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

Abstract

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.

Electrophysiological properties of layer 2/3 pyramidal neurons in the primary visual cortex of a retinitis pigmentosa mouse model (rd10)

“…Similar to our observations after the onset of retinal degeneration, different murine models of retinitis pigmentosa showed heightened excitability in V1 (Wang et al, 2016 ; Chen et al, 2020 ; Leinonen et al, 2022 ), accompanied by impairments in neurophysiological properties such as visual stimulus direction selectivity (Chen et al, 2016 ; Leinonen et al, 2022 ). In addition, human retinitis pigmentosa patients report visual impairments beyond loss of vision, which might be attributed to aberrant retinal activity (Stasheff, 2018 ).…”

Functional integrity of visual coding following advanced photoreceptor degeneration

“…Literature on the degenerate retina's functional capacity is limited, mostly focusing on changes in photoreceptor-driven responses at earlier stages of degeneration. Although contrast sensitivity seems well preserved in those studies, 39,40 some loss of function has been found, including attenuated response amplitude, longer onset latency, smaller receptive fields, and the loss of inhibitory/OFF responses in rd1 mice. 40 Our data are consistent with the view that these features are more a consequence of photoreceptor depletion/dysfunction than network reorganization.…”

Functional integrity of visual coding following advanced photoreceptor degeneration

“…There is limited literature on the functional capacity of the degenerate retina, which has mostly focused on changes to photoreceptor-driven vision in early stages of retinal degeneration. While contrast sensitivity seems to be well preserved (Leinonen et al, 2022;Procyk et al, 2019), there is evidence of loss-of-function in some of the visual properties we tested, including attenuated response amplitude, onset latency, smaller receptive fields and an absence of sustained inhibitory/OFF responses (Procyk et al, 2019). Given that we have found the rd1 retina retains the capacity to support these characteristics during optogenetic interrogation of bipolar cells, it is likely these findings are due to changes in photoreceptors or the first retinal synapse rather than changes later in the visual pathway.…”