The relationship between the neuromodulator adenosine and behavioral symptoms of autism

doi:10.1016/j.neulet.2011.06.007

Neuroscience Letters

Volume 500, Issue 1, 1 August 2011, Pages 1-5

https://doi.org/10.1016/j.neulet.2011.06.007 Get rights and content

Abstract

The neuromodulator adenosine is an endogenous sleep promoter, neuroprotector and anticonvulsant, and people with autism often suffer from sleep disruption and/or seizures. We hypothesized that increasing adenosine can decrease behavioral symptoms of autism spectrum disorders, and, based on published research, specific physiological stimuli are expected to increase brain adenosine. To test the relationship between adenosine and autism, we developed a customized parent-based questionnaire to assess child participation in activities expected to influence adenosine and quantify behavioral changes following these experiences. Parents were naive to study hypotheses and all conditions were pre-assigned. Results demonstrate significantly better behavior associated with events pre-established as predicted to increase rather than decrease or have no influence on adenosine. Understanding the physiological relationship between adenosine and autism could open new therapeutic strategies – potentially preventing seizures, improving sleep, and reducing social and behavioral dysfunction.

Highlights

► Stimuli predicted to increase adenosine reduce symptoms of autism. ► Reduced symptoms of autism were found regardless of gender or age. ► Understanding the interplay between adenosine and autism can yield new therapies.

Section snippets

Acknowledgements

Supported by Interactive Autism Network (IAN), National Institutes of Health (NS066392, NS065957) and Trinity College.

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Inhibition of purinergic P2 receptors prevents synaptic and behavioral alterations in a rodent model of autism spectrum disorders.
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Extracellular nucleotides acting through specific purinergic receptors play a key role in synaptic transmission and neuromodulation. Therefore, any deregulation of purine-dependent signaling may lead to synaptic dysfunction and the development of autism-like behaviors.
Here, we used a well-established autism spectrum disorders (ASD) model of a single prenatal exposure to valproic acid (VPA). Wistar female rats received an i.p. injection of VPA (450 mg/kg body weight) at gestational day 12.5. To study the involvement of purinergic signaling in the alterations of the key synaptic proteins and the development of ASD-like behaviors in VPA offspring at 52. post-natal day, we performed a single i.p. injection of the non-selective P2-purinoceptor antagonists PPADS and isoPPADS (12.5 mg/kg body weight) 24 h before behavioral tests.
The results showed an increased level of ATP and its metabolites, ADP, and AMP in the cerebrospinal fluid of VPA offspring indicating significant dysregulation in extracellular nucleotides- signaling, that may result in synaptic aberrations. Treatment with isoPPADS significantly prevented alterations of the selected synaptic proteins evoked by prenatal VPA exposure along with prevention of the overactivation of mTOR kinase, while both purinergic antagonists reversed autism-like behavior. This suggests that apart from the activation of the mTOR signaling cascade, purinergic deregulation may influence molecular pathways other than synaptic protein imbalance.
Disturbances in the ATP turnover and overstimulation of purinergic receptors are responsible for synaptic proteins' dyshomeostasis and the appearance of ASD-like behaviors. mTOR kinase might be partially responsible for the development of autistic symptoms evoked by hyperpurinergia.
Cognitive profile of male mice exposed to a Ketogenic Diet
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Citation Excerpt :
A plausible explanation for the result obtained in our study is that, in every previous study, anxiety was evaluated 3 months after being on the KD and 8 weeks after supplementation, while we measured anxiety only 7 days after the beginning of KD administration. Adenosine receptors in GABAergic neurons play an essential role in anxiety regulation [49,50] and KD induces modifications in the adenosinergic systems [51], which could explain these initial alterations. The increase in anxiety observed in our study could be due to the short time of habituation to this type of diet.
In recent years, nutritional interventions for different psychiatric diseases have gained increasing attention, such as the ketogenic diet (KD). This has led to positive effects in neurological disorders such as Parkinson's disease, addiction, autism or epilepsy. The neurobiological mechanisms through which these effects are induced and the effects in cognition still warrant investigation, and considering that other high-fat diets (HFD) can lead to cognitive disturbances that may affect the results achieved, the main aim of the present work was to evaluate the effects of a KD to determine whether it can induce such cognitive effects. A total of 30 OF1 male mice were employed to establish the behavioral profile of mice fed a KD by testing anxiety behavior (Elevated Plus Maze), locomotor activity (Open Field), learning (Hebb Williams Maze), and memory (Passive Avoidance Test). The results revealed that the KD did not affect locomotor activity, memory or hippocampal-dependent learning, as similar results were obtained with mice on a standard diet, albeit with increased anxiety behavior. We conclude that a KD is a promising nutritional approach to apply in research studies, given that it does not cause cognitive alterations.
Developmental role of adenosine kinase for the expression of sex-dependent neuropsychiatric behavior
2018, Neuropharmacology
Citation Excerpt :
The purine ribonucleoside adenosine is a key regulator of network function in the brain, which modulates neuronal excitability and plasticity. It is also a regulator of neuropsychiatric behavior and plays an emerging role in conditions such as schizophrenia (Boison et al., 2012; Shen et al., 2012) and autism spectrum disorder (Masino et al., 2011, 2013). Adenosine can bind to one of four G-protein coupled receptor subtypes (A1, A2A, A2B, or A3) which balance inhibitory and stimulatory functions of adenosine in the adult brain (Fredholm, 2010; Fredholm et al., 2011); its role in the developing brain, however, has been under-investigated.
Deficits in social memory, cognition, and aberrant responses to stimulants are common among persons affected by schizophrenia and other conditions with a presumed developmental etiology. We previously found that expression changes in the adenosine metabolizing enzyme adenosine kinase (ADK) in the adult brain are associated with deficits in various cognitive domains. To distinguish between developmental and adult functions of ADK, we used two transgenic mouse lines with widespread disruption of ADK expression in the adult brain, but differences in the onset of ADK deletion. Specifically, we compared Nestin-Cre^+/-:ADK-flox^fl/fl (ADK^ΔBrain) mice with global loss of ADK in the whole brain, beginning in mid-gestation and persisting for life, with Gfa2-Cre^+/-:ADK-flox^fl/fl (ADK^ΔAstro) mice that have normal ADK expression throughout development, but lose astrocyte-specific ADK-expression in young adulthood. Because ADK-expression in adulthood is generally confined to astrocytes, adult ADK^ΔAstro mice show a similar expression profile of ADK in key areas of the brain related to neuropsychiatric behavior, compared to adult ADK^ΔBrain mice. We sought to determine a neurodevelopmental role of ADK on the expression of psychiatric behaviors in adult male and female mice. Adult ADK^ΔBrain mice showed significant deficits in social memory in males, significant contextual learning impairments in both sexes, and a hyper-responsiveness to amphetamine in males. In contrast, ADK^ΔAstro mice showed normal social memory and contextual learning but hypo-responsiveness to amphetamine in males. Our results demonstrate a key developmental role of ADK in mediating behaviors in adulthood related to neuropsychiatric disease and support the greater prevalence of these disorders among males.
Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse
2017, Physiology and Behavior
Citation Excerpt :
Indeed, caloric restriction alone has seizure-reducing effects in EL mice [64,65]. In parallel, evidence is building that limiting glucose is anticonvulsant through an adenosine-based mechanism [54,56,66] and we hypothesized that ASD core symptoms could be alleviated by this same mechanism [67]. Here, for ASD-like symptoms, there appears to be a dissociation among caloric restriction, KD, and blood glucose.
The core symptoms of autism spectrum disorder are poorly treated with current medications. Symptoms of autism spectrum disorder are frequently comorbid with a diagnosis of epilepsy and vice versa. Medically-supervised ketogenic diets are remarkably effective nonpharmacological treatments for epilepsy, even in drug-refractory cases. There is accumulating evidence that supports the efficacy of ketogenic diets in treating the core symptoms of autism spectrum disorders in animal models as well as limited reports of benefits in patients. This study tests the behavioral effects of ketogenic diet feeding in the EL mouse, a model with behavioral characteristics of autism spectrum disorder and comorbid epilepsy. Male and female EL mice were fed control diet or one of two ketogenic diet formulas ad libitum starting at 5 weeks of age. Beginning at 8 weeks of age, diet protocols continued and performance of each group on tests of sociability and repetitive behavior was assessed. A ketogenic diet improved behavioral characteristics of autism spectrum disorder in a sex- and test-specific manner; ketogenic diet never worsened relevant behaviors. Ketogenic diet feeding improved multiple measures of sociability and reduced repetitive behavior in female mice, with limited effects in males. Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior. Taken together these results add to the growing number of studies suggesting that ketogenic and related diets may provide significant relief from the core symptoms of autism spectrum disorder, and suggest that in some cases there may be increased efficacy in females.
Adenosine receptors and epilepsy. Current evidence and future potential
2014, International Review of Neurobiology
Citation Excerpt :
The potential of a KD (perhaps through adenosine-based mechanisms) is that it can improve not only epilepsy as well as various types of neurological disorders (Masino, Kawamura, Wasser, Pomeroy, & Ruskin, 2009), including autism which is often comorbidity with epilepsy (Evangeliou et al., 2003; Ruskin et al., 2013). Furthermore adenosine is reported to improve autism spectrum disorders (Masino, Kawamura, Cote, Williams, & Ruskin, 2013; Masino, Kawamura, et al., 2011, Masino, Li, et al., 2011). Also, local adenosine augmentation therapies ameliorate the cognitive symptoms and psychomotor-related symptoms in schizophrenia (Shen et al., 2012).
Adenosine receptors are a powerful therapeutic target for regulating epileptic seizures. As a homeostatic bioenergetic network regulator, adenosine is perfectly suited to establish or restore an ongoing balance between excitation and inhibition, and its anticonvulsant efficacy is well established. There is evidence for the involvement of multiple adenosine receptor subtypes in epilepsy, but in particular the adenosine A₁ receptor subtype can powerfully and bidirectionally regulate seizure activity. Mechanisms that regulate adenosine itself are increasingly appreciated as targets to thus influence receptor activity and seizure propensity. Taken together, established evidence for the powerful potential of adenosine-based epilepsy therapies and new strategies to influence receptor activity can combine to capitalize on this endogenous homeostatic neuromodulator.
Adenosine and autism: A spectrum of opportunities
2013, Neuropharmacology
Citation Excerpt :
For instance, adenosine, through A2 receptors (and possibly by coactivation of A1 and A2 receptors), reduces perseverative behaviors in rodents (Poleszak and Manuta, 2000; Tanimura et al., 2010) and could aid with this core symptom in ASD. In a parental survey-based study, conditions and events known to or hypothesized to increase adenosine (e.g. fever, high-intensity physical activity, very low carbohydrate diet) significantly improved autistic behaviors, particularly in Asperger's and verbally-fluent individuals (Masino et al., 2011a). Because caffeine is known to modulate the influence of adenosine, and because it is so widely used, it is important to consider the interactions and implications of caffeine use in individuals with ASD.
In rodents, insufficient adenosine produces behavioral and physiological symptoms consistent with several comorbidities of autism. In rodents and humans, stimuli postulated to increase adenosine can ameliorate these comorbidities. Because adenosine is a broad homeostatic regulator of cell function and nervous system activity, increasing adenosine's influence might be a new therapeutic target for autism with multiple beneficial effects.
This article is part of the Special Issue entitled ‘Neurodevelopmental Disorders’.

View all citing articles on Scopus

¹: Present address: Department of Pharmacology, Jikei University, Tokyo, Japan.

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Plenary articleThe relationship between the neuromodulator adenosine and behavioral symptoms of autism

Abstract

Highlights

Section snippets

Acknowledgements

Trends Pharmacol. Sci.

Med. Hypotheses

Epilepsy Behav.

Neuron

Neuroscience

Int. J. Dev. Neurosci.

Neurotoxicology

Epilepsy Behav.

J. Pediatr.

Brain Res.

Behav. Brain Res.

Epilepsy Res.

Compendium of physical activities: an update of activity codes and MET intensities

Med. Sci. Sports Exerc.

Focally injected adenosine prevents seizures in the rat

Exp. Neurol.

Behaviors associated with fever in children with autism spectrum disorders

Pediatrics

Intracellular acidification causes adenosine release during states of hyperexcitability in the hippocampus

J. Neurophysiol.

The role and regulation of adenosine in the central nervous system

Annu. Rev. Neurosci.

Sedative and anticonvulsant effects of adenosine analogs in mouse and rat

J. Pharmacol. Exp. Ther.

Behavioral and physiological effects of deep pressure on children with autism: a pilot study evaluating the efficacy of Grandin's Hug Machine

Am. J. Occup. Ther.

Brief report: improvements in the behavior of children with autism following massage therapy

J. Autism Dev. Disord.

Application of a ketogenic diet in children with autistic behavior: pilot study

J. Child Neurol.

Expression of GABAB receptors is altered in brains of subjects with autism

Cerebellum

GABAA receptor downregulation in brains of subjects with autism

J. Autism Dev. Disord.

P2 receptors and neuronal injury

Pflugers Arch. Eur. J. Physiol.

Plenary article
The relationship between the neuromodulator adenosine and behavioral symptoms of autism

Expression of GABA_B receptors is altered in brains of subjects with autism

GABA_A receptor downregulation in brains of subjects with autism