Rat Model Of Autism Spectrum Disorder Research Articles

Changes in brain metabolic connectivity underlie autistic-like social deficits in a rat model of autism spectrum disorder

The neurobiological basis of social dysfunction and the high male prevalence in autism spectrum disorder (ASD) remain poorly understood. Although network alterations presumably underlie the development of autistic-like behaviors, a clear pattern of connectivity differences specific to ASD has not yet emerged. Because the heterogeneous nature of ASD hinders investigations in human subjects, we explored brain connectivity in an etiologically homogenous rat model of ASD induced by exposure to valproic acid (VPA) in utero. We performed partial correlation analysis of cross-sectional resting-state 18F-fluorodeoxyglucose positron emission tomography scans from VPA-exposed and control rats to estimate metabolic connectivity and conducted canonical correlation analysis of metabolic activity and behavior scores. VPA-treated rats exhibited impairments in social behaviors, and this difference was more pronounced in male than female rats. Similarly, current analyses revealed sex-specific changes in network connectivity and identified distinct alterations in the distributed metabolic activity patterns associated with autistic-like social deficits. Specifically, diminished activity in the salience network and enhanced activity in a cortico-cerebellar circuit correlated with the severity of social behavioral deficits. Such metabolic connectivity features may represent neurobiological substrates of autistic-like behavior, particularly in males, and may serve as a pathognomonic sign in the VPA rat model of ASD.

Motivational wheel running reverses cueing behavioural inflexibility in rodents.

Behavioural inflexibility and associated atypical learning behaviours are common clinical manifestations of the autism spectrum disorder (ASD) phenotype. Despite advances in our understanding of ASD, little research has been devoted to experimental interventions that might help to circumvent behavioural inflexibility in ASD. The current paper suggests that motivational locomotion in the form of wheel running can reduce behavioural inflexibility and learning impairments in an ASD rat model, and discusses how the strategy of reward-coupled locomotor activity may lead to clinical interventions for children with ASD.

Reduced protein expressions of cytomembrane GABAARβ3 at different postnatal developmental stages of rats exposed prenatally to valproic acid

Decreased inhibition plays an extremely important role in pathogenesis of autism spectrum disorder (ASD). Therefore, we aimed to determine whether expression levels of the γ-aminobutyric acid type A receptor β3 subunit (GABAARβ3), K+-Cl− cotransporter 2 (KCC2), and Na+-K+-Cl− cotransporter 1 (NKCC1) related to inhibition transmission are changed in a sodium valproate-induced rat model of ASD. Decreased expression levels of membrane GABAARβ3 (m-GABAARβ3) and KCC2 as well as increased endocytosis of GABAARs were found in the model group. However, there were no significant differences in expression of total GABAARβ3 and NKCC1 between the control and model groups. In addition, we observed growth retardation, impaired spatial memory, limited exploration, increased anxiety, and reduced sociability in the model group. These results suggest alterations in m-GABAARβ3 levels, KCC2 levels, and trafficking of GABAARs in rats prenatally exposed to valproic acid and advance our understanding of the pathogenesis of ASD.

Cerebrolysin prevents deficits in social behavior, repetitive conduct, and synaptic inhibition in a rat model of autism.

Autism spectrum disorder (ASD) is a syndrome of diverse neuropsychiatric diseases of growing incidence characterized by repetitive conduct and impaired social behavior and communication for which effective pharmacological treatment is still unavailable. While the mechanisms and etiology of ASD are still unknown, a consensus is emerging about the synaptic nature of the syndrome, suggesting a possible avenue for pharmacological treatment with synaptogenic compounds. The peptidic mixture cerebrolysin (CBL) has been successfully used during the last three decades in the treatment of stroke and neurodegenerative disease. Animal experiments indicate that at least one possible mechanism of action of CBL is through neuroprotection and/or synaptogenesis. In the present study, we tested the effect of CBL treatment (daily injection of 2.5 mL/Kg i.p. during 15 days) on a rat model of ASD. This was based on the offspring (43 male and 51 female pups) of a pregnant female rat injected with valproic acid (VPA, 600 mg/Kg) at the embryonic day 12.5, which previous work has shown to display extensive behavioral, as well as synaptic impairment. Comparison between saline vs. CBL-injected VPA animals shows that CBL treatment improves behavioral as well as synaptic impairments, measured by behavioral performance (social interaction, Y-maze, plus-maze), maximal response of inhibitory γ-amino butyric acid type A receptor (GABAA R)-mediated synaptic currents, as well as their kinetic properties and adrenergic and muscarinic modulation. We speculate that CBL might be a viable and effective candidate for pharmacological treatment or co-treatment of ASD patients. © 2017 Wiley Periodicals, Inc.

Rapamycin modulated brain-derived neurotrophic factor and B-cell lymphoma 2 to mitigate autism spectrum disorder in rats.

The number of children suffered from autism spectrum disorder (ASD) is increasing dramatically. However, the etiology of ASD is not well known. This study employed mammalian target of rapamycin inhibitor rapamycin to explore its effect on ASD and provided new therapeutic strategies for ASD. ASD rat model was constructed and valproic acid (VPA) was injected intraperitoneally into rats on pregnancy day 12.5. Offspring from VPA group were divided into ASD group and ASD + rapamycin (ASD + RAPA) group. Compared with normal group, the frequency and duration of social behavior and straight times of ASD group were shortened, but the grooming times were extended. Meanwhile, in ASD group, the average escape latency and the frequency of crossing plates were decreased, the apoptotic index (AI) detected by TUNEL assay was increased, and the expression of brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) analyzed was decreased with great difference compared with normal group (P<0.01). However, rapamycin treatment in ASD rats mitigated the ASD-like social behavior, such as the frequencies of straight and grooming. Furthermore, rapamycin shortened the average escape latency, but increased the frequency of crossing plates of ASD rats. In hippocampus, rapamycin decreased the AI, but increased the levels of BDNF and Bcl-2 (P<0.01) of ASD rats. These findings revealed that rapamycin significantly mitigated the social behavior by enhancing the expression of BDNF and Bcl-2 to suppress the hippocampus apoptosis in VPA-induced ASD rats.

Differential Effects of Valproic Acid on Immobility Responses and Locomotor Activity in Female and Male Rats

Valproic acid (VPA) is used in the treatment of epilepsy and behavioral disorders. However, the exposure to VPA during pregnancy increases the risk of having offspring with autism spectrum disorder (ASD). Reports indicate that men are more likely to suffer ASD than women who were exposed to VPA prenatally. Few studies have related the sex differences and behavioral changes in the ASD rat model. Our aim was to determinate whether male and female Wistar rats whose mothers were exposed to either VPA (600 mg/kg; animal model for ASD) or saline (0.9%) i.p. at 12.5 day of gestation, have different effects on immobility induce by clamping (IC), dorsal immobility (DI), catalepsy, locomotor activity, stereotypes, and analgesia (tail flick). For this purpose, we made four groups (n = 8). Group: A) saline male rats, B) saline female rats, C) VPA male rats and D) VPA female rats. At 35 (prepubertal age), 56 (postpubertal age) and 180 days, we tested the behaviors previously mentioned. Finding that VPA has the same effect on IC, catalepsy, and analgesia in male and female rats, the time of these tests was increased. However, VPA only has an effect on DI in males but not in female rats. On the contrary, there is hyperactivity and an increase of stereotypes in female but not in male rats. Thereby, VPA has an effect on the three immobility responses tested (IC, DI and catalepsy), locomotor activity and analgesia but in a differential way on DI, stereotypes and locomotor activity between male and female rats.

Congenital malformation and autism spectrum disorder: Insight from a rat model of autism spectrum disorder.

AIMS AND OBJECTIVES:The primary aim was an evaluation of the pattern of gross congenital malformations in a rat model of autism spectrum disorder (ASD) and the secondary aim was characterization of the most common gross malformation observed.MATERIALS AND METHODS:In females, the late pro-oestrous phase was identified by vaginal smear cytology, and then, they were allowed to mate at 1:3 ratio (male: female). Pregnancy was confirmed by the presence of sperm plug in the vagina and presence of sperm in the vaginal smear. In the ASD group, ASD was induced by injecting valproic acid 600 mg/kg (i.p.) to pregnant female rats (n = 18) on day 12.5 (single injection). Only vehicle (normal saline) was given in the control group (n = 12). After delivery, pups were grossly observed for congenital malformations until the time of sacrifice (3 months) and different types of malformations and their frequency were noted and characterized.RESULTS:In the ASD group, congenital malformation was present in 69.9% of the pups, whereas in the control group, it was 0%. Male pups were most commonly affected (90% in males vs. only 39.72% in female pups). The tail deformity was the most common malformation found affecting 61.2% pups in the ASD group. Other malformations observed were dental malformation (3.82%), genital malformation (3.28%) and paw malformation (1.1%). Hind limb paralysis was observed in one pup. The tail anomalies were characterized as per gross appearance and location of the malformation.CONCLUSION:In this well-validated rat model of ASD, congenital malformation was quite common. It seems screening of congenital malformations should be an integral part of the management of ASD, or the case may be vice versa, i.e., in the case of a baby born with a congenital deformity, they should be screened for ASD.

PI3K/AKT/mTOR-mediated autophagy in the development of autism spectrum disorder.

To investigate the association between PI3K/AKT/mTOR-mediated autophagy and the pathogenesis of autism spectrum disorder (ASD). A sodium valproate (VPA)-induced baby rat model of ASD was built. Nine pregnant rats were randomly assigned into three groups, with three rats for each group: healthy control group, VPA group and mTOR inhibition group, receiving different drug administrations. Baby rats were grouped according to the maternal rats. Social interaction of baby rats (35days after birth) was observed and their bilateral hippocampes were sliced. We used electron microscope analysis for observation of autophagosome formation, double immunofluorescence staining for location of LC3 II, TUNEL assay for observation of cell apoptosis, Western Blot assay was used for measurement of LC3 II, P62, p53, Bcl-2, PI3K/AKT/mTOR-related proteins and p-S6. VPA group had significantly lowered ability of social interaction than the control group and mTOR inhibition group (both P<0.05). The control group and the mTOTR inhibition group presented the visual of autophagosomes, while VPA group seldom had autophagosomes. By comparison with VPA group, mTOR group had a remarkable green fluorescence in the hippocampal CA1 (P<0.05). Western Blot assay revealved that mTOR inhibition group had a significantly higher LC3 II expression, higher LC3 II/LC3 I ratio, higher Bcl-2 expression and lower p53 than VPA group (all P<0.05). TUNEL assay showed that mTOR inhibition group had a significant smaller number of apoptotic cells in the hippocampal CA1. Besides, lowered expressions of p-PI3K, p-AKT and p-S6 were identified in the baby rats in mTOR inhibition group compared with VPA group (all P<0.05). mTOR inhibition can increase PI3K/AKT/mTOR-mediated autophagic activity and improve social interaction in VPA-induced ASD, providing a novel target and direction for the treatment of ASD.