Significant loss of the outer nuclear layer (ONL) and inner nuclear layer (INL) during progression of retinal degeneration in the Cln7 knockout (KO) mouse model. (a) Representative hematoxylin and eosin (H&E)-stained sections from a wild-type (left) and a Cln7 heterozygous (right) mouse eye at six months of age. Spider plot quantification of (b) ONL thickness and (c) INL thickness at six different regions of wild-type (black) and Cln7 heterozygous (teal) mice at six months of age. (d) Representative H&E-stained sections from Cln7 KO mice monthly through six months of age. Spider plot quantification of three month Cln7 heterozygous (teal) and Cln7 KO (orange) mice for (e) ONL thickness and (f) INL thickness. Spider plot quantification of six month Cln7 heterozygous (teal) and Cln7 KO (orange) mice for (g) ONL thickness and (h) INL thickness. N = five eyes per group and five sections per eye. GCL, ganglion cell layer; IS/OS, inner segment/outer segment; RPE, retinal pigmented epithelium; ONH, optic nerve head. Scale bar = 50 μm. Error bars = SD. Multiple comparisons test with Holm-ˇ Sidák's correction. ***P = 0.00018 and P = 0.00017; ****P < 0.0001.

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... for the recessive inheritance, heterozygous Cln7 mice displayed similar retinal morphology compared to wild-type controls at six months of age ( In contrast, the Cln7 KO mice displayed a loss of the ONL beginning at one month of age, with rapid degeneration between one and two months of age, and continuing to decline through six months of age (Fig. 2d). Quantification of ONL thickness showed a significant reduction (approximately 50-65% depending on the region of the retina examined based on distance from the optic nerve head) in the Cln7 KO mice (orange) compared to heterozygous controls (blue) at three months of age (Fig. 2e) (Fig. 2g), but also had a significant -approximately 37% ...

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... months of age, and continuing to decline through six months of age (Fig. 2d). Quantification of ONL thickness showed a significant reduction (approximately 50-65% depending on the region of the retina examined based on distance from the optic nerve head) in the Cln7 KO mice (orange) compared to heterozygous controls (blue) at three months of age (Fig. 2e) (Fig. 2g), but also had a significant -approximately 37% -loss of INL thickness (Fig. 2h) OS, left eye; OD, right eye; OCT, optical coherence tomography; ERG, electroretinography. Five CLN7 Batten disease patients were examined for visual acuity and retinal health with results summarized in this table. "Uncooperative" denotes that ...

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... age, and continuing to decline through six months of age (Fig. 2d). Quantification of ONL thickness showed a significant reduction (approximately 50-65% depending on the region of the retina examined based on distance from the optic nerve head) in the Cln7 KO mice (orange) compared to heterozygous controls (blue) at three months of age (Fig. 2e) (Fig. 2g), but also had a significant -approximately 37% -loss of INL thickness (Fig. 2h) OS, left eye; OD, right eye; OCT, optical coherence tomography; ERG, electroretinography. Five CLN7 Batten disease patients were examined for visual acuity and retinal health with results summarized in this table. "Uncooperative" denotes that examination ...

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... of ONL thickness showed a significant reduction (approximately 50-65% depending on the region of the retina examined based on distance from the optic nerve head) in the Cln7 KO mice (orange) compared to heterozygous controls (blue) at three months of age (Fig. 2e) (Fig. 2g), but also had a significant -approximately 37% -loss of INL thickness (Fig. 2h) OS, left eye; OD, right eye; OCT, optical coherence tomography; ERG, electroretinography. Five CLN7 Batten disease patients were examined for visual acuity and retinal health with results summarized in this table. "Uncooperative" denotes that examination was stopped or produced data with artifacts due to patient distress. "Unable to ...

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... late-(five months) stages of disease compared to wild-type controls (Fig. 3). As expected, the Cln7 KO mice showed elevated glial activation by immunostaining for glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP) at both two and five months of age, indicative of retinal stress during both the early-and late-stages of disease ( Fig. 3; Fig. S2). Microglial activation was also elevated at both the early-and late-stages of disease in the Cln7 KO mice compared to wild-type controls, and ionized calcium-binding adaptor molecule 1 (IBA1) protein was found to be significantly elevated in the Cln7 KO mice compared to controls upon Western blot analysis ( Figs Fig. 3; Fig. S3). ...

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... and two month Cln7 KO retinas with Western blot analysis (Fig. 4) [*P = 0.013; one-way ANOVA with Tukey's multiple comparisons test]. However, there was a thinning of the bipolar cell layer present by late-stage of disease in the Cln7 KO mice ( Fig. 3; Fig. S3), as would be expected with the reduction in INL thickness seen at six months of age (Fig. 2h). Western blot analysis of PKCα showed a significant decline between the early-and late-stage Cln7 KO mice, although it did not show significance against the wild-type controls (Fig. 4) [**P = 0.0038; one-way ANOVA with Tukey's multiple comparisons test]. This trend was also detected, without significance, by examining prospero homeobox ...