Rai1 frees mice from the repression of active wake behaviors by light

Abstract

Besides its role in vision, light impacts physiology and behavior through circadian and direct (aka ‘masking’) mechanisms. In Smith-Magenis syndrome (SMS), the dysregulation of both sleep-wake behavior and melatonin production strongly suggests impaired non-visual light perception. We discovered that mice haploinsufficient for the SMS causal gene, Retinoic acid induced-1 (Rai1), were hypersensitive to light such that light eliminated alert and active-wake behaviors, while leaving time-spent-awake unaffected. Moreover, variables pertaining to circadian rhythm entrainment were activated more strongly by light. At the input level, the activation of rod/cone and suprachiasmatic nuclei (SCN) by light was paradoxically greatly reduced, while the downstream activation of the ventral-subparaventricular zone (vSPVZ) was increased. The vSPVZ integrates retinal and SCN input and, when activated, suppresses locomotor activity, consistent with the behavioral hypersensitivity to light we observed. Our results implicate Rai1 as a novel and central player in processing non-visual light information, from input to behavioral output.DOI: http://dx.doi.org/10.7554/eLife.23292.001

A point mutation in the ion conduction pore of AMPA receptor GRIA3 causes dramatically perturbed sleep patterns as well as intellectual disability

“…The effects of light on period length but not activity suppression suggest that the effects of light may be upon the retina or SCN, rather than at the level of the subparaventricular zone (SPVz), which has been implicated in mediating masking responses ( 50 ). This is in contrast to recent studies on a mouse model of Smith-Magenis Syndrome, in which retinal and SCN responses were attenuated, but SPVz responses were enhanced ( 51 ).…”

Clock-dependent chromatin topology modulates circadian transcription and behavior

“…Estimation of the circadian period was performed as in Diessler et al (2017). Briefly, 8-to 10-wk-old males were single-caged and kept under 12 h/12 h light/dark cycle for 14 d and switched to constant darkness for 21 d. During the 5 wk of the experiment, the locomotor activity was recorded with passive infrared sensors.…”

Melanopsin System Dysfunction in Smith-Magenis Syndrome Patients

“…27 Reduced scotopic ERG responses, with no anatomic or molecular retinal alteration, were found in the RAI1 þ/À , the mouse model of SMS, indicating a possible photoreceptoral cause of light entrainment dysfunction. 34 Considering that rods also send sustained signals to the ipRGCs, which contribute to the PLR, and that rod responses become increasingly prolonged as the stimulus intensity increases, 38 a deficit in rod function is also possible.…”

“…This assumption finds support in several demonstrations of the association between sleep disturbances and alteration in ipRGC activity assessed through the PLR [27][28][29][30][31] and in the demonstration that the lack of one RAI1 allele (the primary gene responsible for most features of SMS, including the inverted circadian rhythm of melatonin 32,33 ) affects the nonvisual light-signaling dependent behavior. 34 In order to evaluate the functionality of this retinal system, we tested SMS patients using the PLR protocol, 26 particularly its sustained component that is controlled by the ipRGC/ melanopsin system. 24,25…”