-dependent, whereby the changes in the a-wave peak times in dark-reared mice had a higher magnitude for responses evoked by low–intermediate light intensities, except for the lowest intensity. However, this light intensity-dependent change in a-wave peak time was largely diminished in dark-reared D2
/
mice (Fig. 6E). For the b-wave peak time, dark rearing had much weaker effects on both WT and D2
/
mice, and the changes across all light intensities had similar magnitudes (Fig. 6F). Overall, these results demonstrate that light deprivation completely abolishes the enhancement of OP amplitude induced by D2 receptor mutation through suppression of the response gain of the inner retina. In addition, D2 receptor mutation diminishes the effects of dark rearing on the outer retinal response gain measured as the bwave/a-wave ratio. Furthermore, D2 receptor mutation reduces the effect of dark rearing on the response kinetics of both photoreceptors and bipolar cells.

Discussion The goal of this study was to determine whether D2 receptors regulate the activity-dependent development of retinal light responsiveness differently from D1 receptors. Our results showed several findings that have not been previously reported. First, D2 receptor

mutation preferentially increases OP amplitudes, presumably through a cone-mediated pathway by enhancing the response gain of the inner retina. This increase in OP amplitudes is opposite to the effect induced by D1 receptor mutation. Second, D2 receptor mutation reduces the developmental increase in ERG b-wave amplitudes after eye-opening. This result is similar to that obtained for D1 receptor mutation. Third, light deprivation of D2
/
mice reduces ERG b-wave amplitudes, which is similar to what occurs in D1
/
mice, but completely abolishes the increase in OP amplitudes, owing to D2 receptor mutation, which is opposite what occurs in D1
/
mice. Taken together, these results demonstrate that D2 receptors play important roles in the activity-dependent functional development of the mouse retina, and D1 and D2 receptor mutations result in similar functional defects in the outer retina light responses but opposite functional defects in the inner retina light responses. The effects of D2 receptors on the ERG of adult mice In the vertebrate retina, dopamine is released by dopaminergic amacrine cells, and is known to alter the physiology of retinal cells. However, specific dopamine receptor subtypes regulate retina physiology differently. Several studies have investigated the effects of D2 receptors on the ERG, with contradictory results. In most vertebrates, the b-wave amplitude varies with the circadian rhythm. The b-wave amplitude is high during the day and low during the night, whereas dopamine levels are high during the day and low during the night (Miranda-Anaya et al., 2002). In the Japanese quail,

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 17–30

D2 receptor regulates retinal light responses 25 A

B

C

D

E

F

Fig. 5. D2 receptors mediate the light-sensitive response gain of both the outer and inner retina. The b-wave/a-wave ratios and OP/b-waves ratios of WT and D2
/
mice raised under cyclic light/dark conditions and constant darkness were used to assess the effects of light deprivation on the response gains of the ERG. (A) The b-wave/a-wave ratios of WT mice raised under cyclic light/dark conditions and constant darkness were plotted as a function of light intensity, showing a significant increase in the outer retina response gain at light intensities of 0.008–0.08 cd*s/m2 of dark-reared WT mice. (B) The OP/b-wave ratios of WT mice raised under cyclic light/dark conditions and constant darkness. (C) The b-wave/a-wave ratios of D2
/
mice raised under cyclic light/dark conditions and constant darkness, showing no significant change in the outer retina response gain in dark-reared D2
/
mice. (D) The OP/b-wave ratios of D2
/
mice raised under cyclic light/dark conditions and constant darkness, showing a significant decrease in the inner retina response gain selective to high-intensity light. (E) The b-wave/a-wave ratios of D2
/
mice raised in constant dark were normalised to those of D2
/
mice raised in cyclic light/dark conditions, and the bwave/a-wave ratios of WT mice raised in constant dark were normalised to those of WT mice raised in cyclic light/dark conditions. These normalised b-wave/awave ratios were plotted as a function of light intensities, and showed that light deprivation significantly increased the b-wave/a-wave ratios of light responses evoked by low-intensity light in WT but not in D2
/
mice. (F) The OP/b-wave ratios of D2
/
and WT mice raised in constant dark were normalised to those of control mice raised in cyclic light/dark conditions, respectively, and plotted as a function of light intensity.

blocking D2 receptors during the day increases the b-wave amplitude, whereas activating D2 receptors at night decreases the b-wave amplitude (Manglapus et al., 1999). In contrast, activating D2 receptors during the night increases the b-wave amplitude in the green iguana (Miranda-Anaya et al., 2002), and blocking D2 receptors in rabbits decreases the b-wave amplitude (Hupp
e-Gourgues et al., 2005). Further complicating matters, the D2 antagonist sulpiride enhances the amplitude of the b-wave mediated by rods but diminishes the b-wave mediated by cones in dark-adapted frogs (Popova

& Kupenova, 2013). In the inner retina, activating D2 receptors increases the amplitude of OPs mediated by the rod pathway in the tiger salamander (Perry & George, 2007), and blocking of D2 receptors decreases the OP amplitude in the mudpuppy (Wachtmeister & Dowling, 1978; Wachtmeister, 1981, 1998). Our results seem to increase the complexity of the effects mediated by D2 receptors in retinal light responses. D2
/
mice at P30 show minimal changes in a-wave and b-wave amplitudes with all light intensities except for the lowest light intensity. At this lowest

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 17–30

26 N. Tian et al. A

B

C

D

E

F

Fig. 6. D2 receptor mutation diminishes the effects of light deprivation on the kinetics of the ERG. The times to peak of a-waves and b-waves of WT and D2
/
mice raised under cyclic light/dark conditions and constant darkness were measured and plotted as a function of light intensity. (A) The times to peak of a-waves of WT mice raised under cyclic light/dark conditions and constant darkness plotted as a function of light intensity. (B) The times to peak of b-waves of WT mice raised under cyclic light/dark conditions and constant darkness plotted as a function of light intensity. (C) The times to peak of a-waves of D2
/
mice raised under cyclic light/dark conditions and constant darkness plotted as a function of light intensity. (D) The times to peak of b-waves of D2
/
mice raised under cyclic light/dark conditions and constant darkness plotted as a function of light intensity. (E) The times to peak of a-waves of D2
/
and WT mice raised in constant dark were normalised to those of D2
/
and WT mice raised in cyclic light/dark conditions, respectively, and plotted as a function light intensity, showing that the effects of light deprivation on the time to peak of a-waves of WT mice were diminished in D2
/
mice. (F) The times to peak of b-waves of D2
/
and WT mice raised in constant dark were normalised to those of control mice raised in cyclic light/dark conditions, respectively, and plotted as a function of light intensity.

light intensity, D2
/
mice have a slightly increased a-wave amplitude and a slightly reduced b-wave amplitude, which is similar to the effects mediated by D2 receptor antagonists in the rabbit ERG (Hupp
e-Gourgues et al., 2005), but opposite to what is seen in frogs (Popova & Kupenova, 2013) and Japanese quail (Manglapus et al., 1999). In the inner retina, D2
/
mice have slightly reduced OP amplitudes with low-intensity light, which is similar to what has been reported in the mudpuppy (Wachtmeister & Dowling, 1978; Wachtmeister, 1981, 1998), but significantly increased OP amplitudes with high-intensity light, which is opposite to what has been

reported in lower vertebrates (Wachtmeister & Dowling, 1978; Wachtmeister, 1981, 1998; Perry & George, 2007). Although both D1 and D2 receptors are expressed by retinal neurons (Nguyen-Legros et al., 1999; Dowling, 2012), these two subtypes of dopamine receptor are considered to have distinct features in many respects (Lasater, 1987; Witkovsky et al., 1988; DeVries & Schwartz, 1989; Mills & Massey, 1995; Derouiche & Asan, 1999; Nguyen-Legros et al., 1999; Weber et al., 2001; Ribelayga et al., 2002, 2008; Urschel et al., 2006; Mills et al., 2007; Bloomfield & V€ olgyi, 2009; Kothmann et al., 2009; Ribelayga & Mangel, 2010;

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 17–30

D2 receptor regulates retinal light responses 27 Zhang et al., 2011). In the ERG, adult D1
/
mice have reduced awave, b-wave and OP amplitudes (Herrmann et al., 2011; Jackson et al., 2012; He et al., 2013; Lavoie et al., 2014), whereas adult D2
/
mice have minimal changes in a-wave and b-wave amplitudes, but significant changes in OP amplitudes. These results support the idea that D1 receptors regulate the light responses of both the inner and outer retina, whereas D2 receptors preferentially regulate the light response of the inner retina. In addition, genetic mutation of the D2 receptor, the potential autoreceptor for controlling dopamine release from dopaminergic amacrine cells (Derouiche & Asan, 1999; Nguyen-Legros et al., 1999; Weber et al., 2001), does not seem to cause detectable over-excitation of D1 receptors at the outer retina, whereas pharmacological over-excitation of D1 receptors profoundly increases a-wave, b-wave and OP amplitudes (Wachtmeister & Dowling, 1978; Oliver et al., 1987; Kim & Jung, 2012). In the inner retina, D2
/
mice have a biphasic change in OP amplitude: a slightly reduced OP amplitude with low-intensity light, and a significantly increased OP amplitude with high-intensity light. The increased OP amplitude is consistent with a recent report on the ERG of D2
/
mice (Lavoie et al., 2014). Given that OPs are likely to be generated by the synaptic activity between the bipolar cells, the amacrine cells, and the RGCs (Wachtmeister, 1998), and that both D1 and D2 receptors are expressed by amacrine cells and RGCs (Mills & Massey, 1995; Derouiche & Asan, 1999; NguyenLegros et al., 1999; Weber et al., 2001; Urschel et al., 2006; Mills et al., 2007; Kothmann et al., 2009; Zhang et al., 2011), it is possible that both inactivation of D2 receptors and over-excitation of D1 receptors could contribute to the changes in OP amplitude of D2
/
mice. Consistently, activating D2 receptors increases the amplitude of OPs mediated by the rod pathway (Perry & George, 2007), and blocking of D1 receptors or D1 receptor mutation reduces OP amplitude (Holopigian et al., 1994; He et al., 2013; Lavoie et al., 2014). This possibility is further supported by the results that dark rearing D2
/
mice, which could potentially block dopamine release from dopaminergic amacrine cells and D1 receptor activation, completely abolishes the effect of D2 receptor mutation on OP amplitude. The effects of D2 receptors on the ERG of developing mice The changes in the ERG during postnatal development have been widely reported, and the ages at which ERG parameters reach adult values vary considerably across species. In humans, a-waves and bwaves appear at birth, and the amplitudes of these waves increase considerably during postnatal development and reach the adult level by the age of 3–15 years (Rodriguez-Saez et al., 1993; Breton et al., 1995; Flores-Guevara et al., 1996; Westall et al., 1999), whereas the a-wave/b-wave ratio remains constant during postnatal development (Flores-Guevara et al., 1996), suggesting that the response gain at the outer retina is balanced and stabilised during the whole course of postnatal development. On the other hand, OPs are the most immature components of the ERG in early infancy, but develop quickly and reach the adult level by 2 years of age (Westall et al., 1999). In the guinea pig, the ERG amplitude detected at birth was 50% of the adult level, and reached maximal values 12 days after birth (Bui & Vingrys, 1999). In rabbits and rats, a-waves appear during the second postnatal week, and the a-wave amplitude reaches the adult value by P30–P40. After a-waves, b-waves and OPs appear, and rapidly grow between the second and third weeks but continue to increase slowly after P40 (Weidman & Kuwabara, 1968, 1969; Braekevelt & Hollenberg, 1970; Reuter, 1976; Masland,

1977; Gorfinkel et al., 1988; el-Azazi & Wachtmeister, 1990; Gorfinkel & Lachapelle, 1990; el Azazi & Wachtmeister, 1991a,b). We recently reported that all three major components of the mouse ERG are detectable before eye-opening (P10) and that the amplitudes of these three components increase by up to four-fold to six-fold from P13 to P30. Interestingly, the age-dependent increase in ERG amplitudes is light intensity-dependent, and the light intensity dependency of a-waves, b-waves and OPs have different patterns. The amplitudes of both a-waves and OPs have much weaker age-dependent enhancement with low-intensity light stimulation, but much stronger age-dependent enhancement with high-intensity light stimulation. On the other hand, the b-wave amplitude has much stronger age-dependent enhancement with low-intensity light, but much weaker age-dependent enhancement with high-intensity light. These results suggest that the maturation of the retina has a strong effect on cone-mediated responses at the photoreceptors and the inner retina, but that bipolar cells are influenced more through the rod-mediated responses (He et al., 2013). Therefore, the developmental profiles of the retina vary significantly among different species of rodents, and the increases in ERG amplitudes in postnatal development seem to be related to the maturation of retinal neurons (Tucker et al., 1982; Hamasaki & Maguire, 1985; Bui & Vingrys, 1999). We also found that D1 receptors selectively regulate the postnatal development of bipolar cell light responses by increasing the b-wave amplitude at P13 and decreasing the b-wave amplitude, especially the response evoked by high-intensity light, at P30, and therefore diminishes the light intensity-dependent developmental increase in b-wave amplitude. Surprisingly, the light intensity-dependent developmental increase in b-wave amplitude is also diminished in D2
/
mice. Therefore, both D1 and D2 receptors seem to regulate b-waves in a similar manner, which appears to occur by inhibition of b-waves during early postnatal development but enhancement of b-waves in adulthood (He et al., 2013). The role of D2 receptors in the activity-dependent developmental changes in the ERG The effects of visual experience on the developmental changes in ERG responses have been reported previously. Dark rearing or monocular light deprivation of cats for 2–4 weeks suppresses b-wave amplitudes (Baxter & Riesen, 1961; Babkoff, 1975). Dark rearing mice from birth to P30–P90 decreases a-wave, b-wave and OP amplitudes (Vistamehr & Tian, 2004). In the inner retina, light deprivation-induced suppression of OP amplitudes can be completely reversed by returning the mice back to cyclic light/dark conditions for 1–2 weeks (Vistamehr & Tian, 2004). Although dopamine has been thought to regulate activity-dependent synaptic plasticity in the central nervous system (Smith et al., 2005; Sun et al., 2005; Surmeier et al., 2007, 2010, 2011; Wolf, 2010; Xing et al., 2010; Xu & Yao, 2010; Chergui, 2011; Herwerth et al., 2012; Zhu et al., 2012; Edelmann & Lessmann, 2013) and synapse formation, synaptic transmission, and light adaptations in the retina (Lankford et al., 1987; Stone et al., 1990; Nguyen-Legros et al., 1999; Vaquero et al., 2001; Dowling, 2012; Van Hook et al., 2012), little is known about whether and how different subtypes of dopamine receptor regulate the activity-dependent development of retinal light responsiveness. Our recent studies showed that dark rearing of WT mice reduces b-wave and OP amplitudes, increases the outer retinal light response gain with low-intensity light, and alters the light response kinetics of both a-waves and b-waves (Tian & Copenhagen, 2003; Vistamehr & Tian, 2004; He et al., 2013).

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 17–30

28 N. Tian et al. D1 receptor mutation diminishes the effects of dark rearing on OP amplitude, and reverses the dark rearing-induced effects on the response gain of the outer retina and the changes in the kinetics of a-waves (He et al., 2013). This demonstrates the multiple roles of D1 receptors in the activity-dependent functional development of the mouse retina. The results of this study show that dark rearing of D2
/
mice has similar effects to those of dark rearing of D1
/
mice on the light responses in the outer retina. The fact that b-wave amplitudes are reduced by dark rearing in WT, D1
/
and D2
/
mice rules out the possibility that light deprivation suppresses b-wave amplitudes through D1 or D2 receptors. In addition, genetic disruption of the gene for the D4 receptor has no effect on b-waves of a darkadapted retina, although it reduces b-wave amplitude during dark and light adaptation (Nir et al., 2002; Herrmann et al., 2011). Therefore, it is unlikely that light deprivation suppresses b-wave amplitude through D4 receptors. In the inner retina, dark rearing of D2
/
mice completely abolishes the increase in OP amplitude induced by D2 receptor mutation, indicating that activation of D2 receptors normally suppresses the light-dependent increase in OP amplitude. D2 receptor mutation eliminates the suppression, and blocking light stimulation completely abolishes the enhancement of OPs. Taken together with our earlier findings that D1 receptor mutation results in a reduction in OP amplitude of mice raised under cyclic light conditions to that of dark-reared WT mice, and that dark rearing of D1
/
mice has no additional effect on OP amplitudes (He et al., 2013), it strongly suggests a push–pull effect on OP amplitude mediated by light through D1 and D2 receptors. Light stimulation increases dopamine release and the activation of D1 receptors, which results in an increase in OP amplitude. The D1 receptor-dependent enhancement of OPs is normally counterbalanced by the activation of D2 receptors, most likely through regulating dopamine release from dopaminergic amacrine cells. Activation of D2 receptors on dopaminergic amacrine cells or light deprivation decreases dopamine release, and therefore decreases OP amplitude through reduced activation of D1 receptors.

Acknowledgements This work was supported by NIH grants R01EY012345, 5P30EY014800 and Research to Prevent Blindness (RPB). We would also like to thank Brent Young and Kevin Huang for their critical and constructive reading of and comments on this manuscript.

Abbreviations ERG, electroretinogram; OP, oscillatory potential; P, postnatal day; RGC, retinal ganglion cell; WT, wild type.

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