The Contribution of Anterior Segment Abnormalities to Changes in Intraocular Pressure in the DBA/2J Mouse Model of Glaucoma: DBA/2J-Gpnmb+/SjJ Mice as Critical Controls

Rohowetz, Landon J.; Mardelli, Marc E.; Duncan, R. Scott; Riordan, Sean M.; Koulen, Peter

doi:10.3389/fnins.2021.801184

Cited by 4 publications

(3 citation statements)

References 34 publications

(62 reference statements)

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“…1 B , C ), similar to what we have observed previously ( Bierlein et al, 2022 ) and is apparent in figures from other prior studies ( Libby et al, 2005 ; A.J. Turner et al, 2017 ; Rohowetz et al, 2021 ). While female DBA/2J mice had, on average, higher IOP than males at ages more than eight months, consistent with prior work ( Libby et al, 2005 ), the male and female IOP measurements overlapped considerably.…”

Section: Resultssupporting

confidence: 91%

Loss of Retinogeniculate Synaptic Function in the DBA/2J Mouse Model of Glaucoma

SMITH

Zhang

Sladek

et al. 2022

eNeuro

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Retinal ganglion cell (RGC) axons comprise the optic nerve and carry information to the dorsolateral geniculate nucleus (dLGN) which is then relayed to the cortex for conscious vision. Glaucoma is a blinding neurodegenerative disease that commonly results from intraocular pressure (IOP)-associated injury leading to RGC axonal pathology, disruption of RGC outputs to the brain, and eventual apoptotic loss of RGC somata. The consequences of elevated IOP and glaucomatous pathology on RGC signaling to the dLGN are largely unknown yet are likely to contribute to vision loss. Here, we used anatomical and physiological approaches to study the structure and function of retinogeniculate (RG) synapses in male and female DBA/2J (D2) mice with inherited glaucoma before and after IOP elevation. D2 mice showed progressive loss of anterograde optic tract transport to the dLGN and vGlut2 labeling of RGC axon terminals while patch-clamp measurements of RG synaptic function showed that synaptic transmission was reduced in 9 and 12-month D2 mice due to the loss of individual RGC axon inputs. TC neuron dendrites had reduced Sholl complexity at 12 months, suggestive of delayed reorganization following reduced synaptic input. There was no detectable change in RGC density in 11-12m D2 retinas, quantified as the number of ganglion cell layer-residing somata immuno-positive for NeuN and immuno-negative for the amacrine marker choline acetyltransferase (ChAT). Thus, observed synaptic defects appear to precede RGC somatic loss. These findings identify glaucoma- and IOP-associated deficits in an important subcortical RGC projection target, shedding light on processes linking IOP to vision loss.Significance StatementGlaucoma is the leading cause of irreversible blindness worldwide and is commonly associated with elevated intraocular pressure (IOP), which triggers loss of retinal ganglion cell (RGC) somata and connections in the retina, axons in the optic nerve, and outputs to visual centers of the brain. We show here that elevated IOP in the DBA/2J mouse model of inherited glaucoma leads to an early-stage and progressive dysfunction of RGC output synapses in the dorsolateral geniculate nucleus (dLGN). As the dLGN is critical for sending signals to the cortex for conscious vision, these findings demonstrate how RGC output synapse loss can contribute to vision loss in glaucoma.

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Section: Resultssupporting

confidence: 91%

Loss of Retinogeniculate Synaptic Function in the DBA/2J Mouse Model of Glaucoma

SMITH

Zhang

Sladek

et al. 2022

eNeuro

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“…Compared to DBA/2J-gpnmb + (D2-control mice, n = 110 eyes, 55 mice), IOP was significantly elevated after 8 months. Notably, IOP in D2 mice was significantly lower than in D2-controls at 5 months and 6 months (Figure 1 B&C), similar to what we have observed previously [49] and is apparent in figures from other prior studies [32,50,51]. While female DBA/2J mice had, on average, higher IOP than males at ages >8 months, consistent with prior work [32], the male and female IOP measurements overlapped considerably.…”

Section: Resultssupporting

confidence: 90%

Loss of retinogeniculate synaptic function in the DBA/2J mouse model of glaucoma

SMITH

Zhang

Sladek

et al. 2022

Preprint

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Background: Retinal ganglion cell (RGC) axons comprise the optic nerve and carry information to the dorsolateral geniculate nucleus (dLGN) that is relayed to the cortex for conscious vision. Glaucoma is a blinding neurodegenerative disease that commonly results from intraocular pressure (IOP)-associated injury leading to RGC axonal pathology, disruption of RGC outputs to the brain, and eventual apoptotic loss of RGC somata. The consequences of elevated IOP and glaucomatous pathology on RGC signaling to the dLGN are largely unknown and likely to be important contributors to visual system dysfunction in glaucoma. Thus, the goal of this study was to determine how glaucoma affects RGC outputs to the dLGN. Methods: We used a combination of anatomical and physiological approaches to study the structure and function of retinogeniculate synapses in male and female DBA/2J mice at multiple ages before and after IOP elevation. These included measures of anterograde axonal transport, immunofluorescence staining of RGC axon terminals, patch-clamp recording retinogeniculate (RG) synapses in living brain slices, Sholl analysis of thalamocortical relay neuron dendrites, measurements of RGC somatic density, and treatment with a topical ophthalmic alpha-2 adrenergic agonist (brimonidine). Results: DBA/2J mice showed progressive loss of anterograde optic tract transport to the dLGN and vGlut2 labeling of RGC axon terminals. Patch-clamp measurements of RG synaptic function showed that the strength of synaptic transmission was lower in 9 and 12-month DBA/2J mice and that this was the result of loss of individual RGC axon contributions. TC neuron dendrites showed a reduction in complexity at 12 months, suggestive of a delayed reorganization following reduced synaptic input. There was no detectable change in RGC soma density in 11-12m DBA/2J retinas indicating that observed effects occurred prior to RGC somatic loss. Finally, treatment with brimonidine eye drops prevented the loss of vGlut2-labeled RGC terminals in the dLGN. Conclusions: These findings identify glaucoma- and IOP-associated functional deficits in an important subcortical RGC projection target. This sheds light on the processes linking IOP to vision loss and will be critical for informing future diagnostic approaches and vision-restoration therapies.

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“…In one case, a spurious association was caused by a series of >40 abstracts, each covering a different topic, that were published together as a conference summary. In another case, a diverse set of phenotypes exhibited by an inbred strain (which included hearing loss) were summarized in the introduction to a paper, which characterized the effect of a gene knockout on an unrelated phenotype [44]. Secondly, a scalable LLM based AI system for genetic discovery can be designed to overcome the current limitations of the knowledge encoded in LLMs.…”

Section: Discussionmentioning

confidence: 99%

Genetic Discovery Enabled by A Large Language Model

Tu,

Fang,

Cheng

et al. 2023

Preprint

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Artificial intelligence (AI) has been used in many areas of medicine, and recently large language models (LLMs) have shown potential utility for clinical applications. However, since we do not know if the use of LLMs can accelerate the pace of genetic discovery, we used data generated from mouse genetic models to investigate this possibility. We examined whether a recently developed specialized LLM (Med-PaLM 2) could analyze sets of candidate genes generated from analysis of murine models of biomedical traits. In response to free-text input, Med-PaLM 2 correctly identified the murine genes that contained experimentally verified causative genetic factors for six biomedical traits, which included susceptibility to diabetes and cataracts. Med-PaLM 2 was also able to analyze a list of genes with high impact alleles, which were identified by comparative analysis of murine genomic sequence data, and it identified a causative murine genetic factor for spontaneous hearing loss. Based upon this Med-PaLM 2 finding, a novel bigenic model for susceptibility to spontaneous hearing loss was developed. These results demonstrate Med-PaLM 2 can analyze gene-phenotype relationships and generate novel hypotheses, which can facilitate genetic discovery.

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The Contribution of Anterior Segment Abnormalities to Changes in Intraocular Pressure in the DBA/2J Mouse Model of Glaucoma: DBA/2J-Gpnmb+/SjJ Mice as Critical Controls

Cited by 4 publications

References 34 publications

Loss of Retinogeniculate Synaptic Function in the DBA/2J Mouse Model of Glaucoma

Loss of Retinogeniculate Synaptic Function in the DBA/2J Mouse Model of Glaucoma

Loss of retinogeniculate synaptic function in the DBA/2J mouse model of glaucoma

Genetic Discovery Enabled by A Large Language Model

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