Melatonin rescues visual-behavioral deficits in rd10 mouse model of retinal degeneration

Abstract

Background/Objective: Retinal degeneration 10 (rd10) is a mouse model of retinitis pigmentosa with rapid retinal photoreceptors degeneration peaking around postnatal day 28. Accumulating evidence indicate that degeneration of retina not only leads to visual impairment or blindness but also develops neuropsychiatry symptoms and neurocognitive impairment by affecting the function of the limbic system mainly hippocampus through ventral visual pathway. Although a recent study has indicated that melatonin treatment diminishes the photoreceptors death in rd10 mice, the mechanisms by which melatonin induced neuroprotection and the functional outcome of melatonin treatment in this rd10 model remained largely obscure. Methodology: 1-month old male rd10 mice treated with melatonin (10 mg/kg, 4 weeks, i.p.) were tested electrophysiologically and behaviorally to evaluate the visual and behavioral functions. Morphological and biochemical studies were conducted to further evaluate the neuroprotective effects of melatonin treatment. Results and Discussion: Our results demonstrated that melatonin treatment improved both a- and bwaves in electroretinography and restored visual-evoked potentials recorded from primary visual cortical neurons, indicating the retention of functional interaction and integrity between the retina and visual-cortex. Furthermore, melatonin treatment rescued the rd10 behavioral deficits of anxiety, social and visual memory function as measured by the novelty-suppressed feeding test, social novelty, and visual memory tests. Interestingly, experiments with temozolomide treatment demonstrated that melatonin mediated improvement of rd10 behavioral deficits was through both neurogenesis-dependent and -independent mechanisms. These findings were further supported by an increase of NeuN, BrdU, DCX cells in the hippocampus, and biochemical studies on the neurogenesis as well as synaptogenesis related markers in visual cortical and hippocampal regions. Conclusion: Our findings suggest that melatonin could be a potential therapeutic drug in rescuing visual and behavioural deficits through neurogenesis-dependent and -independent mechanisms in retinal degeneration.