Neuronal and synaptic plasticity in the visual thalamus in mouse models of glaucoma

Hook, Matthew J. Van; Monaco, Corrine F.; SMITH, JENNIE

doi:10.1101/2020.10.23.352310

Cited by 4 publications

(8 citation statements)

References 94 publications

(113 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We showed in the Rho P23H/WT mouse, representing a common form of human autosomal dominant RP, increased sensitivity to visual inputs at the photoreceptor-to-bipolar cell synapse and maintained rod-driven contrast sensitivity regardless of rod population loss of >50% ( Leinonen et al, 2020 ). Importantly, functional adaptation to retinal stress has also been observed in glaucoma models, wherein increased excitability of RGCs and dLGN neurons may mitigate the loss of axon function caused by elevated intraocular pressure ( Calkins, 2021 ; Van Hook et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Visual System Hyperexcitability and Compromised V1 Receptive Field Properties in Early-Stage Retinitis Pigmentosa in Mice

Leinonen

Lyon²,

Palczewski³

et al. 2022

eNeuro

View full text Add to dashboard Cite

Inherited retinal degenerative diseases are a prominent cause of blindness. Although mutations causing death of photoreceptors are mostly known, the pathophysiology downstream in the inner retina and along the visual pathway is incompletely characterized in the earliest disease stages. Here, we investigated retinal, midbrain and cortical visual function using electroretinography (ERG), the optomotor response (OMR), visual evoked potentials (VEPs), respectively, and single unit electrophysiology at the primary visual cortex (V1) in light-adapted juvenile (approximately one-month-old) and young adult (three-month-old) Rho P23H/WT mice, representative of early-stage retinitis pigmentosa (RP). Photopic ERG revealed up to ∼30% hypersensitivity to light in Rho P23H/WT mice, as measured by the light intensity required to generate half-maximal b-wave (I 50 parameter). Rho P23H/WT mice also showed increased OMRs toward low spatial frequency (SF) drifting gratings, indicative of visual overexcitation at the midbrain level. At the V1 level, VEPs and single-cell recordings revealed prominent hyperexcitability in the juvenile Rho P23H/WT mice. Mean VEP amplitudes for light ON stimuli were nearly doubled in one-month-old Rho P23H/WT mice compared with controls, and more than doubled for light OFF. Single-cell recordings showed a significantly increased spontaneous V1 neuron firing in the Rho P23H/WT mice, and persistent contrast and temporal sensitivities. In contrast, direction selectivity was severely compromised. Our data suggest that during early RP, the visual pathway becomes hyperexcited. This could have both compensatory and deleterious consequences for visual behavior. Further studies on the mechanisms of hyperexcitability are warranted as this could lead to therapeutic interventions for RP.

show abstract

Section: Discussionmentioning

confidence: 99%

Visual System Hyperexcitability and Compromised V1 Receptive Field Properties in Early-Stage Retinitis Pigmentosa in Mice

Leinonen

Lyon²,

Palczewski³

et al. 2022

eNeuro

View full text Add to dashboard Cite

show abstract

“…We showed in the Rho P23H/WT mouse, representing a common form of human autosomal dominant RP, increased sensitivity to visual inputs at the photoreceptor-to-bipolar cell synapse and maintained rod-driven contrast sensitivity regardless of rod population loss of more than 50% (Leinonen et al ., 2020). Importantly, functional adaptation to retinal stress has also been observed in glaucoma models, wherein increased excitability of RGCs and dLGN neurons may mitigate the loss of axon function caused by elevated intraocular pressure (Calkins, 2021; Van Hook et al ., 2021).…”

Section: Discussionmentioning

confidence: 99%

Visual system hyperexcitability and compromised V1 receptive field properties in early-stage retinitis pigmentosa in mice

Leinonen

Lyon

Palczewski

et al. 2022

Preprint

View full text Add to dashboard Cite

Inherited retinal degenerative diseases are a prominent cause of blindness. Even though mutations causing death of photoreceptors are mostly known, the pathophysiology downstream in the inner retina and along the visual pathway is incompletely characterized in the earliest disease stages. Here we investigated retinal, midbrain and cortical visual function using electroretinography (ERG), the optomotor response (OMR), visual evoked potentials (VEPs), respectively, and single unit electrophysiology at the primary visual cortex (V1) in light-adapted juvenile (∼ 1-month-old) and young adult (3-month-old) RhoP23H/WT mice, representative of early-stage retinitis pigmentosa (RP). Photopic ERG revealed up to ∼ 30 % hypersensitivity to light in RhoP23H/WT mice, as measured by the light intensity required to generate half-maximal b-wave (I50 parameter). RhoP23H/WT mice also showed increased optomotor responses towards low spatial frequency drifting gratings, indicative of visual overexcitation at the midbrain level. At the V1 level, VEPs and single-cell recordings revealed prominent hyperexcitability in the juvenile RhoP23H/WT mice. Mean VEP amplitudes for light ON stimuli were nearly doubled in 1-month-old RhoP23H/WT mice compared to controls, and more than doubled for light OFF. Single-cell recordings showed a significantly increased spontaneous V1 neuron firing in the RhoP23H/WT mice, and persistent contrast and temporal sensitivities. In contrast, direction selectivity was severely compromised. Our data suggest that during early RP, the visual pathway becomes hyperexcited. This could have both compensatory and deleterious consequences for visual behavior. Further studies on the mechanisms of hyperexcitability are warranted as this could lead to therapeutic interventions for RP.Significance statementLost retinal function in many blinding retinal degenerative disorders could soon be alleviated by advanced therapies that restore photoreception. However, it is unknown whether a visual system rewired downstream of the photoreceptors can process signals adequately. We studied the functional consequences of early rod death along the visual pathway in young retinitis pigmentosa (RP) mice. Photopic inner retina responses were moderately hypersensitized in the electroretinograms of RP mice. Reflex-based visual behavior and visual cortex electrophysiology showed hyperexcitability. Some aspects of complex visual processing were remarkably resistant to degeneration, whereas others were severely impacted. We conclude that the visual system adapts to lost photoreception by increasing sensitivity, but simultaneously becomes detrimentally hyperexcited. Mechanistic understanding could lead to therapeutic preservation and restoration of vision.

show abstract

“…However, elevated IOP also has effects that profoundly alter the function of RGC axons distal to the optic nerve head as well as to their downstream visual targets in the brain. These include disruption of optic nerve active transport [17], metabolism [18][19][20][21], and glia [22] as well as alterations to mitochondria [23], RGC excitatory output synapses [17,24], and the structure and response properties of neurons residing in visual brain nuclei [14,25]. Evidence to date indicates that many of these functional changes are relatively early events in the pathological process.…”

Section: Introductionmentioning

confidence: 99%

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

SMITH

Zhang

Sladek

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Neuronal and synaptic plasticity in the visual thalamus in mouse models of glaucoma

Cited by 4 publications

References 94 publications

Visual System Hyperexcitability and Compromised V1 Receptive Field Properties in Early-Stage Retinitis Pigmentosa in Mice

Visual System Hyperexcitability and Compromised V1 Receptive Field Properties in Early-Stage Retinitis Pigmentosa in Mice

Visual system hyperexcitability and compromised V1 receptive field properties in early-stage retinitis pigmentosa in mice

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

Contact Info

Product

Resources

About