Suppression of Akt-mTOR pathway rescued the social behavior in Cntnap2-deficient mice

Xing, Xiao-Liang; Zhang, Jing; Wu, Kunyang; Cao, Bangwei; Li, Xianfeng; Jiang, Fang; Hu, Zhengmao; Xia, Kun; Li, Jia‐Da

doi:10.1038/s41598-019-39434-5

Cited by 49 publications

(50 citation statements)

References 44 publications

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“…The adverse changes in brain metabolism in offspring from obese dams include altered mammalian target of rapamycin (mTOR) signalling in the rat hypothalamus [ 79 ] and in the mouse hippocampus [ 97 ]. Dysregulation of mTOR signalling has been implicated in memory formation [ 104 , 105 ], developmental disorders such as autism spectrum disorder [ 106 , 107 ] and mood disorders [ 108 ]. mTOR signalling and proinflammatory mediators such as IL1β and TNFα have a reciprocal relationship and together maintain innate immune homeostasis [ 109 , 110 ].…”

Section: Underlying Mechanisms By Which Maternal Obesity Programs mentioning

confidence: 99%

Mechanisms Underlying the Cognitive and Behavioural Effects of Maternal Obesity

2021

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The widespread consumption of ‘western’-style diets along with sedentary lifestyles has led to a global epidemic of obesity. Epidemiological, clinical and preclinical evidence suggests that maternal obesity, overnutrition and unhealthy dietary patterns programs have lasting adverse effects on the physical and mental health of offspring. We review currently available preclinical and clinical evidence and summarise possible underlying neurobiological mechanisms by which maternal overnutrition may perturb offspring cognitive function, affective state and psychosocial behaviour, with a focus on (1) neuroinflammation; (2) disrupted neuronal circuities and connectivity; and (3) dysregulated brain hormones. We briefly summarise research implicating the gut microbiota in maternal obesity-induced changes to offspring behaviour. In animal models, maternal obesogenic diet consumption disrupts CNS homeostasis in offspring, which is critical for healthy neurodevelopment, by altering hypothalamic and hippocampal development and recruitment of glial cells, which subsequently dysregulates dopaminergic and serotonergic systems. The adverse effects of maternal obesogenic diets are also conferred through changes to hormones including leptin, insulin and oxytocin which interact with these brain regions and neuronal circuits. Furthermore, accumulating evidence suggests that the gut microbiome may directly and indirectly contribute to these maternal diet effects in both human and animal studies. As the specific pathways shaping abnormal behaviour in offspring in the context of maternal obesogenic diet exposure remain unknown, further investigations are needed to address this knowledge gap. Use of animal models permits investigation of changes in neuroinflammation, neurotransmitter activity and hormones across global brain network and sex differences, which could be directly and indirectly modulated by the gut microbiome.

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Section: Underlying Mechanisms By Which Maternal Obesity Programs mentioning

confidence: 99%

Mechanisms Underlying the Cognitive and Behavioural Effects of Maternal Obesity

2021

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“…In the TRIM32 -/model, the authors generated impaired GABAergic interneurons and leading autism relevant behaviors in mice, concomitant with an increased autophagy mechanism. Therefore, they suggested that theTRIM32 -/mouse is a novel autism mouse model [84] .…”

Section: Mtor Related Modelsmentioning

confidence: 99%

Animal models of autism: a perspective from autophagy mechanisms

Dana¹,

Tahtasakal²,

Şener³

2020

jtgg

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Autism spectrum disorder (ASD) is characterized by impairments in social interaction and the presence of stereotypy and restrictive behavior. The clinical heterogeneity of ASD makes it difficult to explain the mechanisms underlying the disease. In recent years, the association between autophagy and neuropsychiatric diseases has been investigated. In this review, we aimed elucidate the relationship between autism and autophagy mechanism in well-known autism relevant animal models. Autophagy is a cell-protective mechanism that allows cell survival in low nutrient conditions, often through the degradation of aging and damaged proteins and organelles. The target of rapamycin (TOR) complex is activated for the activation of autophagy. Apart from mTOR animal models, the valproic acid model is frequently used in autism studies. The coiled-coil and C2 domain containing 1A (CC2D1A) gene is one of the new candidate genes associated with ASD. In a recent study that used Cc2d1a knockout mice, microtubule-associated protein 1A/1B-light chain 3 (LC3) and Beclin 1 expression levels were dysregulated in the hippocampus. It is thought that the impaired autophagy mechanism contributes to the etiology of ASD. These results showed that CC2D1A acts as a new biological pathway in autophagy. Choosing the right model is crucial for ASD studies, and further progress will be made as these results become available in the clinic. In particular, it is expected that further studies on CC2D1A will provide new information in this field.

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“…Abnormal phenotypes in mouse models relevant to ASD have reportedly been improved by statins 9 , Akt/mTOR inhibitors 10 , mGlu5 receptor negative allosteric modulators 11 , mGlu5 receptor positive allosteric modulators 12 , 13 , and GABA-B receptor agonists 14 – 16 . However, these findings have not translated successfully to clinical trials 17 – 19 ; see also 20 .…”

Section: Introductionmentioning

confidence: 99%

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions

Mitchell

Thomson

Openshaw

et al. 2020

Sci Rep

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There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT 1B/1D/1F receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data suggest that 16p11.2 DEL mice show an autism-relevant phenotype that becomes overt after an acute stressor, emphasising the importance of gene-environmental interactions in phenotypic analysis. Further, they add to an emerging view that NAC, or 5-HT 1B/1D/1F receptor agonist treatment, may be a promising strategy for further investigation as a future treatment. Autism is extremely common, affecting males more than females (estimated to affect roughly 4/1,000 boys and 1/1,000 girls) 1,2 , and characterised by communication difficulties, social dysfunction, and repetitive or restricted behaviour patterns, with a high rate of comorbid conditions such as anxiety. There are no available drug treatments for autism. Development of improved treatments will only be enabled by increased understanding of the causes of the disease and how they impact on neurobiology, informed by better preclinical models of facets of the disease. The genetic architecture of autism is complex 3. While a large number of common sequence variations increase disease risk, each has only a very small effect individually, and it is the cumulative burden of a range of risk, and protective, gene variants that underlies the aetiological mechanisms ultimately resulting in the manifestation of the common, sporadic disease. However, it is now clear that very rare copy number variants (CNVs), where small numbers of genes are present in one or three, rather than two, copies, substantially increase disease risk. For example, carriers of the deletions of the 16p11.2 locus have dramatically increased risk of autism-spectrum disorders (ASD) and also intellectual disability (8-40x) 4-6. Interestingly, a high proportion of carriers of the corresponding 16p11.2 duplication develop schizophrenia, suggesting that studying the neurobiological impact of CNVs at this locus may be particularly informative. The 16p11.2 deletion is one of the most powerful genetic risk factors for autism 3. Various drug classes have been tested in mouse models relevant to ASD, for efficacy in reversing behavioural...

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Suppression of Akt-mTOR pathway rescued the social behavior in Cntnap2-deficient mice

Cited by 49 publications

References 44 publications

Mechanisms Underlying the Cognitive and Behavioural Effects of Maternal Obesity

Mechanisms Underlying the Cognitive and Behavioural Effects of Maternal Obesity

Animal models of autism: a perspective from autophagy mechanisms

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions

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