Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: Reduced social interaction and attenuated response to novelty.
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ABSTRACT:
SUBMITTER: Ohashi R
PROVIDER: S-EPMC4749962 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aims: Synaptic Ras GTPase-activating protein 1 (SYNGAP1) regulates synaptic plasticity through AMPA receptor trafficking. SYNGAP1 mutations have been found in human patients with intellectual disability (ID) and autism spectrum disorder (ASD). Almost every individual with SYNGAP1-related ID develops epilepsy, and approximately 50% have ASD. SYNGAP1-related ID is estimated to account for at least 1% of ID cases. In mouse models with Syngap1 mutations, strong cognitive and affective dysfunctions have been reported, yet some findings are inconsistent across studies. To further understand the behavioral significance of the SYNGAP1 gene, we assessed various domains of behavior in Syngap1 heterozygous mutant mice using a behavioral test battery.Methods: Male mice with a heterozygous mutation in the Syngap1 gene (Syngap1-/+ mice) created by Seth Grant's group were subjected to a battery of comprehensive behavioral tests, which examined general health, and neurological screens, rotarod, hot plate, open field, light/dark transition, elevated plus maze, social interaction, prepulse inhibition, Porsolt forced swim, tail suspension, gait analysis, T-maze, Y-maze, Barnes maze, contextual and cued fear conditioning, and home cage locomotor activity. To control for type I errors due to multiple-hypothesis testing, P-values below the false discovery rate calculated by the Benjamini-Hochberg method were considered as study-wide statistically significant.Results: Syngap1-/+ mice showed increased locomotor activity, decreased prepulse inhibition, and impaired working and reference spatial memory, consistent with preceding studies. Impairment of context fear memory and increased startle reflex in Syngap1 mutant mice could not be reproduced. Significant decreases in sensitivity to painful stimuli and impaired motor function were observed in Syngap1-/+ mice. Decreased anxiety-like behavior and depression-like behavior were noted, although increased locomotor activity is a potential confounding factor of these phenotypes. Increased home cage locomotor activity indicated hyperlocomotor activity not only in specific behavioral test conditions but also in familiar environments.Conclusion: In Syngap1-/+ mice, we could reproduce most of the previously reported cognitive and emotional deficits. The decreased sensitivity to painful stimuli and impaired motor function that we found in Syngap1-/+ mice are consistent with the common characteristics of patients with SYNGAP-related ID. We further confirmed that the Syngap1 heterozygote mouse recapitulates the symptoms of ID and ASD patients.
| S-EPMC7292322 | biostudies-literature
Project description:DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinA(ΔE)). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinA(ΔE) does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia.
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Project description:FOXG1 Syndrome (FS) is a devastating neurodevelopmental disorder that is caused by a heterozygous loss-of-function (LOF) mutation of the FOXG1 gene, which encodes a transcriptional regulator important for telencephalic brain development. People with FS have marked developmental delays, impaired ambulation, movement disorders, seizures, and behavior abnormalities including autistic features. Current therapeutic approaches are entirely symptomatic, however the ability to rescue phenotypes in mouse models of other genetic neurodevelopmental disorders such as Rett syndrome, Angelman syndrome, and Phelan-McDermid syndrome by postnatal expression of gene products has led to hope that similar approaches could help modify the disease course in other neurodevelopmental disorders such as FS. While FoxG1 protein function plays a critical role in embryonic brain development, the ongoing adult expression of FoxG1 and behavioral phenotypes that present when FoxG1 function is removed postnatally provides support for opportunity for improvement with postnatal treatment. Here we generated a new mouse allele of Foxg1 that disrupts protein expression and characterized the behavioral and structural brain phenotypes in heterozygous mutant animals. These mutant animals display changes in locomotor behavior, gait, anxiety, social interaction, aggression, and learning and memory compared to littermate controls. Additionally, they have structural brain abnormalities reminiscent of people with FS. This information provides a framework for future studies to evaluate the potential for post-natal expression of FoxG1 to modify the disease course in this severe neurodevelopmental disorder.
| S-EPMC9555627 | biostudies-literature
Project description:MAGEL2 is one of five protein-coding, maternally imprinted, paternally expressed genes in the Prader-Willi syndrome (PWS)-critical domain on chromosome 15q11-q13. Truncating pathogenic variants of MAGEL2 cause Schaaf-Yang syndrome (SHFYNG) (OMIM #615547), a neurodevelopmental disorder related to PWS. Affected individuals manifest a spectrum of neurocognitive and behavioral phenotypes, including intellectual disability and autism spectrum disorder (ASD). Magel2 knockout mice carrying a maternally inherited, imprinted wild-type (WT) allele and a paternally inherited Magel2-lacZ knock-in allele, which abolishes endogenous Magel2 gene function, exhibit several features reminiscent of the human Prader-Willi phenotypes, including neonatal growth retardation, excessive weight gain after weaning and increased adiposity in adulthood. They were shown to have altered circadian rhythm, reduced motor activity and reduced fertility. An extensive assessment for autism-like behaviors in this mouse model was warranted, because of the high prevalence of ASD in human patients. The behavior of Magel2 knockout mice and their WT littermates were assayed via open field, elevated plus maze, tube, three-chamber and partition tests. Our studies confirm decreased horizontal activity of male and female mice and increased vertical activity of females, in the open field. Both sexes spent more time in the open arm of the elevated plus maze, suggestive of reductions in anxiety. Both sexes displayed a lack of preference for social novelty, via a lack of discrimination between known and novel partners in the partition test. The in-depth investigation of behavioral profiles caused by Magel2 loss-of-function helps to elucidate the etiology of behavioral phenotypes both for SHFYNG and PWS in general.
| S-EPMC5495607 | biostudies-literature
Project description:Early life experience profoundly impacts behavior and cognitive functions in rats. The present study investigated how the presence of conspecifics and/or novel objects, could independently influence individual differences in impulsivity and behavioral flexibility. Twenty-four rats were reared in an isolated condition, an isolated condition with a novel object, a pair-housed social condition, or a pair-housed social condition with a novel object. The rats were then tested on an impulsive choice task, a behavioral flexibility task, and an impulsive action task. Novelty enrichment produced an overall increase in impulsive choice, while social enrichment decreased impulsive choice in the absence of novelty enrichment and also produced an overall increase in impulsive action. In the behavioral flexibility task, social enrichment increased regressive errors, whereas both social and novelty enrichment reduced never-reinforced errors. Individual differences analyses indicated a significant relationship between performance in the behavioral flexibility and impulsive action tasks, which may reflect a common psychological correlate of action inhibition. Moreover, there was a relationship between delay sensitivity in the impulsive choice task and performance on the DRL and behavioral flexibility tasks, suggesting a dual role for timing and inhibitory processes in driving the interrelationship between these tasks. Overall, these results indicate that social and novelty enrichment produce distinct effects on impulsivity and adaptability, suggesting the need to parse out the different elements of enrichment in future studies. Further research is warranted to better understand how individual differences in sensitivity to enrichment affect individuals' interactions with and the resulting consequences of the rearing environment.
| S-EPMC5473952 | biostudies-literature
Project description:BACKGROUND: Calpastatin is an endogenous inhibitor of calpain, intracellular calcium-activated protease. It has been suggested to be involved in molecular mechanisms of long-term plasticity and excitotoxic pathways. However, functions of calpastatin in vivo are still largely unknown. To examine the physiological roles of calpastatin, we subjected calpastatin-knockout mice to a comprehensive behavioral test battery. RESULTS: Calpastatin-knockout mice showed decreased locomotor activity under stressful environments, and decreased acoustic startle response, but we observed no significant change in hippocampus-dependent memory function. CONCLUSION: These results suggest that calpastatin is likely to be more closely associated with affective rather than cognitive aspects of brain function.
| S-EPMC2561015 | biostudies-literature
Project description:Impairment in social communication skills is a hallmark feature of autism spectrum disorder (ASD). The role of G-protein coupled receptor 158 (GPR158) in ASD remains largely unexplored. In this study, we observed both constitutive and cell/tissue-specific knockouts of Gpr158 in pyramidal neurons or medial prefrontal cortex (mPFC) result in impaired novelty preference, while sociability remains unaffected in male mice. Notably, loss of GPR158 leads to a significant decline in excitatory synaptic transmission, characterized by the reduction in glutamate vesicles, as well as the expression and phosphorylation of GluN2B in the mPFC. We successfully rescue the phenotype of social novelty deficits either by reintroducing GPR158 in the mPFC of Gpr158 deficient mice or by chemogenetic activation of pyramidal neurons where Gpr158 is specifically ablated. Our findings indicate that GPR158 in pyramidal neurons plays a specific role in modulating social novelty, and may represent a potential target for treating social disorder.
2024-09-04 | GSE276304 | GEO
Project description:To study the functions of 5-HT4 receptors, a null mutation was engineered in the corresponding gene. 5-HT4 receptor knock-out mice displayed normal feeding and motor behaviors in baseline conditions but abnormal feeding and locomotor behavior in response to stress and novelty. Specifically, stress-induced hypophagia and novelty-induced exploratory activity were attenuated in the knock-out mice. In addition, pentylenetetrazol-induced convulsive responses were enhanced in the knock-out mice, suggesting an increase in neuronal network excitability. These results provide the first example of a genetic deficit that disrupts the ability of stress to reduce feeding and body weight and suggest that 5-HT4 receptors may be involved in stress-induced anorexia and seizure susceptibility.
| S-EPMC6729986 | biostudies-literature
Project description:Aim: Indoleamine 2,3-dioxygenase 1 (IDO1) metabolizes the essential amino acid tryptophan into kynurenine derivatives, which are involved in neural activity via the kynurenine pathway (KP). IDO1 is an initial rate-limiting enzyme in the KP and is activated by stress and/or inflammation. The perturbation of IDO1 activity, which causes KP imbalance, is associated with psychiatric and neurological disorders. It has been reported that wild-type (WT) mice under inflammatory conditions show increased anxiety-like behavior and decreased novel object recognition, whereas Ido1 knockout (KO) mice do not display these behaviors. However, the behavioral phenotypes of Ido1 KO mice have not yet been fully examined under non-inflammatory conditions.Methods: We subjected Ido1 KO mice to a comprehensive behavioral test battery under normal conditions.Results: Ido1 KO mice and WT mice showed similar locomotor activity, anxiety-like behavior, social behavior, depression-like behavior, and fear memory. In the T-maze test, Ido1 KO mice exhibited weak but nominally significant impairment in the working memory task of the T-maze, but this result failed to reach study-wide significance.Conclusions: Ido1 KO mice did not show any clear behavioral abnormalities under normal conditions. Further studies may be necessary to investigate their behavioral phenotype under inflammatory conditions due to their known roles in inflammation.
| S-EPMC7292290 | biostudies-literature
Project description:Accumulating evidence from human genetic studies implicates the pituitary adenylate cyclase-activating polypeptide (PACAP) gene as a risk factor for psychiatric disorders, including schizophrenia and stress-related diseases. Mice with homozygous disruption of the PACAP gene display profound behavioral and neurological abnormalities that are ameliorated with the atypical antipsychotic and dopamine D2 and serotonin (5-HT)2 antagonist risperidone and the 5-HT2 receptor antagonist ritanserin; however, the underlying mechanisms remain unknown. Here, we investigated if PACAP heterozygous mutant (PACAP(+/-)) mice, which appear behaviorally normal, are vulnerable to aversive stimuli. PACAP(+/-) mice were administered a 5-HT2 receptor agonist, (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), a hallucinogenic drug, and their responses were compared with the littermate wild-type mice. After DOI injection, PACAP(+/-) mice showed increased head-twitch responses, while their behavior was normal after saline. DOI induced deficits in sensorimotor gating, as determined by prepulse inhibition, specifically in PACAP(+/-) mice. However, other 5-HT2 receptor-dependent responses, such as corticosterone release and hypothermia, were similarly observed in PACAP(+/-) and wild-type mice. c-Fos expression analysis, performed in various brain regions, revealed that the DOI-induced increase in the number of c-Fos-positive cells was more pronounced in 5-HT2A receptor-negative cells in the somatosensory cortex in PACAP(+/-) mice compared with wild-type mice. These results indicate that PACAP(+/-) mice exhibit specific vulnerability to DOI-induced deficits in cortical sensory function, such as exaggerated head-twitch responses and sensorimotor gating deficits. Our findings provide insight into the neural mechanisms underlying impaired behavioral responses in which 5-HT2 receptors are implicated.
| S-EPMC3930680 | biostudies-literature