Melatonin treatment of repetitive behavioral deficits in the Cntnap2 mouse model of autism spectrum disorder

Wang, Huei-Bin; Tahara, Yu; Luk, Shu Hon Christopher; Kim, Yoon Sik; Hitchcock, Olivia N.; Kaswan, Zoe A. MacDowell; Kim, Yang In; Block, Gene D.; Ghiani, Cristina A.; Loh, Dawn H.

doi:10.1016/j.nbd.2020.105064

Cited by 22 publications

(29 citation statements)

References 79 publications

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“…2C, Table 2 ). We had previously shown that DLaN reduces social behavior in C57 mice (Wang et al, 2020), hence, the effect of the short λ illumination was examined on this behavior in the Opn4 DTA . In WT mice, the DLaN greatly reduced social interactions (57.4 ± 10%), while the mutant mice were resistant to this negative effect of night-time illumination (8.9 ± 8.2%, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It has been speculated that this exposure to DLaN via screens and other lighting sources could be detrimental to ASD populations. In support of this speculation, we previously reported that an animal model with a genetic risk factor associated with ASD (contactin associated protein-like 2, Cntnap2 ) shows reduced social preference and increased stereotypic grooming behavior after a 2-week exposure to DLaN (Wang et al, 2020).…”

Section: Introductionmentioning

confidence: 82%

“…After the habituation to the testing room for at least 30 mins, the testing mice were introduced to the testing arena and their behavior was recorded by a camcorder for 30 mins. The duration of grooming behavior was scored as previously described (Wang et al, 2020).…”

Section: Methodsmentioning

confidence: 99%

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Long wavelength light reduces the negative consequences of dim light at night in the Cntnap2 mouse model of autism

Wang

Luk

et al. 2022

Preprint

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Many patients with autism spectrum disorders (ASD) show disturbances in their sleep/wake cycles, and may be particularly vulnerable to the impact of circadian disruptors. We have previously shown that exposure to dim light at night (DLaN) in contactin associated protein-like 2 knock out (Cntnap2 KO) mice disrupts diurnal rhythms, increases repetitive behaviors while reducing social interactions. These negative effects of DLaN may be mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin, which is maximally sensitive to blue light (480nm). In this study, we used a light-emitting diode (LED) array that enabled us to shift the spectral properties of the DLaN while keeping the intensity at 10 lx. First, using wild-type (WT) mice, we confirmed that the short-wavelength enriched lighting produced a strong acute suppression of locomotor activity (masking), a robust light-induced phase shifts and c-Fos expression in the suprachiasmatic nucleus, while the long-wavelength enriched lighting evoked much weaker responses. Furthermore, exposure of WT mice to the short-wavelength light at night reduced the amplitude of locomotor activity rhythms and impaired social interactions. Mice lacking the melanopsin expressing ipRGCs (Opn4DTA mice) were resistant to these negative effects of DLaN. Importantly, the shift of the DLaN stimulus to longer wavelengths ameliorated the negative impact on the activity rhythms and autistic behaviors (i.e. reciprocal social interactions, repetitive grooming) of the Cntnap2 KO model. The short-, but not the long-wavelength enriched, DLaN triggered cFos expression in the peri-habenula region as well as in the basolateral amygdala (BLA). Finally, DLaN-driven c-Fos induction in BLA glutamatergic neurons was about 3-fold higher in the Cntnap2 KO mice, suggesting that these cells may be particularly vulnerable to the effects of photic disruption. Broadly, our findings suggest that the spectral properties of light at night should be considered in the management of ASD and other neurodevelopmental disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 82%

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Long wavelength light reduces the negative consequences of dim light at night in the Cntnap2 mouse model of autism

Wang

Luk

et al. 2022

Preprint

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“…Since a large proportion of people with neurodevelopmental disorders such as ASD are disturbed in their daily sleep/wake cycles ( Robinson-Shelton and Malow, 2016 ). In response to this phenomenon, researchers tried melatonin treatment in CNTNAP2 KO mice and found that it improved excessive grooming in mice ( Wang et al, 2020 ). Furthermore, MTHFR polymorphism was associated with an increased risk of ASD, and the offspring of Mthfr + / − mice ( Pu et al, 2013 ), whether wild-type or heterozygous, exhibited autism-like behaviors.…”

Section: Treatment and Intervention Of Repetitive Restricted Behaviorsmentioning

confidence: 99%

Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics

2022

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication, social interaction, and repetitive restricted behaviors (RRBs). It is usually detected in early childhood. RRBs are behavioral patterns characterized by repetition, inflexibility, invariance, inappropriateness, and frequent lack of obvious function or specific purpose. To date, the classification of RRBs is contentious. Understanding the potential mechanisms of RRBs in children with ASD, such as neural connectivity disorders and abnormal immune functions, will contribute to finding new therapeutic targets. Although behavioral intervention remains the most effective and safe strategy for RRBs treatment, some promising drugs and new treatment options (e.g., supplementary and cell therapy) have shown positive effects on RRBs in recent studies. In this review, we summarize the latest advances of RRBs from mechanistic to therapeutic approaches and propose potential future directions in research on RRBs.

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“…Recent findings demonstrate mental health has deteriorated as a result of the pandemic, evident through increased anxiety and depression and greater stress levels (8,9). Also, it has been suggested that susceptibility to viral infections may be more prevalent in autistic adults due to health vulnerabilities such as co-occurring complex physical and mental conditions and melatonin deficiencies (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

The Impact of COVID-19 on Sleep in Autistic Adults: Longitudinal Comparisons pre and During Lockdown

2021

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Background: The longer-term impact of the pandemic on autistic adults' sleep are yet to be revealed, with studies concentrating on sleep in autistic children or mental health outcomes and coping strategies of autistic adults. Given the prevalence of sleep problems experienced by autistic adults and the changes in routine that have occurred as a result of COVID-19 societal restrictions, this study assessed the impact of the COVID-19 pandemic on sleep problems via a longitudinal subjective assessment method.Methods: Sleep data were gathered at three time points from 95 autistic adults, namely prior to the pandemic, at the start of COVID-19 and several months into COVID-19 to obtain a rich longitudinal dataset ascertaining how/if sleep patterns have changed in autistic adults over these several months.Results: In comparison to pre-lockdown, several sleep components were shown to improve during the lockdown. These improvements included reduced sleep latency (time taken to fall asleep), longer sleep duration, improved sleep efficiency, improved sleep quality, as well as improved daytime functioning. Pre-sleep cognitive arousal scores were found to decrease compared to pre-lockdown, meaning cognitive arousal improved. Approximately 65% of participants reported that they felt their sleep had been impacted since COVID-19 since Time 1, with the most common reasons reported as waking up exhausted (36.92%), not being able to get to sleep (33.85%), waking up in the night (29.23%), having a disrupted sleep pattern (27.69%), and nightmares (18.46%).Conclusions: Improvements in sleep may be related to societal changes (e.g., working from home) during the pandemic. Some of these changes are arguably beneficial for autistic adults in creating a more autism-inclusive society, for example telehealth opportunities for care. Further exploration of the associations between mental health and sleep are warranted.

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Melatonin treatment of repetitive behavioral deficits in the Cntnap2 mouse model of autism spectrum disorder

Cited by 22 publications

References 79 publications

Long wavelength light reduces the negative consequences of dim light at night in the Cntnap2 mouse model of autism

Long wavelength light reduces the negative consequences of dim light at night in the Cntnap2 mouse model of autism

Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics

The Impact of COVID-19 on Sleep in Autistic Adults: Longitudinal Comparisons pre and During Lockdown

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