Rodent Model Of Autism Research Articles

Focus On Prebiotic and Probiotic Preventive and Therapeutic Diet Approaches to Restore Gut Homeostasis in Rodent Models of Autism

Although variable diet approaches shaped the gut bacterial abundance differently, they are considered the core factors in modulating gut microbiota throughdifferent mechanisms. Our aim in this study is to focus on the dietary candidates that could maintain a healthy gut microbiota by promoting commensal bacteria and reducingor inhibiting pathogens. In the current study, our objective is to demonstrate that a novel combined dietary approach of pre-and probiotic mixtures could be more effectivein inducing significant improvements in gut bacterial composition as a target to treat ASD. Luteolin complex veggie capsules (Swanson, USA), artichoke extract, as well asyogurt and Lactobacillus rhamnosus veggie capsules (5 billion CFU) (Swanson, USA), recently known as Lacticaseibacillus rhamnosus were selected as prebiotics and probioticsrespectively and were screened for their protective and therapeutic effects on the gut microbiota. They were all administered orally over 5 weeks to propionic acid PPAtreatedrats as rodent models of Autism (groups 4-10). Their results were compared to the control animal group undertaking a standard diet (group 1) and to post and pre-PPA-treated groups (groups 2 and 3). Lactobacillus and Bifidobacterium were noted as the most dominant, non-fluctuating strains in response to all diet intakes, and theynegatively influenced the presence of Proteobacteria (Enterobacteriaceae), which decreased in almost all treated groups during weeks 2 and 3, and 4.Interestingly, Clostridiumsp. was observed to be high in number at week 1, mainly in the control group (1) and pre and post-PPA groups (2 and 3), but were inhibited in all treated groups over theextended treatment period. Bacteroidetes were positively increased with the high presence of Lactobacillus and Bifidobacterium spp. Levels throughout the experiment in almostall animal groups. Thus, both prebiotics and probiotics study designed candidates (Luteolin complex capsules, artichoke extract, yogurt, and L. rhamnosus capsules) inhibitedClostridium sp., promoted commensal bacteria, specifically Lactobacillus and Bifidobacterium spp., restored the normal gut bacterial niches and therefore could be consideredas potential promising dietary approaches for maintaining healthy physical and microbial gut strategies.

In a rodent model of autism, probiotics decrease gut leakiness in relation to gene expression of GABA receptors: Emphasize how crucial the gut-brain axis.

Rodent models may help investigations on the possible link between autism spectrum disorder and increased permeability of the gastrointestinal (GI) tract since autistic patients frequently manifested GI troubles as comorbidities. Forty young male western Albino rats, weighing approximately 60-70 g and aged 3-4 weeks, were used. In each of the six experimental groups, eight animals were treated as follows. The mice in the control group (I) received phosphate-buffered saline orally. For 3 days, the animals in the propionic acid (PPA)-treated groups (II and III) were given an oral neurotoxic dose of PPA (250 mg/kg body weight each day). Group II was euthanized after 3 days; however, Group III was left alive to be euthanized alongside the other groups. The animals were kept at 22 ± 1°C and allowed to access water and normal food as needed. Identical dosages of PPA were given to the rats in the three treatment groups (IV, V, and VI), and for 3 weeks, they were given the following treatments: 0.2 g/kg body weight of pure Bifidobacterium infantis, a probiotic mixture of PROTEXIN®, Somerset, UK and pure Lactobacillus bulgaricus, respectively. The six groups underwent measurements of serum zonulin and occludin as variables associated with leaky gut, glutathione, malondialdehyde, and catalase as oxidative stress-related variables, with gamma-aminobutyric acid (GABA) receptor gene expression. This study demonstrated the potential effects of pure or mixed probiotics in lowering zonulin and occludin as markers of increased intestinal permeability, enhancing GABA receptor expression, and reducing oxidative stress as neurotoxic effects of PPA. This study demonstrates that various probiotics protect gut barrier function and could be used to alleviate increased intestinal permeability caused by oxidative stress and impaired GABA signaling as a result of PPA neurotoxicity, addressing the clinical implications of probiotic supplements.

Influence of environmental enrichment on sexual behavior and the process of learning and memory in a rat model of autism with valproic acid

Autism spectrum disorder (ASD) is a psychiatric disorder with severe behavioral consequences and no specific therapy. Its etiology is multifactorial, as it is caused by a complex interaction of genetic and environmental factors. In rats, prenatal exposure to the antiepileptic drug valproic acid (VPA) has been associated with an increased risk of autistic-like behaviors in offspring, including social behavior deficits, increased repetitive behaviors, and cognitive impairments. In addition, VPA-treated rats have shown altered sociosexual behaviors. However, the mechanisms underlying these alterations in reproductive processes in VPA-treated rats are not fully understood. Interestingly some abnormal behaviors in VPA autism models are improved by an enriched environment (EE). In the present study, we examined the effects of EE on memory performance and sexual behavior in male rats. We found that on postnatal day 90, EE reduced the time it took for both control and VPA-treated groups to find a hidden platform in the Morris water maze. On PND 100, prenatal exposure to VPA reduced total exploring time in object recognition tests. On PND 110, EE reduced mount and intromission latency and increased ejaculatory frequency in VPA-treated male rats. These results suggest that environmental stimuli significantly influence the onset of sexual behavior in VPA-treated male rats and that EE may be a potential tool for improving a variety of behavioral deficiencies in rodent models of autism.

Mouse Behavior on the Trial-Unique Nonmatching-to-Location (TUNL) Touchscreen Task Reflects a Mixture of Distinct Working Memory Codes and Response Biases.

The trial-unique nonmatching to location (TUNL) touchscreen task shows promise as a translational assay of working memory (WM) deficits in rodent models of autism, ADHD, and schizophrenia. However, the low-level neurocognitive processes that drive behavior in the TUNL task have not been fully elucidated. In particular, it is commonly assumed that the TUNL task predominantly measures spatial WM dependent on hippocampal pattern separation, but this proposition has not previously been tested. In this project, we tested this question using computational modeling of behavior from male and female mice performing the TUNL task (N = 163 across three datasets; 158,843 trials). Using this approach, we empirically tested whether TUNL behavior solely measured retrospective WM, or whether it was possible to deconstruct behavior into additional neurocognitive subprocesses. Overall, contrary to common assumptions, modeling analyses revealed that behavior on the TUNL task did not primarily reflect retrospective spatial WM. Instead, behavior was best explained as a mixture of response strategies, including both retrospective WM (remembering the spatial location of a previous stimulus) and prospective WM (remembering an anticipated future behavioral response) as well as animal-specific response biases. These results suggest that retrospective spatial WM is just one of a number of cognitive subprocesses that contribute to choice behavior on the TUNL task. We suggest that findings can be understood within a resource-rational framework, and use computational model simulations to propose several task-design principles that we predict will maximize spatial WM and minimize alternative behavioral strategies in the TUNL task.SIGNIFICANCE STATEMENT Touchscreen tasks represent a paradigm shift for assessment of cognition in nonhuman animals by automating large-scale behavioral data collection. Their main relevance, however, depends on the assumption of functional equivalence to cognitive domains in humans. The trial-unique, delayed nonmatching to location (TUNL) touchscreen task has revolutionized the study of rodent spatial working memory. However, its assumption of functional equivalence to human spatial working memory is untested. We leveraged previously untapped single-trial TUNL data to uncover a novel set of hierarchically ordered cognitive processes that underlie mouse behavior on this task. The strategies used demonstrate multiple cognitive approaches to a single behavioral outcome and the requirement for more precise task design and sophisticated data analysis in interpreting rodent spatial working memory.

Ameliorative Effect of Omega-3-Rich Fish Diet on the Neurotoxic Effects of Propionic Acid in a Rodent Model of Autism

Despite the increased social and financial burden associated with autism spectrum disorder (ASD), no particular treatment for this illness has been identified. A detailed examination of prior trials conducted to treat autism revealed that nutrition intervention was commonly utilised as an additional method of therapy. Indeed, the early detection of nutritional deficiencies and metabolic problems, together with appropriate therapeutic measures, can be a cornerstone for enhancing the metabolic and behavioural abilities of individuals with autism. In this work, a propionic acid (PPA)-induced rodent model of ASD was fed Spangled emperor (Lethrinus nebuloses), Dusky grouper (Epinephelus marginatus), and Parrot Fish (Scaridae), which are locally named Hammour, Shour, and Hareed, respectively, in Saudi Arabia. The aim of this study was to investigate the effect of dietary intervention with three kinds of whole fish (Lethrinus nebuloses, Epinephelus marginatus, and Scaridae), as a rich source of ω-3 fatty acids, on selected biochemical markers (reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS), creatine kinase (CK), lactate dehydrogenase (LDH), dopamine) together with a histopathological examination of the cerebellum and hippocampus as neurotoxic features of propionic acid in a rodent model of autism. Briefly, our findings give preliminary evidence in favour of employing fish as a rich supply of omega-3 fatty acids to reduce the neurotoxic effect of a PPA-induced ASD in a rat model. It may be beneficial to provide an extra marine omega-3-rich diet for improving certain metabolic autistic features related to oxidative stress, energy metabolism, and brain neurotransmitters.

Unveiling sex-based differences in developing propionic acid-induced features in mice as a rodent model of ASD.

Males are more likely to develop autism as a neurodevelopmental disorder than females are, although the mechanisms underlying male vulnerability are not fully understood. Therefore, studying the role of autism etiologies considering sex differences in the propionic acid (PPA) rodent model of autism would build greater understanding of how females are protected from autism spectrum disorder, which may be used as a treatment strategy for males with autism. This study aimed to investigate the sex differences in oxidative stress, glutamate excitotoxicity, neuroinflammation, and gut microbiota impairment as etiological mechanisms for many neurological diseases, with specific reference to autism. Forty albino mice were divided into four groups of 10 animals each with two control and two treated groups of both sexes received only phosphate-buffered saline or a neurotoxic dose of PPA (250 mg/kg body weight) for 3 days, respectively. Biochemical markers of energy metabolism, oxidative stress, neuroinflammation, and excitotoxicity were measured in mouse brain homogenates, whereas the presence of pathogenic bacteria was assessed in mouse stool samples. Furthermore, the repetitive behavior, cognitive ability, and physical-neural coordination of the animals were examined. Collectively, selected variables related to oxidative stress, glutamate excitotoxicity, neuroinflammation, and gut bacteria were impaired concomitantly with altered behavior in PPA-induced rodent model, with males being more susceptible than females. This study explains the role of sex in the higher vulnerability of males to develop autistic biochemical and behavioral features compared with females. Female sex hormones and the higher detoxification capacity and higher glycolytic flux in females serve as neuroprotective contributors in a rodent model of autism.

A comprehensive assay of social motivation reveals sex-specific roles of autism-associated genes and oxytocin

Social motivation is critical to the development of typical social functioning. Social motivation, specifically one or more of its components (e.g., social reward seeking or social orienting), could be relevant for understanding phenotypes related to autism. We developed a social operant conditioning task to quantify effort to access a social partner and concurrent social orienting in mice. We established that mice will work for access to a social partner, identified sex differences, and observed high test-retest reliability. We then benchmarked the method with two test-case manipulations. Shank3B mutants exhibited reduced social orienting and failed to show social reward seeking. Oxytocin receptor antagonism decreased social motivation, consistent with its role in social reward circuitry. Overall, we believe that this method provides a valuable addition to the assessment of social phenotypes in rodent models of autism and the mapping of potentially sex-specific social motivation neural circuits.

Alteration in social interaction and tactile discrimination of juvenile autistic-like rats following tactile stimulation and whisker deprivation.

Autism spectrum disorder is a developmental disorder that can affect sensory-motor behaviors in the valproic acid (Val) rodent model of autism. Although whisker deprivation (WD) induces plastic changes in the cortical neurons, tactile stimulation (TS) during the neonatal period may reverse it. Here, we investigate the interaction effects of TS and WD on behavioral and histologic features of barrel cortex neurons in juvenile Val-treated. Control (CTL, CTL-TS, CTL-WD, and CTL-TS-WD groups) and Val-treated (Val, Val-TS, Val-WD, and Val-TS-WD groups) rats of both sexes were subjected to behavioral tests of social interaction, and novel texture recognition, and Nissl staining. The TS groups were exposed to sensory stimulation for 15min, three times/day; moreover, all whiskers in the WD groups were trimmed every other day from postnatal days 1 to 21. Both prenatal valproic acid administration and postnatal WD decreased the rats' performance percentage of the Val and CTL-WD groups of both sexes compared with the CTL groups in the social interaction and texture discrimination tests. Following TS, the performance of the Val-TS-WD group increased significantly compared to the Val group (p<.05), whereas the performance of the CTL-TS-WD group rescued to the CTL group. Nissl staining results also revealed the neuron degeneration percentage in the barrel field area of the Val and CTL-WD groups was increased significantly (p<.05) compared with the CTL group. In this regard, TS decreased the neuron degeneration percentage of the Val-TS-WD and the CTL-TS-WD groups, compared with the CTL group, significantly (p<.05). TS in juvenile male and female rats can act as a modulator and compensate for the behavioral and histological consequences of WD and prenatal valproic acid exposure.

Psychobiotics improve propionic acid-induced neuroinflammation in juvenile rats, rodent model of autism.

This study aimed to evaluate the protective and therapeutic potency of bee pollen and probiotic mixture on brain intoxication caused by propionic acid (PPA) in juvenile rats. Five groups of six animals each, were used: the control group only receiving phosphate-buffered saline; the bee pollen and probiotic-treated group receiving a combination of an equal quantity of bee pollen and probiotic (0.2 kg/kg body weight); the PPA group being treated for 3 days with an oral neurotoxic dose of PPA (0.25 kg/kg body weight); the protective and therapeutic groups receiving bee pollen and probiotic mixture treatment right before and after the neurotoxic dose of PPA, respectively. The levels of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor α, and interferon γ (IFN-γ) were investigated to evaluate the neuroinflammatory responses in brain tissues from different animal groups. The much higher IL-1β, IL-8, and IFN-γ, as pro-inflammatory cytokines (P < 0.001), together with much lower IL-10, as anti-inflammatory cytokine (P < 0.001) compared to controls clearly demonstrated the neurotoxic effects of PPA. Interestingly, the mixture of bee pollen and probiotics was effective in alleviating PPA neurotoxic effects in both therapeutic and protective groups demonstrating highly significant changes in IL-1β, IL-8, IL-10, and IFN-γ levels together with non-significant reduction in IL-6 levels compared to PPA-treated rats. Overall, our findings demonstrated a new approach to the beneficial use of psychobiotics presenting as bee pollen and probiotic combination in neuroinflammation through cytokine changes as a possible role of glial cells in gut–brain axis.

Probiotic Ameliorating Effects of Altered GABA/Glutamate Signaling in a Rodent Model of Autism.

Autism spectrum disorders (ASDs) comprise a heterogeneous group of pathological conditions, mainly of genetic origin, characterized by stereotyped behavior, such as marked impairment in verbal and nonverbal communication, social skills, and cognition. Excitatory/inhibitory (E/I) imbalances have been recorded as an etiological mechanism of ASD. Furthermore, GABA, the main inhibitory neurotransmitter in adult life, is known to be much lower in both patients and rodent models of ASD. We propose correcting GABA signaling as a therapeutic strategy for ASD. In this study, 40 young male western Albino rats, 3–4 weeks in age, weighing about 60–70 g, were used. The animals were randomly assigned into six experimental groups, each including eight rats. Group I served as the control group and was orally administered phosphate-buffered saline. Groups II and III served as rodent models of ASD and were orally administered a neurotoxic dose of propionic acid (PPA). The rats in the three therapeutic groups (IV, V, and IV) received the same doses of PPA, followed by 0.2 g/kg body weight of pure Bifidobacterium infantis, a probiotic mixture of ProtexinR, and pure Lactobacillus bulgaricus, respectively, for 3 weeks. Selected variables related to oxidative stress, glutamate excitotoxicity, and gut bacteria were measured in the six groups. Both pure and mixed Lactobacillus and Bifidobacterium were effective in ameliorating glutamate excitotoxicity as an autistic feature developed in the PPA-induced rodent model. Their therapeutic effects mostly involved the correction of oxidative stress, restoration of depleted GABA, and up-regulation of GABA receptor gene expression. Pure Bifidobacterium was the most effective, followed by the mixture of probiotics and finally lactobacillus. In conclusion, Bifidobacteria and lactobacilli can be used independently or in combination as psychobiotics to ameliorate oxidative stress and glutamate excitotoxicity as two confirmed etiological mechanisms through the gut–brain axis.

The Efficacy of Fecal Transplantation and Bifidobacterium Supplementation in Ameliorating Propionic Acid-Induced Behavioral and Biochemical Autistic Features in Juvenile Male Rats.

Gut microbiota plays a major role in neurological disorders, including autism. Modulation of the gut microbiota through fecal microbiota transplantation (FMT) or probiotic administration, such as Bifidobacteria, is suggested to alleviate autistic symptoms; however, their effects on the brain are not fully examined. We tested both approaches in a propionic acid (PPA) rodent model of autism as treatment strategies. Autism was induced in Sprague-Dawley rats by administering PPA orally (250mg/kg) for 3days. Animals were later treated with either saline, FMT, or Bifidobacteria for 22days. Control animals were treated with saline throughout the study. Social behavior and selected brain biochemical markers related to stress hormones, inflammation, and oxidative stress were assessed. PPA treatment induced social impairments, which was rescued by the treatments. In the brain, Bifidobacteria treatment increased oxytocin relative to control and PPA groups. Moreover, Bifidobacteria treatment rescued the PPA-induced increase in IFN-γ levels. Both treatments increased GST levels, which was diminished by the PPA treatment. These findings indicate the potential of gut microbiota-targeted therapeutics in ameliorating behavioral deficit and underlying neural biochemistry.

Comparative Study on the Exacerbating Effects of Casein-Rich vs. Gluten-Rich Diets on Biochemical-Induced Features in Rodent Model of Autism.

In relation to dietary intervention in individuals with autism spectrum disorder (ASD), certain food constituents especially gluten and casein are recognized to be challenging and should be restricted. In this study, levels of glutathione S-transferase, glutathione, lipid peroxides, serotonin (5-HT), interleukin-6 (IL-6), glutamate, and gamma aminobutyric acid (GABA) were measured in the brain homogenates of ASD rodent model. Rats were treated either with single dose clindamycin (30mg/kg) or with propionic acid (PPA) (250mg/kg) for 3days and then fed a standard diet, casein-rich diet (CRD), or gluten-rich diet (GRD). The obtained data demonstrates that clindamycin and PPA induced oxidative stress, which was slightly affected by CRD. A marked increase in the proinflammatory cytokine (IL-6) concentration found in clindamycin- and PPA-treated groups was lower in CRD fed rats. Both CRDs and GRDs produced similar trends in glutamate levels. 5-HT levels were higher in the clindamycin- and PPA-treated groups and increased with a GRD but were less affected by a CRD. CRD could be less deleterious compared to GRD. Although the underlying cause of gastrointestinal symptoms in patients with ASD is not exactly known, the most widely accepted one is the opioid theory which is related to GRD and CRD.

Association of Maternal Diabetes and Autism Spectrum Disorders in Offspring: a Study in a Rodent Model of Autism.

The present study investigated that maternal type 1 diabetes may contribute to autism pathogenesis in offspring, and that insulin therapy during pregnancy may prevent the onset of autism. As evidenced, selected brain biomarkers representing the accepted etiological mechanism of autism in newborn rats from diabetic mothers and diabetic mothers receiving insulin therapy compared to the propionic acid (PPA) rodent model of autism were screened. Female Wistar rats with a controlled fertility cycle were randomly divided into three groups: a control group, a group treated with a single dose of 65mg/kg streptozotocin (STZ) to induce type 1 diabetes (T1D), and a group treated with a single dose of STZ to induce T1D along with insulin therapy. Neonatal rats from these groups were divided into four experimental groups of six animals each: the control group, oral buffered PPA-treated group administered a neurotoxic dose of 250mg/kg PPA for 3days to induce autism, neonatal rats from mothers with T1D, and neonatal rats from mothers with T1D receiving insulin therapy. Biochemical parameters of oxidative stress, neuroinflammation, and glutamate excitotoxicity were examined in brain homogenates from all neonatal rats. The development of pathogenic bacteria was monitored in stool samples from all rat groups. Descriptive analyses of changes in fecal microbiota and overgrowth of Clostridium species were performed in diabetic mothers, diabetic mothers treated with insulin therapy, and their offspring. Clostridium species may induce autism-relevant behaviors in offspring from mothers with T1D. Maternal T1D without insulin therapy increased lipid peroxidation levels, reduced GST activity, and lower offspring' vitamin C and GSH levels. Increased IL-6 levels and reduced GABA levels were detected in brain homogenates from neonatal rats whose mothers had T1D. Interestingly, insulin therapy reduced MDA and IL-6 levels and increased GST, GSH, and vitamin C levels in brain homogenates of neonatal rats from mothers with T1D receiving insulin therapy compared to the PPA-treated group. Based on our results, the PPA-treated group and neonatal rats from mothers with T1D exhibited similar results. These findings suggest that neonatal rats from mothers with T1D may develop autism-relevant biochemical autistic features and that insulin therapy may ameliorate oxidative stress, poor detoxification, inflammation, and excitotoxicity as ascertained mechanisms involved in the etiology of autism.

Fecal Transplant and Bifidobacterium Treatments Modulate Gut Clostridium Bacteria and Rescue Social Impairment and Hippocampal BDNF Expression in a Rodent Model of Autism.

Autism is associated with gastrointestinal dysfunction and gut microbiota dysbiosis, including an overall increase in Clostridium. Modulation of the gut microbiota is suggested to improve autistic symptoms. In this study, we explored the implementation of two different interventions that target the microbiota in a rodent model of autism and their effects on social behavior: the levels of different fecal Clostridium spp., and hippocampal transcript levels. Autism was induced in young Sprague Dawley male rats using oral gavage of propionic acid (PPA) for three days, while controls received saline. PPA-treated animals were divided to receive either saline, fecal transplant from healthy donor rats, or Bifidobacterium for 22 days, while controls continued to receive saline. We found that PPA attenuated social interaction in animals, which was rescued by the two interventions. PPA-treated animals had a significantly increased abundance of fecal C. perfringens with a concomitant decrease in Clostridium cluster IV, and exhibited high hippocampal Bdnf expression compared to controls. Fecal microbiota transplantation or Bifidobacterium treatment restored the balance of fecal Clostridium spp. and normalized the level of Bdnf expression. These findings highlight the involvement of the gut–brain axis in the etiology of autism and propose possible interventions in a preclinical model of autism.

Comparative Studies on Phospholipase A2 as a Marker for Gut Microbiota- liver-brain Axis in a rodent Model of Autism

Background:Lipid homeostasis and gut flora can be related to many metabolic diseases, especially autism. Lipid metabolism in the brain can control neuronal structure and function and can also take part in signal transduction pathways to control metabolism in peripheral tissues, especially in the liver. Impaired phospholipid metabolism promotes oxidative stress and neuroinflammation and is, therefore, directly related to autism.Objective:The effect of propionic acid (PPA) toxicity on lipid homeostasis in the gut-liver-brain axis was evaluated to understand their inter-connection. Cytosolic phospholipase A2 (cPLA2) concentration and activity was measured in autistic model and protective role of omega-3 (ω-3) and vitamin B12 was evaluated.Methods:Animals were divided into five groups: Group I (control group); Group II (autistic model treated with neurotoxic dose of PPA); Group III (treated with vitamin B12 (16.7 mg/kg/day) for 30 days post PPA treatment); Group IV (treated with ω-3 (200 mg/kg body weight/day) for 30 days post PPA treatment; Group V (combined dose of ω-3 and Vitamin B12, for 30 days post PPA treatment). Phospholipase A2 activity and protein expression level in the liver homogenate of all the groups was analyzed by western blotting and was compared to brain cPLA2.Results:PPA increased the levels of liver and brain cPLA2. However, independent or combined treatment with ω-3 and vitamin B12 was effective in neutralizing its effect. Moreover, PPA-induced dysbiosis, which was ameliorated with the above treatments.Conclusions:This study showed the role of cPLA2 as a lipid metabolism marker, related to PPA-induced inflammation through a highly interactive gut-liver-brain axis.

Maternal immune activation targeted to a window of parvalbumin interneuron development improves spatial working memory: Implications for autism

Maternal immune activation (MIA) increases risk for neuropsychiatric disorders such as autism spectrum disorder (ASD) in offspring later in life through unknown causal mechanisms. Growing evidence implicates parvalbumin-containing GABAergic interneurons as a key target in rodent MIA models. We targeted a specific neurodevelopmental window of parvalbumin interneurons in a mouse MIA model to examine effects on spatial working memory, a key domain in ASD that can manifest as either impairments or improvements both clinically and in animal models.Pregnant dams received three consecutive intraperitoneal injections of Polyinosinic:polycytidylic acid (poly(I:C), 5 mg/kg) at gestational days 13, 14 and 15. Spatial working memory was assessed in young adult offspring using touchscreen operant chambers and the Trial-Unique Non-matching to Location (TUNL) task. Anxiety, novelty seeking and short-term memory were assessed using Elevated Plus Maze (EPM) and Y-maze novelty preference tasks. Fluorescent immunohistochemistry was used to assess hippocampal parvalbumin cell density, intensity and co-expression with perineuronal nets. qPCR was used to assess the expression of putatively implicated gene pathways.MIA targeting a window of parvalbumin interneuron development increased spatial working memory performance on the TUNL touchscreen task which was not influenced by anxiety or novelty seeking behaviour. The model reduced fetal mRNA levels of Gad1 and adult hippocampal mRNA levels of Pvalb and the distribution of low intensity parvalbumin interneurons was altered.We speculate a specific timing window for parvalbumin interneuron development underpins the apparently paradoxical improved spatial working memory phenotype found both across several rodent models of autism and clinically in ASD.

Gestational exposure to a ketogenic diet increases sociability in CD-1 mice.

Postnatal administration of high-fat, low-carbohydrate ketogenic diets (KDs) is an established and effective treatment option for refractory epilepsy, with more recently identified therapeutic potential across a wide range of preclinical models of neurological and psychiatric disorders. However, the impact of gestational exposure to a KD (GKD) on offspring development remains unclear. Previous work has found that GKD exposure reduces depression- and anxiety-like behaviors in CD-1 mice, whereas postnatal KD improves sociability in several different rodent models of autism. Here we examined how sociability is impacted by GKD. Given that the neuropeptide oxytocin positively regulates affect, anxiety, and sociability, we also examined the effects of GKD on brain oxytocin expression. Male and female CD-1 mice exposed to either a standard diet (SD) or a KD gestationally were cross-fostered with SD dams at birth and remained on a SD from that point onward. These offspring were then tested for sociability and social novelty (three-chambered test) and depressive-like behaviors (forced swim test) at 10 weeks of age. At the conclusion of testing, brain tissue was collected and immunohistochemically processed for oxytocin expression in hypothalamic and limbic areas. We found that GKD increased sociability and reduced depressive-like symptoms, without affecting oxytocin expression in quantified areas. By expanding the scope of the lasting impact of gestational exposure to a ketogenic diet to include positive effects on sociability, these results indicate that GKDs may have novel therapeutic applications for individuals at risk for developmental disorders of social behavior, including autism and schizophrenia. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

1331-P: Correlation between Sleep Deduction and Neurobehavioral Deficits in the Mouse Offspring of Mother with Diabetes

Lines of human cohort studies reported increased risk of neurobehavioral abnormalities as well as sleep problems in offspring of mother with diabetes (OMD). Preclinical studies demonstrated that forced sleep disturbance leads to poor cognitive function in mice. Based on these findings, our hypothesis posits that wide spectrum of neurobehavior issues in OMD is due to their sleep disturbance. To test this hypothesis, we first established mouse OMD models for examining the correlation between sleep disturbance and performance in a battery of neurobehavior tests. Female C57BL/6 mice received intraperitoneal injection of Streptozocin at 6 weeks old. DM was confirmed before start of mating. OMD in juvenile were placed to neurobehavior tests as well as piezoelectric sensor system of sleep under 12 h light/12 h dark cycles. In open field test, OMD spent significantly more time in the center of the field, suggesting the increased risk-taking behavior or/and reduced anxiety. Interestingly, several rodent models of autism showed similar behavior changes, and human OMD patients have increased risk of autism. Furthermore, the change of the behavior in our model was augmented in male and this may be consistent with the human OMD in which male patients has higher risk of autism than female. In water T maze test, the ability of spatial learning in OMD was comparable to that of control animals, while the reversal learning was impaired. Sleep time of OMD was significantly shorter than that of control in both dark and light phases. We also found positive correlation between sleep time and cognitive flexibility that was measured as reversal learning level in water T maze. However, the proxy for risk taking behavior did not show correlation with the sleep time. Altogether, our results demonstrate the correlation between sleep disturbance and impaired cognitive flexibility, and thus shed light on the potential mechanisms underlying intellectual disability that is frequently observed in OMD. Disclosure K. Sugai: None. J. Sasaki: None. M. Odawara: Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. M. Torii: None. K. Hashimoto-Torii: None. Funding Scott-Gentle Foundation

Inhibition of striatal-enriched protein tyrosine phosphatase (STEP) activity reverses behavioral deficits in a rodent model of autism

Autism spectrum disorders (ASDs) are highly prevalent childhood illnesses characterized by impairments in communication, social behavior, and repetitive behaviors. Studies have found aberrant synaptic plasticity and neuronal connectivity during the early stages of brain development and have suggested that these contribute to an increased risk for ASD. STEP is a protein tyrosine phosphatase that regulates synaptic plasticity and is implicated in several cognitive disorders. Here we test the hypothesis that STEP may contribute to some of the aberrant behaviors present in the VPA-induced mouse model of ASD. In utero VPA exposure of pregnant dams results in autistic-like behavior in the pups, which is associated with a significant increase in the STEP expression in the prefrontal cortex. The elevated STEP protein levels are correlated with increased dephosphorylation of STEP substrates GluN2B, Pyk2 and ERK, suggesting upregulated STEP activity. Moreover, pharmacological inhibition of STEP rescues the sociability, repetitive and abnormal anxiety phenotypes commonly associated with ASD. These data suggest that STEP may play a role in the VPA model of ASD and STEP inhibition may have a potential therapeutic benefit in this model.

Bee pollen and propolis improve neuroinflammation and dysbiosis induced by propionic acid, a short chain fatty acid in a rodent model of autism

BackgroundNeuroinflammation plays a major role in the pathogenesis of autism because the cytokine levels are typically disturbed in the brain in autistic patients. Prebiotics-rich diet maintains the healthy gut microbiota and hence can regulate the neuroinflammation indirectly. The study aimed to investigate the role of bee pollen and propolis in ameliorating neuroinflammation, including cytokine levels, in an animal model of autism.MethodsHamsters were classified as four groups: Group I, control; Group II, autistic model/animals treated with 250 mg propionic acid (PPA)/kg body weight (BW)/day for 3 days; Group III, animals treated with bee pollen at a dose of 250 mg/kg BW/day for 4 weeks; and Group IV, animals treated with propolis at a dose of 250 mg/kg BW/day for 4 weeks. Neuroinflammatory responses were evaluated using the levels of interferon γ (IFN-γ), interleukin 1 alpha (IL-1α), IL-6, IL-10, IL-12 (p70), vascular endothelial growth factor (VEGF), and tumor necrosis factor α (TNFα).ResultsSignificant decrease of IL-10 (P<0.026), VEGF (P<0.005), and TNFα(P<0.005) levels and increased IL-1α (P<0.032), IL-6(P<0.028), and IFN-γ (P<0.013) levels were observed between the four studied groups. The neurotoxic effects of PPA was clearly presented as much higher IL-6, as pro-inflammatory cytokine (P<0.05), concomitant with much lower IL-10, as anti-inflammatory cytokine(P<0.015) compared to controls. Both bee pollen and propolis were effective in ameliorating the neurotoxic effects of PPA demonstrating non-significant changes of IL-6 and IL-10 when compared to control healthy hamsters.ConclusionsOur findings indicate that both bee pollen and propolis protect against neuroinflammation in the rodent model of autism. However, further studies are needed to investigate the clinical benefits of prebiotics-rich diet in neurodevelopmental disorders, such as autism.