The role of the endocannabinoid system in autism spectrum disorders: Evidence from mouse studies

Abstract

Recent years have seen an impressive amount of research devoted to understanding the etiopathology of Autism Spectrum Disorder (ASD) and developing therapies to treat this complex syndrome. This work has been largely based on the employment of rodent models, based on a multitude of genetic and environmental manipulations. Unfortunately, the task of identifying suitable candidates playing a relevant etiopathological role in ASD is highly challenging, due to a number of problems specifically affecting the research in this field. These include (i) the heterogeneity of ASD itself, including several disorders, (ii) the complexity of ASD etiology, involving a plethora of genetic and environmental factors, (iii) the presence of a huge variety of rodent models, without a universal consensus on their validity. Here we highlight how the endocannabinoid system (ECS) emerges within this complex context as a valid therapeutic target and etiopathological factor in ASD. The multiple roles of the ECS in modulating neuronal functions are described, to underline the overall relevance of this system. We summarize then the most recent results showing alterations of the ECS in rodent models of ASD (with an emphasis on mouse studies), and demonstrating ASD-like behaviours in mice with altered ECS, induced either by genetic or pharmacological manipulations.We also give a critical overview of the most relevant advances in designing treatments and novel mouse models for ASD targeting the ECS, highlighting the approaches that seem more promising to simplify the complex field of research on treatments for ASD.

Communication and social interaction in the cannabinoid‐type 1 receptor null mouse: Implications for autism spectrum disorder

“…Importantly, the adult USV alterations were not confounded by differences in anxiety or sensori‐motor abilities, as assessed by the elevated plus maze and auditory startle tests. These findings add to previous evidence showing that CB1 inhibition in mice induces repetitive and inflexible behaviors (Gomes et al, 2011; Pietropaolo et al, 2020; Terzian et al, 2011; Varvel & Lichtman, 2002), that is, another core ASD‐like symptom. Hence, our results further support the potential role of the ECS in the etiopathology of ASD and therefore its relevance as a therapeutic target for autistic pathologies.…”

“…We employed intact and ovariectomized NMRI stimulus females, for the adult assessment of USVs (Experiment 1b) and social interest/investigation (Experiment 2), respectively. This allowed us to be in line with most ASD‐relevant previous studies assessing USVs in adult male and female mice, including a recent mouse study on USVs and pharmacological inhibition of CB1r (Pietropaolo et al, 2020). These USV experiments mostly employed intact stimulus females (Caruso et al, 2020), concomitantly assessing their estrous phase, as controversial findings have been reported on the impact of estrous phase on USVs (Hanson & Hurley, 2012; Kim et al, 2016; Moles et al, 2007; Nyby et al, 1979; Yang et al, 2015).…”

“…Stimulus mice used for the adult assessment of USVs (Experiment 1b) and of social interest and investigation (Experiment 2) were adult (10 weeks of age) female NMRI mice (Janvier, Le Genest‐Saint‐Isle), as this strain is commonly employed in social studies (Moles et al, 2000; Moles et al, 2007) since (a) it is characterized by high levels of sociability, (b) is an albino strain, so it facilitates the behavioral analysis during social encounters with B6 mutants, and (c) it has been used in several social tests with mouse models of ASD (Gaudissard et al, 2017; Gauducheau et al, 2017; Hébert et al, 2014; Oddi et al, 2015; Pietropaolo et al, 2014; Pietropaolo, Guilleminot, et al, 2011) and other neurodevelopmental and neurological disorders (Pietropaolo et al, 2015; Pietropaolo, Delage, et al, 2011; Pietropaolo et al, 2012), as well as in mouse social studies with CB1r antagonists (Pietropaolo et al, 2020). They were housed in groups of 3–4 per cage in the same conditions used for test subjects and left undisturbed for 2 weeks before being used in behavioral tests.…”

From an Alternative Medicine to a New Treatment for Refractory Epilepsies: Can Cannabidiol Follow the Same Path to Treat Neuropsychiatric Disorders?

“…Among the possibilities, CBD seems to be the safest and most promising alternative ( 12 , 172 , 173 ), although other phytocannabinoids like CBDV also present themselves as candidates ( 171 ). The reestablishment of the balance of the eCB system and the anti-neuroinflammatory activity seems to support these compounds' activities as a treatment to ASD [for a more detailed review, see ( 86 , 163 , 164 , 166 , 174 )].…”

Increasing Endocannabinoid Tone Alters Anxiety-Like and Stress Coping Behaviour in Female Rats Prenatally Exposed to Valproic Acid

“…Sex-specific effects of cannabinoid modulators have been reported in several conditions including anxiety and nociception [ 35 , 36 , 37 ]. Increasing clinical and preclinical evidence have implicated a key role for the ECS in the pathophysiology and treatment of symptoms associated with autism (for reviews, see [ 38 , 39 , 40 ]). Alterations in the ECS have been described in the VPA model including altered levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) [ 41 , 42 ], altered mRNA and protein expression of components of the ECS [ 15 , 21 , 41 , 42 ] and changes in cannabinoid 1 (CB) 1 receptor activation [ 12 , 15 ].…”