Altering the trajectory of early postnatal cortical development can lead to structural and behavioural features of autism

Chomiak, Taylor; Karnik, Vikram; Block, E. W.; Hu, Bin

doi:10.1186/1471-2202-11-102

Cited by 41 publications

(49 citation statements)

References 62 publications

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“…Schneider and Przewlocki, 2005;Dufour-Rainfray et al, 2010;Bambini-Junior et al, 2011;Banerjee et al, 2014), in some studies that have compared males and females, no differences between the sexes were found (e.g. Chomiak et al, 2010), whereas in others that did find a sex difference, the effects could be more pronounced in either males (e.g. Schneider et al, 2008) or females (Raza et al, 2015).…”

Section: Introductionmentioning

confidence: 78%

“…Thus, it is likely that play fighting may not only offer insight into the dynamics of social interactions but may also highlight some of the neural mechanisms that are being altered or compromised in VPA-exposed rats. Interestingly, Schneider and Przewlocki (2005) and Chomiak et al (2010) have reported attenuated social play behavior in rats prenatally exposed to VPA, indicating impaired sociality. However, although these studies indicate reduced sociality, the measures used to evaluate play fighting do not allow for the characterization of altered behavioral mechanisms (e.g.…”

Section: Introductionmentioning

confidence: 96%

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Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats

Raza

Himmler

et al. 2015

Behavioural Pharmacology

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Autism is a severe neurodevelopmental disorder characterized by qualitative impairments in social behavior, communication, and aberrant repetitive behaviors. A major focus of animal models of autism has been to mimic the social deficits of the disorder. The present study assessed whether rats exposed prenatally to valproic acid (VPA) show deficits in social play as juveniles that are consistent with the social deficits observed in autism. Dams were exposed to an acute dose of VPA on gestational day 12.5. Later, the playful interactions and associated ultrasonic vocalizations of the juveniles were examined. It was predicted that VPA-treated rats should play less than the controls. Characteristic of neurobehavioral insult at this early age, the VPA-treated juveniles showed significant increases in the frequency of body shakes and sexual mounting, but played at the same frequency as the controls. However, when playing, they were less likely to use tactics that facilitated bodily contact and vocalized less. These data suggest that prenatal VPA exposure disrupts some aspects of being able to communicate effectively and engage partners in dynamic interactions - deficits that are consistent with those observed in autism.

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Section: Introductionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 96%

Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats

Raza

Himmler

et al. 2015

Behavioural Pharmacology

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“…VPA-exposed offspring have Akt-mTOR signaling deficits consistent with human autistic brain tissue [132]. They also exhibit ASD-like behaviors including decreased social play behavior [179][180]. These data suggest that VPA-treated rodents are a suitable animal model for further studies of autism and can be used to determine the contribution of BDNF/TrkB/mTOR signaling abnormalities to the behavioral symptoms and synaptic deficits of autism.…”

Section: Maternal Challenge With Vpa As a Model Of Idiopathic Autismmentioning

confidence: 77%

Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism

Fahnestock¹

2015

Autism Open Access

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Although autism is highly genetic, "idiopathic" cases, for which there is no known genetic basis, may be due to epigenetic or environmental factors. Indeed, recent efforts have been highly successful in identifying hundreds of genes, as well as interacting epigenetic and environmental factors that contribute to autism susceptibility, corroborating the importance of gene x environment interactions in the etiology of autism. Nevertheless, a more thorough understanding of the proteins and pathways that lead from genes to behavior is desperately needed.Genetic studies have implicated molecules involved in synapse development and plasticity in autism pathogenesis. Among these are brain-derived neurotrophic factor (BDNF), its receptor, tropomyosin-related kinase B (TrkB), and their signaling pathways including mammalian target of rapamycin (mTOR), which is increased in most forms of syndromic autism. Notably, abnormalities in these molecules have also been found in idiopathic autism. Postmortem brain tissue of subjects with idiopathic autism exhibits imbalances in BDNF isoforms, reduced TrkB and downstream effectors PI3 kinase (PI3K), mTOR, Epidermal growth factor receptor pathway substrate 8 (Eps8) and the excitatory synaptic marker postsynaptic density protein 95 kDa (PSD-95). Furthermore, similar TrkB pathway deficits including reduced TrkB/mTOR signaling and PSD-95, along with autistic-like behavior, have been found in valproic acid-exposed rodents, a model of environmental/epigenetic causes of autism. Our studies in both human idiopathic autism and the valproic acid-induced rodent model suggest that decreased signaling through the mTOR pathway can be as damaging as its over-activation. AutismAutism is a lifelong neurodevelopmental disorder characterized by disturbances in social interactions and communication and stereotyped, repetitive patterns of interests, activities and behaviors [1,2]. It is one of a heterogeneous group of disorders called Autism Spectrum Disorders (ASD) that share these characteristics but differ in course, symptom pattern or level of functioning. ASD is perhaps the most common and handicapping neurological disorder of childhood in terms of prevalence, morbidity, outcome and cost to society. ASD represents a significant public health problem and poses a huge burden for education and social service systems. Recent estimates of the prevalence of ASD in the US and Canada (CDC, NEDSAC) were 1 in 68 [3,4]. There is currently no diagnostic test or cure available for autism, and its etiology is unknown.Epidemiological and twin studies point to a major role for genetic factors in ASD [5,6], with a complex pattern of transmission thought to be the result of perhaps as many as 1000 interacting genes [7-9]. Hundreds of rare genetic events that carry increased risk for ASD, many of them arising de novo [10][11][12][13][14], have been identified [15][16][17][18][19][20][21].However, genetic changes account for only half of all autistic cases; environmental influences are responsible for the rema...

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“…The dosing volume was 500 mg/kg and the dosage was adjusted according to the body weight of the dam on the day of injection. Treated dams (n = 6) received a single intraperitoneal injection of 500 mg/kg VPA sodium salt and control dams (n = 6) received a single intraperitoneal injection of saline on embryonic day 12.5 [35,36]. The rats were born and reared in a quiet, temperature-controlled room and entrained to a 12-hour light-dark cycle.…”

Section: Methodsmentioning

confidence: 99%

“…The animals were socially isolated in standard shoe-box cages (43 × 15 × 28 cm) for 24 h prior to testing as previously described [10,36]. The play behavior test consisted of placing 2 rats that were previously cage mates (both of which were matched for treatment and diet) into a Plexiglas® box (43.2 × 43.2 × 30.5 cm) for a period of 10 min.…”

Section: Methodsmentioning

confidence: 99%

The Ketogenic Diet Modifies Social and Metabolic Alterations Identified in the Prenatal Valproic Acid Model of Autism Spectrum Disorder

et al. 2014

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Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by abnormal social interactions, communication deficits and stereotyped or repetitive behaviors. Although the etiology of ASD remains elusive, converging lines of research indicate that mitochondrial dysfunction may play a substantive role in disease pathophysiology. Without an established causal link, the generation of therapeutic targets for ASD has been relatively unsuccessful and has focused solely on individual symptoms. The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has previously been used for the treatment of intractable epilepsy and is known to enhance mitochondrial function. The purpose of this study was to determine if the KD could reverse the social deficits and mitochondrial dysfunction identified in the prenatal valproic acid (VPA) rodent model of ASD. Sprague-Dawley dams were administered VPA or saline on gestational day 12.5. The pups were treated with the KD or their standard diet (SD) for 10 days beginning on postnatal day 21 (PD21). On PD35 juvenile play behavior was tested with the play-fighting paradigm and rats were then sacrificed for mitochondrial bioenergetic analysis. The offspring exposed to VPA prenatally demonstrated a significant decrease in the number of play initiations/attacks and this was reversed with the KD. Prenatal VPA exposure also disrupted the pattern of play responses; VPA/SD animals used complete rotations more often than saline control animals. Treatment with the KD did not affect the number of complete rotations. In addition, while prenatal exposure to VPA altered mitochondrial respiration, the KD was able to restore aspects of bioenergetic dysfunction. As the KD was able to modify complex social behaviors and mitochondrial respiration, it may be a useful treatment option for ASD. Future studies will need to examine the effectiveness of the KD to reverse the two additional core deficits of ASD and to explore various treatment regimens to determine optimal treatment duration and formulation.

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Altering the trajectory of early postnatal cortical development can lead to structural and behavioural features of autism

Cited by 41 publications

References 62 publications

Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats

Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats

Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism

The Ketogenic Diet Modifies Social and Metabolic Alterations Identified in the Prenatal Valproic Acid Model of Autism Spectrum Disorder

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