Preservation of Visual Cortex Plasticity in Retinitis Pigmentosa

NEUROSCIENCE RESEARCH ARTICLE T. Begenisic et al. / Neuroscience 424 (2020) 205–210

Preservation of Visual Cortex Plasticity in Retinitis Pigmentosa Tatjana Begenisic, a Raffaele Mazziotti, a,b Giulia Sagona, b,c Leonardo Lupori, d Alessandro Sale, a Lucia Galli a and Laura Baroncelli a,c* a

Institute of Neuroscience, National Research Council (CNR), I-56124 Pisa, Italy

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Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA, University of Florence, I-50135 Florence, Italy

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Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, I-56128 Pisa, Italy

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BIO@SNS lab, Scuola Normale Superiore di Pisa, I-56125 Pisa, Italy

Abstract—Retinitis Pigmentosa (RP) is a class of inherited disorders caused by the progressive death of photoreceptors in the retina. RP is still orphan of an effective treatment, with increasing optimism deriving from research aimed at arresting neurodegeneration or replacing light-responsive elements. All these therapeutic strategies rely on the functional integrity of the visual system downstream of photoreceptors. Whereas the inner retinal structure and optic radiation are known to be considerably preserved at least in early stages of RP, very little is known about the visual cortex. Remarkably, it remains completely unclear whether visual cortex plasticity is still present in RP. Using a well-established murine model of RP, the rd10 mouse, we report that visual cortical circuits retain high levels of plasticity, preserving their capability of input-dependent remodelling even at a late stage of retinal degeneration. Ó 2019 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: Retinitis Pigmentosa, visual cortex, plasticity, rd10 mouse model.

that retinal and thalamic structures are rather preserved with RP, although inner retinal neurons and glial cells undergo progressive remodelling (Milam et al., 1998; Marc et al., 2003; Strettoi et al., 2003; Schoth et al., 2006; Aguirre et al., 2007; Margolis et al., 2008; Mazzoni et al., 2008; Stasheff, 2008; Menzler and Zeck, 2011; Sekirnjak et al., 2011; Ohno et al., 2015). In contrast, the visual cortex has surprisingly received far less attention. Only few studies reported general alterations of brain activity in individuals with RP (Jacobson et al., 1985; Jana´ky et al., 2008; Huang et al., 2018) and animal models (Amendola et al., 2003; Chen et al., 2016), but the effects of photoreceptor degeneration on cortical circuit function and plasticity remain largely unknown. This knowledge gap is a severe handicap for the advancement of RP research, as visual cortex plasticity is a potential limiting factor in the responsivity of cortical circuits to a restored visual input. Short-term plasticity has been recently reported in RP patients by testing the response of binocular rivalry to brief monocular deprivation (MD) (Lunghi et al., 2019). However, these results might reflect a transient adaptive effect of cortical responses and a clear evidence of stable changes of visual cortical synapses is still missing. Here, we investigated whether the RP visual cortex retains the capability for synaptic plasticity and functional plasticity in response to sensory input changes. We used an established murine model of RP,

INTRODUCTION Retinitis Pigmentosa (RP) is a family of inherited disorders caused by the progressive loss of retinal photoreceptors and affecting about 2.5 millions of people worldwide. Typically, rod photoreceptors and night vision are the first to be affected. Then, cone photoreceptors, which mediate high-resolution daytime vision, progressively die out, the visual field shrinks and blindness occurs in most patients (Hartong et al., 2006; Dias et al., 2018). There is no cure for RP, but research aimed at preventing further photoreceptor loss, or substituting light-responsive elements, is attracting large interest and generating new hopes for patients (e.g., Aguirre et al., 2007; Cohen, 2007; Lagali et al., 2008; Strettoi et al., 2010; Thyagarajan et al., 2010; Maya-Vetencourt et al., 2017; for a review Dias et al. (2018)). All potential therapeutic strategies for RP rely on the integrity of the visual system downstream of the photoreceptors, which represents a fundamental constraint for the effective success of the attempted procedures. Anatomical and functional studies showed *Corresponding author at: Institute of Neuroscience, National Research Council (CNR), via Moruzzi 1, Pisa I-56124, Italy. E-mail address: [email protected] (L. Baroncelli). Abbreviations: RP, Retinitis Pigmentosa; IOS, intrinsic optical signal; R, reflectance; MD, monocular deprivation; fEPSPs, field excitatory post-synaptic potentials; LTP, long-term potentiation; ERG, electroretinogram. https://doi.org/10.1016/j.neuroscience.2019.10.045 0306-4522/Ó 2019 IBRO. Published by Elsevier Ltd. All rights reserved. 205

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the rd10 mouse, carrying a recessive mutation of the rodspecific phosphodiesterase gene (Chang et al., 2002). This model has a fully characterized retinal degeneration time-course, which superimposes only minimally to the window of retinal development (Gargini et al., 2007). We report that visual cortical circuits in rd10 mice show levels of plasticity not significantly different from those of wt animals, thus maintaining the capability of input-dependent remodelling until an advanced stage of retinal damage.

MATERIAL AND METHODS Animals We used rd10 mutants (B6.CXB1-Pde6brd10/J, on a C57Bl6J background; https://www.jax.org/strain/004297; (Chang et al., 2002) RRID IMSR_JAX:004297) and wildtype mice (wt, C57BL/6J) from The Jackson Laboratory. To prevent possible litter effects, animals in each experimental group came from independent litters, with a minimum of three litters even for the smallest groups. Females and males were equally distributed in both experimental groups. Animals were maintained at 22 °C under a 12-h light–dark cycle (average illumination levels of 1.2 cd/m2). Food (4RF25 GLP Certificate, Mucedola) and water were available ad libitum. All experiments were carried out in accordance with the European Communities Council Directive of 22 September 2010 (EU/63/2010) and approved by the Italian Ministry of Health (authorization number 358/2015-PR). Intrinsic optical signal (IOS) imaging For chronic IOS preparations, mice were anesthetized with isoflurane (1–3%) and placed on a stereotaxic frame (wt, n = 7; rd10, n = 6). Surgery was performed as previously described (Mazziotti et al., 2017). A thin layer of cyanoacrylate was poured over the skull to fix a custom-made metal ring (9 mm internal diameter) centred over the binocular visual cortex. To ameliorate optical access, a drop of transparent nail polish was also spotted over the area. IOS recordings were performed under isoflurane (0.5–1%) and chlorprothixene anaesthesia (1.5 mg/kg, i.p.) at P53-54 and at P60-61 (after 7 days of MD). The animal was secured under the objective using a ring-shaped neodynium magnet mounted on an arduino-based 3D printed imaging chamber (http://labrigger.com/blog/2015/11/30/open-source-intrinsic-imaging/ ). Images were visualized using an Olympus microscope (BX50WI) and 8 red LEDs (625 nm, Knight Lites KSB1385-1P) fixed to the objective (Zeiss PlanNEOFLUAR 5x, NA: 0.16). Visual stimuli were generated using Matlab Psychtoolbox and presented on a monitor placed 13 cm away from the eyes of the mouse. Sinusoidal wave gratings were presented in the binocular portion of the visual field with spatial frequency 0.03 cyc/deg, mean luminance 20 cd/m2 and contrast 90%. The stimulus consisted in the abrupt contrast reversal of a grating with a temporal frequency of 4 Hz for 1 s. Frames were acquired at 30 fps with a resolution of 512  512 pixels. The signal was averaged for at least 80 trials. Fluctuations of reflectance (R) for each pixel were computed as

the normalized difference from the average baseline (DR/R). See (Mazziotti et al., 2017) for further details on signal analysis. ODI was calculated as (C I)/(C + I), where C and I indicate, respectively, the amplitude of contralateral and ipsilateral responses. Monocular deprivation Monocular deprivation (MD) was performed through eyelid suture under isoflurane anesthesia. Subjects with even minimal spontaneous reopening were excluded from the study. One rd10 animal was excluded from the analysis of ocular dominance plasticity because of a partial reopening of the suture. In vitro electrophysiology Brains were rapidly removed and immersed in ice-cold cutting solution containing (in mM): 130 NaCl, 3.1 KCl, 1.0 K2HPO4, 4.0 NaHCO3, 5.0 dextrose, 2.0 MgCl2, 1.0 CaCl2, 10 HEPES, 1.0 ascorbic acid, 0.5 myo-Inositol, 2.0 pyruvic acid, and 1.0 kynurenate, pH 7.3. Coronal slices of visual cortex (350 lm thick) were obtained using a vibratome (Leica, Germany). Slices were allowed to equilibrate at room temperature for at least 1.5 h before being transferred to a recording interface chamber and perfused at a rate of 2 ml/min with 35 °C oxygenated recording solution. The recording solution was identical to the cutting solution with the following differences (in mM): 1.0 MgCl2, 2.0 CaCl2, 0.01 glycine, and no kynurenate. Electrical stimulation (100 ls duration) was delivered with a bipolar concentric stimulating electrode (FHC, St. Bowdoinham, ME) placed in the middle of the layer IV. Field excitatory post-synaptic potentials (fEPSPs) in layer II/III were recorded by means of a micropipette (1–3 MX) filled with the recording solution. Basal recording was carried out using stimulus intensity capable of evoking a response whose amplitude was 50–60% of the maximal amplitude. Baseline responses were obtained every 30 s with a stimulation intensity that yielded a half-maximal response in the input–output curve. We recorded 10 slices from 7 wt animals and 20 slices from 12 rd10 mice at P60, while 28 slices from 15 wt animals and 11 slices from 5 rd10 mice were used for the analysis of input–output curves at P180. After achievement of at least a 15 min stable baseline, LTP was induced by a single TBS. LTP expression was measured in 7 slices from 5 animals for both wt and rd10 groups at P60, while 8 slices from 7 wt animals and 8 sliced from 5 rd10 animals were used for the analysis of LTP at P180. Slices not achieving at least 1 h of recording after TBS were excluded from the analysis. Statistical analysis All statistical analyses were performed using GraphPad Prism 8 and SigmaPlot 14.0 Software. Differences between two groups were assessed with a two-tailed ttest. The significance of factorial effects and differences among the two groups were evaluated with ANOVA/RM ANOVA followed by post hoc Holm-Sidak/Bonferroni

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Whitney test, p < 0.01, U = 3, effect size = 1.36 Fig. 1a). However, when the contralateral and ipsilateral evoked signal for each animal were paired to calculate the ODI, a normal contralateral dominance was detectable (Fig. 1b). After 7 days of MD, the ODI in the cortex contralateral to the deprived eye shifted negatively towards the non-deprived, ipsilateral eye in both wt and rd10 animals (Two-way RM ANOVA, effect of genotype p = 0.187, F(1,10) = 2.007, effect size = 0.326, effect of time p < 0.001, F(1,10) = 24.45, effect size = 0.641, interaction genotype  time p = 0.520, F(1,10) = 0.5205, effect size = 0.207, post hoc Holm-Sidak test pre-MD vs. post-MD p < 0.05 for wt and p < 0.01 for rd10; Fig. 1b), indicating that visual cortical plasticity is not hampered in the visual cortex of rd10 mice. A replication of the same experiment at P180 was precluded by massive retinal damage resulting in the inability to visualize specific IOS changes in response to visual stimulation.

test. Normality of data was checked using a Shapiro-Wilk test. The level of significance was p < 0.05.

RESULTS Ocular dominance plasticity in adult rd10 mice To determine the impact of rd10 mutation on visual cortical plasticity, we examined cortical responses to visual stimulation using intact skull repeated IOS imaging in adult (P60) animals, tracking in the same subjects the response to MD in the binocular visual cortex. Fig. 1a, b shows typical examples of responses from the different experimental groups before and after MD, consisting in a decrease in reflectance (dark area) induced by visual stimulation in the visual cortex. As expected, data quantitation showed that the amplitude of responses to binocular stimulation in rd10 animals was significantly lower with respect to wt mice (Mann-

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Fig. 1. Monocular deprivation (MD) induces an ocular dominance (OD) shift in the visual cortex of rd10 mice at P60. (A) IOS amplitude in response to binocular stimulation at P60 in wt (n = 7) and rd10 (n = 6) mice. Data quantitation showed that rd10 mice had a significantly reduced response with respect to wt (Mann-Whitney test, p < 0.01). Symbols represent individual values for each subject. (B) Ocular dominance index (ODI) in wt (n = 6) and rd10 (n = 6) mice before (pre-MD) and after 7 days monocular deprivation (post-MD). No change in ODI was present before MD in rd10 mice compared to controls (Two-way RM ANOVA, effect of genotype p = 0.187, interaction genotype  time p = 0.520). MD resulted in a strong OD shift toward the open eye in both wt and rd10 mice (Two-way RM ANOVA, effect of time p < 0.001, post hoc Holm-Sidak method p < 0.05 for wt group, p < 0.01 for rd10 group). Thin lines represent the ODI shift in individual subjects. Representative images for wt and rd10 mice are reported on the right. Responses to contralateral (contra) and ipsilateral (ipsi) eye stimulation pre-MD and post-MD are depicted. Data are expressed as mean ± s.e.m. *p < 0.05, #p < 0.01.

In order to evaluate cortical synaptic transmission and plasticity bypassing the masking effects of retinal input degeneration, we performed ex vivo electrophysiological recordings of fEPSPs in layer II/III of V1 slices from rd10 and wt mice at P60 and P180. We investigated vertical thalamocortical connections by placing the stimulating electrode in the visual cortex layer IV, which receives most visual input from the lateral geniculate nucleus. Basal synaptic transmission, assessed by measuring the amplitude of field potentials as a function of stimulus intensity (input/output, or I/O curves), showed a significantly shallower response in rd10 mice compared to wt animals (Two-way RM ANOVA, effect of genotype p < 0.05, F(1,28) = 4.309, effect size = 0.108, interaction genotype  stimulus p < 0.001, F(40,1120) = 4.221, effect size = 0.155, post hoc HolmSidak method p < 0.05 in the 120– 190 lA range; Fig. 2a). Theta burst stimulation applied to layer IV was able to induce long-term potentiation (LTP) in layer II-III of both control wt and rd10 mice (Fig. 2b), with levels of average potentiation not significantly different between the two groups (Two-way RM ANOVA, effect of genotype p = 0.596, F (1,12) = 0.2971, effect size = 0.066). Strikingly, at P180 I/O curves recorded in slices from rd10 mice

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2017). Recently, electrophysiological recordings in transgenic rat models wt showed progressive loss of spatial rd10 80 140 and temporal responsiveness to 60 visual stimuli in V1 (Gias et al., 120 2011; Chen et al., 2016) and wave40 * 100 form alterations of cortical activity 20 have been reported in the population 80 of RP patients (Jana´ky et al., 2008; 0 60 Huang et al., 2018). These are indirect indications that cortical decay Stimulus (µA) Time (min) may occur in RP, but the competence C 100 D 180 of visual cortex for plastic changes is wt poorly explored. Since successful rd10 160 application of any eye-targeted inter80 ventions requires that cortical circuits 140 60 are able to adjust to the restored 120 40 visual input, this basic question is 100 highly relevant in therapeutic 20 80 perspective. 0 Here, we report that cortical circuits 60 of rd10 mice show physiological levels of plasticity not statistically different Time (min) Stimulus (µA) from those of wt controls, suggesting Fig. 2. Synaptic plasticity in visual cortex from rd10 mice at P60. (A) Input-output curves; the that the visual cortex of a percentage relative amplitude as a function of stimulus intensity measured in microampere (lA) well-established RP model retains a did show a significant rightward shift in rd10 visual cortex (red circles, n = 12, 20 slices) with remarkable capability of inputrespect to wt (black circles, n = 7, 10 slices; Two-way RM ANOVA, effect of genotype p < 0.05, dependent remodelling. Cortical interaction genotype  stimulus p < 0.001, post hoc Holm-Sidak method p < 0.05 in the 120– 190 lA range). Values were expressed as mean ± s.e.m. percentage change relative to their circuits of rd10 mice were fully average maximal amplitude. (B) Magnitude of LTP was calculated as the average of relative responsive to MD at P60, which amplitudes (compared to the baseline) of field potentials recorded in the last 10 min. Despite high corresponds to a very advanced variability, LTP expression was not affected in visual cortical slices from P60 rd10 mice (n = 5, 7 stage of photoreceptor degeneration slices), as it was reliably inducible by TBS stimulation (Two-way RM ANOVA, effect of HFS (Gargini et al., 2007; Barone et al., stimulation vs. baseline p < 0.05) and comparable to that recorded in wt slices (n = 5, 7 slices; Two-way RM ANOVA, effect of genotype p = 0.596). Values were expressed as mean ± s.e.m. 2012). Noticeably, this is the time point percentage change relative to their average baseline amplitude. (C) Input-output curves for at which cone degeneration is virtually individual subjects. (D) Baseline and post-TBS traces representing relative fEPSP amplitudes as a complete, and no photopic elecfunction of time in individual subjects. *p < 0.05. troretinogram (ERG) response can be recorded in this mouse model at P60 (Gargini et al., 2007; Cronin et al., and wt controls were clearly overlapping (Two-way RM 2012). Our results are in agreement with a recent work in ANOVA, effect of genotype p = 0.103, F(1,37) = 2.794, humans showing that the adult brain of RP patients retains effect size = 0.085, interaction genotype  stimulus a good level of short-term plasticity and that a stronger p = 0.941, F(41,1517) = 0.668, effect size = 0.016), visual impairment is associated with higher plasticity in and LTP could be fully elicited in the rd10 visual cortex the visual cortex (Lunghi et al., 2019). (Two-way RM ANOVA, effect of genotype p = 0.883, F Then, we focused the analysis at P180, when retinal (1,14) = 0.0339, effect size = 0.024; Fig. 3). degeneration is complete and no light-evoked input can These results indicate that, while rd10 mice display a arise at retinal level. We found that local layer IV ? transient reduction of cortical responsiveness alongside layer II-III vertical connections were still able to undergo photoreceptor degeneration, plasticity of visual circuits functional rearrangements following theta burst electrical remains in the physiological range even at very late stimulation; however, analysis of plastic responses of stages of retinal degeneration. visual cortical circuits to MD was not possible. It is plausible that the prolonged and sustained deterioration of visual inputs could unmask the processing of different DISCUSSION sensory modalities in the visual cortex (Merabet and So far, very few studies have addressed cortical plasticity Pascual-Leone, 2010). Accordingly, it is known that, as in RP. When optical imaging and electrophysiology tools RP progresses, patients rely more heavily on other senhave been used to evaluate the ability of specific rescue sory inputs, and in late-blind RP patients the visual cortex strategies in evoking visual responses in the cortex of becomes activated by tactile or auditory inputs (Voss RP mouse models, these experiments have been et al., 2008; Cunningham et al., 2015). limited to only a very general assessment of the In summary, our results provide a new perspective on possibility to restore a cortical signal (e.g., Lagali et al., RP condition and demonstrate that cortical circuits retain 2008; Thyagarajan et al., 2010; Maya-Vetencourt et al.,

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The datasets generated during the current study are available from the corresponding author on reasonable request.

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(Received 10 June 2019, Accepted 27 October 2019)