Retinoic Acid Supplementation Rescues the Social Deficits in Fmr1 Knockout Mice.
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ABSTRACT:
SUBMITTER: Yang L
PROVIDER: S-EPMC9247356 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Autism spectrum disorder (ASD) is a hereditary intellectual disability. Fragile X syndrome (FXS) is the leading cause of ASD and mainly results from the abnormal CGG amplification (>200 repeats) of the fragile X mental retardation 1 (Fmr1) gene. All-trans retinoic acid (RA) is involved in synaptic plasticity, neuronal differentiation and brain maturation. RA-mediated synaptic strength regulation was abolished in FXS patient-derived induced pluripotent stem (iPS) cells. Previous work on the ASD model with excessive UBE3A expression, of which the ASD-like behaviors caused by repression in RA signaling were successfully ameliorated by oral supplementation of RA. In this study, we used male Fmr1 knock-out (KO) mice to explore the effect of RA exerting on the behaviors. Our results indicated that RA supplementation can alleviate the defects in social novelty. We performed RNA sequencing to find out the differentially expressed genes (DEGs) in the Fmr1 KO group, of which the expression levels were restored to the similar level as those in the wild-type (WT) group after RA supplementation, such as Per1, Per2 and Foxp2. Besides, several DEGs associated with neuronal functions were also identified, like Arc, Ccn2, Foxp2, Xdh, Lepr, Serpina3n andTnfsf10. our findings that RA supplementation improved social novelty behavior in Fmr1 KO mice provided a potential therapeutic intervention method for FXS, which may further be used in other disease models with defective RA signaling.
2022-04-30 | GSE201672 | GEO
Project description:Retinoic acid supplementation rescues the social deficits in Fmr1 knockout mice
| PRJNA832607 | ENA
Project description:Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder with complex pathophysiology including both genetic and environmental factors. Recent evidence demonstrates the gut microbiome and its resultant metabolome can influence brain and behavior and have been implicated in ASD. To investigate gene by microbiome interactions in a model for genetic risk of ASD, we utilize mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3KO). Shank3KO have altered microbiome composition and function at baseline in addition to social deficits. Further depletion of the microbiome with antibiotics exacerbates social deficits in Shank3KO, and results in transcriptional changes in the frontal cortex. Supplementation with the microbial metabolite acetate leads to reversal of social behavioral phenotypes even in mice with a depleted microbiome, and significantly alters transcriptional regulation in the prefrontal cortex. These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.
2023-03-02 | GSE225983 | GEO
Project description:The current study aimed to further address important questions regarding the therapeutic efficacy of omega-3 fatty acids for various behavioral and neuroimmune aspects of the Fmr1 phenotype. To address these questions, our experimental design utilized two different omega-3 fatty acid administration timepoints, compared to both standard laboratory chow controls ("Standard") and a diet controlling for the increase in fat content ("Control Fat"). In the first paradigm, post-weaning supplementation (after postnatal day 21) with the omega-3 fatty acid diet ("Omega-3") reversed deficits in startle threshold, but not deficits in prepulse inhibition, and the effect on startle threshold was not specific to the Omega-3 diet. However, post-weaning supplementation with both experimental diets also impaired acquisition of a fear response, recall of the fear memory and contextual fear conditioning compared to the Standard diet. The post-weaning Omega-3 diet reduced hippocampal expression of IL-6 and this reduction of IL-6 was significantly associated with diminished performance in the fear conditioning task. In the perinatal experimental paradigm, the Omega-3 diet attenuated hyperactivity and acquisition of a fear response. Additionally, perinatal exposure to the Control Fat diet (similar to a "Western" diet) further diminished nonsocial anxiety in the Fmr1 knockout. This study provides significant evidence that dietary fatty acids throughout the lifespan can significantly impact the behavioral and neuroimmune phenotype of the Fmr1 knockout model.
| S-EPMC8797197 | biostudies-literature
Project description:ENGRAILED 2 (En2), a homeobox transcription factor, functions as a patterning gene in the early development and connectivity of rodent hindbrain and cerebellum, and regulates neurogenesis and development of monoaminergic pathways. To further understand the neurobiological functions of En2, we conducted neuroanatomical expression profiling of En2 wildtype mice. RTQPCR assays demonstrated that En2 is expressed in adult brain structures including the somatosensory cortex, hippocampus, striatum, thalamus, hypothalamus and brainstem. Human genetic studies indicate that EN2 is associated with autism. To determine the consequences of En2 mutations on mouse behaviors, including outcomes potentially relevant to autism, we conducted comprehensive phenotyping of social, communication, repetitive, and cognitive behaviors. En2 null mutants exhibited robust deficits in reciprocal social interactions as juveniles and adults, and absence of sociability in adults, replicated in two independent cohorts. Fear conditioning and water maze learning were impaired in En2 null mutants. High immobility in the forced swim test, reduced prepulse inhibition, mild motor coordination impairments and reduced grip strength were detected in En2 null mutants. No genotype differences were found on measures of ultrasonic vocalizations in social contexts, and no stereotyped or repetitive behaviors were observed. Developmental milestones, general health, olfactory abilities, exploratory locomotor activity, anxiety-like behaviors and pain responses did not differ across genotypes, indicating that the behavioral abnormalities detected in En2 null mutants were not attributable to physical or procedural confounds. Our findings provide new insight into the role of En2 in complex behaviors and suggest that disturbances in En2 signaling may contribute to neuropsychiatric disorders marked by social and cognitive deficits, including autism spectrum disorders.
| S-EPMC3400671 | biostudies-literature
Project description:Pten germline haploinsufficient (Pten+/-) mice, which model macrocephaly/autism syndrome, show social and repetitive behavior deficits, early brain overgrowth, and cortical-subcortical hyperconnectivity. Previous work indicated that altered neuronal connectivity may be a substrate for behavioral deficits. We hypothesized that exposing Pten+/- mice to environmental enrichment after brain overgrowth has occurred may facilitate adaptation to abnormal "hard-wired" connectivity through enhancing synaptic plasticity. Thus, we reared Pten+/- mice and their wild-type littermates from weaning under either standard (4-5 mice per standard-sized cage, containing only bedding and nestlet) or enriched (9-10 mice per large-sized cage, containing objects for exploration and a running wheel, plus bedding and nestlet) conditions. Adult mice were tested on social and non-social assays in which Pten+/- mice display deficits. Environmental enrichment rescued sex-specific deficits in social behavior in Pten+/- mice and partially rescued increased repetitive behavior in Pten+/- males. We found that Pten+/- mice show increased excitatory and decreased inhibitory pre-synaptic proteins; this phenotype was also rescued by environmental enrichment. Together, our results indicate that environmental enrichment can rescue social behavioral deficits in Pten+/- mice, possibly through normalizing the excitatory synaptic protein abundance.
| S-EPMC8468545 | biostudies-literature
Project description:We used AAV transfection of Shank3 shRNA to study the effect of Shank3 knock down in Nucleus Accumbens neurons. We find that Shank3 knock down leads to social deficits and hyperexcitability of Nucleus Accumbens D1-MSN. Bulk RNA sequencing shows that D1-MSN with Shank3 knock down upregulate TRPV4 and its subsequent antagonist driven inhibition leads to both a rescue of D1-MSN hyperexcitability and social deficit.
2022-10-01 | GSE139683 | GEO
Project description:Background: Loss of FMR1 is associated with Fragile X syndrome, amongst the most prevalent inherited intellectual disability. Despite extensive research in this area, previous studies have failed to detect consistent evidence of cognitive impairments in the Morris water maze (MWM) task in the Fmr1 knockout (KO) mouse. However, few studies have examined cognitive flexibility in a reversal form of the MWM task, which may illuminate subtle learning deficits. Methods: Adult male Fmr1 wildtype (WT) and KO mice were bred and tested in the MWM reversal paradigm. The testing paradigm consisted of two blocks per day, with 4 trials per block to locate a hidden platform. After the last trials on the fourth day of testing, the animals were given a probe trial with the platform removed. The following week, the location of the platform was switched to the opposite quadrant and the animals received 2 more days of testing, with 4 blocks in total. Results: As expected, Fmr1 KO mice did not display a learning deficit during the acquisition phase, F genotype (1, 24) = 0.034, p = 0.854, and performed similarly on the probe trial, F genotype (1, 23) = 0.024, p = 0.877. However, during the reversal phase of learning, Fmr1 KO mice showed deficits in their ability to learn the new location of the platform, F genotype (1, 23) = 3.93, p = 0.059. Further independent samples t-testing revealed that KO animals displayed significantly higher latency to reach the hidden platform during the third trial, t(23) = -2.96, p < 0.01. Conclusions: While previous studies have not demonstrated deficits in spatial memory in the Fmr1 KO model, it is possible that the acquisition phase of the task is less sensitive to deficits in learning. Future studies using this model to evaluate therapeutic interventions should consider utilizing the MWM reversal paradigm.
| S-EPMC6051189 | biostudies-literature
Project description:Genetic ablation of calcium homeostasis modulator 1 (CALHM1), which releases adenosine triphosphate from Type 2 taste cells, severely compromises the behavioral and electrophysiological responses to tastes detected by G protein-coupled receptors, such as sweet and bitter. However, the contribution of CALHM1 to salty taste perception is less clear. Here, we evaluated several salty taste-related phenotypes of CALHM1 knockout (KO) mice and their wild-type (WT) controls: 1) In a conditioned aversion test, CALHM1 WT and KO mice had similar NaCl avoidance thresholds. 2) In two-bottle choice tests, CALHM1 WT mice showed the classic inverted U-shaped NaCl concentration-preference function but CALHM1 KO mice had a blunted peak response. 3) In brief-access tests, CALHM1 KO mice showed less avoidance than did WT mice of high concentrations of NaCl, KCl, NH(4)Cl, and sodium lactate (NaLac). Amiloride further ameliorated the NaCl avoidance of CALHM1 KO mice, so that lick rates to a mixture of 1000 mM NaCl + 10 µM amiloride were statistically indistinguishable from those to water. 4) Relative to WT mice, CALHM1 KO mice had reduced chorda tympani nerve activity elicited by oral application of NaCl, NaLac, and sucrose but normal responses to HCl and NH(4)Cl. Chorda tympani responses to NaCl and NaLac were amiloride sensitive in WT but not KO mice. These results reinforce others demonstrating that multiple transduction pathways make complex, concentration-dependent contributions to salty taste perception. One of these pathways depends on CALHM1 to detect hypertonic NaCl in the mouth and signal the aversive taste of concentrated salt.
| S-EPMC4064958 | biostudies-literature
Project description:Recent preclinical and clinical studies suggest that lorcaserin, a preferential serotonin 2C receptor (5-HT2CR) agonist that was approved for the treatment of obesity, possesses antiepileptic properties. Here, we tested whether lorcaserin (1, 3, 5.6, 10 mg/kg) is prophylactic against audiogenic seizures (AGSs) in juvenile Fmr1 knockout mice, a mouse model of fragile X syndrome (FXS). MPEP (30 mg/kg), a non-competitive mGluR5 receptor antagonist, was used as a positive control. As lorcaserin likely engages 5-HT2ARs at therapeutic doses, we pretreated one group of mice with the selective 5-HT2AR antagonist/inverse agonist, M100907 (0.03 mg/kg), alone or before administering lorcaserin (5.6 mg/kg), to discern putative contributions of 5-HT2ARs to AGSs. We also assessed lorcaserin's in vitro pharmacology at human (h) and mouse (m) 5-HT2CRs and 5-HT2ARs and its in vivo interactions at m5-HT2CRs and m5-HT2ARs. MPEP significantly decreased AGS prevalence (P = 0.011) and lethality (P = 0.038). Lorcaserin, 3 mg/kg, attenuated AGS prevalence and lethality by 14 % and 32 %, respectively, however, results were not statistically significant (P = 0.5 and P = 0.06); other doses and M100907 alone or with lorcaserin also did not significantly affect AGSs. Lorcaserin exhibited full efficacy agonist activity at h5-HT2CRs and m5-HT2CRs, and near full efficacy agonist activity at h5-HT2ARs and m5-HT2ARs; selectivity for activation of 5-HT2CRs over 5-HT2ARs was greater for human (38-fold) compared to mouse (13-fold) receptors. Lorcaserin displayed relatively low affinities at antagonist-labeled 5-HT2CRs and 5-HT2ARs, regardless of species. Lorcaserin (3 and 5.6 mg/kg) increased the 5-HT2AR-dependent head-twitch response (HTR) elicited by (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) in mice (P = 0.03 and P = 0.02). At 3 mg/kg, lorcaserin alone did not elicit an HTR. If mice were treated with the selective 5-HT2CR antagonist SB 242084 (0.5 or 1 mg/kg) plus lorcaserin (3 mg/kg), a significantly increased HTR was observed, relative to vehicle (P = 0.01 and P = 0.03), however, the HTR was much lower than what was elicited by DOI or DOI plus lorcaserin. Lorcaserin, 3 mg/kg, significantly reduced locomotor activity on its own, an effect reversed by SB 242084, and lorcaserin also dose-dependently reduced locomotor activity when administered prior to DOI (Ps<0.002). These data suggest that lorcaserin may engage 5-HT2CRs as well as 5-HT2ARs in mice at doses as low as 3 mg/kg. The similar activity at m5-HT2CRs and m5-HT2ARs suggests careful dosing of lorcaserin is necessary to selectively engage 5-HT2CRs in vivo. In conclusion, lorcaserin was ineffective at preventing AGSs in Fmr1 knockout mice. Lorcaserin may not be a suitable pharmacotherapy for seizures in FXS.
| S-EPMC8296307 | biostudies-literature