In this study, the role of melanopsin-expressing retinal ganglion cells (mRGCs) in the glaucoma-induced depressive behavioral response pattern was investigated. The CFP-D2 transgenic glaucoma animal model from five age groups was used in this study. Immunohistochemical labeling, quantitative analysis of mRGC morphology, open field test (OFT), and statistical analysis were used. In comparison with C57 BL/6 mice, the age-matched CFP-D2 mice had significantly elevated intraocular pressure (IOP). We observed parallel morphological changes in the retina, including a reduction in the density of cyan fluorescent protein-(CFP) expressing cells (cells mm(-2) at 2 months of age, 1309 +/- 26; 14 months, 878 +/- 30, P < 0.001), mRGCs (2 months, 48 +/- 3; 14 months, 19 +/- 4, P < 0.001), Brn3b-expressing RGCs (2 months, 1283 +/- 80; 14 months, 950 +/- 31, P < 0.001), Brn-3b expressing mRGCs (5 months, 50.17%+/- 5.5%; 14 months, 12.61%+/- 3.8%, P < 0.001), and reduction in the dendritic field size of mRGCs (mm(2) at 2 months, 0.077 +/- 0.015; 14 months, 0.065 +/- 0.015, P < 0.05). CFP-D2 mice had hyperactive locomotor activity patterns based on OFT findings of the total distance traveled, number of entries into the center, and time spent in the center of the testing apparatus. The glaucoma induced hyperactive response pattern could be associated with dysfunctional mRGCs, most likely Brn-3b-positive mRGCs in CFP-D2 mice.