Dietary Zinc Supplementation Prevents Autism Related Behaviors and Striatal Synaptic Dysfunction in Shank3 Exon 13–16 Mutant Mice

Fourie, Chantelle; Vyas, Yukti; Lee, Kevin; Jung, Yewon; Garner, Craig C.; Montgomery, Johanna M.

doi:10.3389/fncel.2018.00374

Cited by 53 publications

(100 citation statements)

References 73 publications

(136 reference statements)

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“…These activity and social specificities are consistent with the results of previous studies using the same mutant mouse strain (de Chaumont et al, 2019;Vicidomini et al, 2016). Other genetic models of Shank3 mutant mice also display reduced social interest (Shank3-KO ex4-9: (Bozdagi et al, 2010;Wang et al, 2011;Yang et al, 2012); Shank3-KO in ex21: (Duffney et al, 2015); Shank3 ex4-9: (Jaramillo et al, 2016); Shank3-cKI: (Mei et al, 2016); Shank3 exon 4-22 complete KO: (Wang et al, 2016); Shank3B: (Balaan et al, 2019); Shank3 exon 13-16: (Fourie et al, 2018;Peca et al, 2011); Shank3B +/-: (Orefice et al, 2019;Pagani et al, 2019)). Nevertheless, other models failed to detect any atypical social interest in Shank3 mutant mice (Shank3-KO ex4-9: (Drapeau et al, 2014); Shank3-KO ex9: (Lee et al, 2015); Shank3-KO ex 21: (Kouser et al, 2013); Shank3-KO and HZ in ex21: (Speed et al, 2015); Shank3-KO ex11-21 rat model: (Song et al, 2019); conditional Shank3 exon 4-22 knockout in forebrain, striatum, and striatal D1 and D2 cells: (Bey et al, 2018); Shank3 +/Q321R and Shank3 Q321R/Q321R : (Yoo et al, 2019)).…”

Section: Subtle Social Communication Abnormalities In Shank3 Mutant Micesupporting

confidence: 89%

Spontaneous social communication in laboratory mice - placing ultrasonic vocalizations in their behavioral context

Chaumont

Bourgeron

2020

Preprint

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AbstractIn their natural habitat, mice interact and communicate to regulate major functions, such as reproduction, group coordination, and protection. Nevertheless, little is currently known about their spontaneous emission of ultrasonic vocalizations (USVs), despite their broad use as a phenotypic marker in mouse models of neuropsychiatric disorders. Here, we investigated mouse spontaneous communication by coupling automatic recording, segmentation, and analysis of USVs to the tracking of complex behaviors. We continuously recorded undisturbed same-sex pairs of C57BL/6J males and females at 5 weeks and 3 and 7 months of age over three days. Males emitted only a few short USVs, mainly when isolated from their conspecific, whereas females emitted a high number of USVs, especially when engaged in intense dynamic social interactions. The context-specific use of call types and acoustic variations emerged with increasing age. The emission of USVs also reflected a high level of excitement in social interactions. Finally, mice lacking Shank3, a synaptic protein associated with autism, displayed atypical USV usage and acoustic structure, which did not appear in classical protocols, highlighting the importance of studying spontaneous communication. The methods are freely available for the research community (https://usv.pasteur.cloud).

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Section: Subtle Social Communication Abnormalities In Shank3 Mutant Micesupporting

confidence: 89%

Spontaneous social communication in laboratory mice - placing ultrasonic vocalizations in their behavioral context

Chaumont

Bourgeron

2020

Preprint

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“…In comparison to SHANK1 and SHANK2 mutations, ASD-associated SHANK3 mutations are highly penetrant and more extensively studied. Several lines of Shank3 mutant mice have been created with germline deletions of Shank3 exons encoding different Shank protein domains, however, these Shank3 −/− models consistently present deficits in social interactions and heightened self-grooming [ 10 , 21 , 33 , 36 , 50 , 57 , 65 , 66 , 70 , 72 , 73 ]. Shank3 −/− mice display glutamatergic synaptic structural changes including reduced levels of PSD proteins such as synaptic Homer and SAPAP, and reduced expression of AMPAR and NMDAR subunits [ 33 , 50 , 57 , 65 , 66 , 73 ].…”

Section: Introductionmentioning

confidence: 99%

“…Shank3 is most abundantly expressed in the striatum, and electron microscopy examination of cortico-striatal synapses onto medium spiny neurons (MSNs) demonstrated reduced PSD thickness and length, and reduced spine density [ 50 ]. Functionally, Shank3 −/− mice display impaired striatal synaptic transmission [ 21 , 33 , 50 , 65 , 73 ], and reduced hippocampal CA1 synaptic transmission is evident in some Shank3 −/− mouse models [ 10 , 41 , 59 , 70 ], but not in others [ 50 , 66 ]. Overall, Shank3 mutations negatively impact synapse physiology.…”

Section: Introductionmentioning

confidence: 99%

Influence of maternal zinc supplementation on the development of autism-associated behavioural and synaptic deficits in offspring Shank3-knockout mice

et al. 2020

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Autism Spectrum Disorders (ASD) are characterised by deficits in social interactions and repetitive behaviours. Multiple ASD-associated mutations have been identified in the Shank family of proteins that play a critical role in the structure and plasticity of glutamatergic synapses, leading to impaired synapse function and the presentation of ASD-associated behavioural deficits in mice. Shank proteins are highly regulated by zinc, where zinc binds the Shank SAM domain to drive synaptic protein recruitment and synaptic maturation. Here we have examined the influence of maternal dietary zinc supplementation during pregnancy and lactation on the development of ASD-associated behavioural and synaptic changes in the offspring Shank3 knockout ( Shank3 −/− ) mice. Behavioural and electrophysiological experiments were performed in juvenile and adult Shank3 −/− and wildtype littermate control mice born from mothers fed control (30 ppm, ppm) or supplemented (150 ppm) dietary zinc. We observed that the supplemented maternal zinc diet prevented ASD-associated deficits in social interaction and normalised anxiety behaviours in Shank3 −/− offspring mice. These effects were maintained into adulthood. Repetitive grooming was also prevented in adult Shank3 −/− offspring mice. At the synaptic level, maternal zinc supplementation altered postsynaptic NMDA receptor-mediated currents and presynaptic function at glutamatergic synapses onto medium spiny neurons in the cortico-striatal pathway of the Shank3 −/− offspring mice. These data show that increased maternal dietary zinc during pregnancy and lactation can alter the development of ASD-associated changes at the synaptic and the behavioural levels, and that zinc supplementation from the beginning of brain development can prevent ASD-associated deficits in Shank3 −/− mice long term.

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“…Prenatal Zn treatment protects the prenatal valproic acid 52 and lipopolysaccharide 53 exposure mouse models of ASD. Zn supplementation also prevents repetitive and anxiety behaviors in the Phelan-McDermid Syndrome mouse model of ASD 54 .…”

Section: The Importance Of Copper and Zinc Metabolismmentioning

confidence: 96%

Early life metal exposure dysregulates cellular bioenergetics in children with regressive autism spectrum disorder

et al. 2020

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Neurodevelopmental regression (NDR) is a subtype of autism spectrum disorder (ASD) that manifests as loss of previously acquired developmental milestones. Early life dysregulation of nutritional metals and/or exposure to toxic metals have been associated with ASD, but the underlying biological mechanisms by which metals influence neurodevelopment remain unclear. We hypothesize that metals influences neurodevelopment through dysregulation of bioenergetics. Prenatal and early postnatal metal exposures were measured using validated tooth-matrix biomarkers in 27 ASD cases (13 with NDR) and 7 typically-developing (TD) controls. Mitochondrial respiration and glycolysis were measured in peripheral blood mononuclear cells using the Seahorse XF96. Children with ASD demonstrated lower prenatal and postnatal Copper (Cu) and prenatal Nickel concentrations and Copper-to-Zinc (Cu/Zn) ratio as compared with TD children. Children with ASD and NDR showed greater metal-related disruption of cellular bioenergetics than children with ASD without NDR. For children with ASD and NDR mitochondrial respiration decreased as prenatal Manganese concentration increased and increased as prenatal Zinc concentration increased; glycolysis decreased with increased exposure to prenatal Manganese and Lead and postnatal Manganese. For children with ASD without a history of NDR, glycolysis increased with increased postnatal exposure to Tin. Language and communication scores in children with ASD were positively related to prenatal Cu exposure and Cu/Zn ratio. This study suggests that prenatal nutritional metals may be important for neurodevelopment in children with ASD, and that exposure to toxic metals and differences in nutritional metal exposures is associated with dysregulation of cellular bioenergetics, particularly in the NDR subtype of ASD.

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Dietary Zinc Supplementation Prevents Autism Related Behaviors and Striatal Synaptic Dysfunction in Shank3 Exon 13–16 Mutant Mice

Cited by 53 publications

References 73 publications

Spontaneous social communication in laboratory mice - placing ultrasonic vocalizations in their behavioral context

Spontaneous social communication in laboratory mice - placing ultrasonic vocalizations in their behavioral context

Influence of maternal zinc supplementation on the development of autism-associated behavioural and synaptic deficits in offspring Shank3-knockout mice

Early life metal exposure dysregulates cellular bioenergetics in children with regressive autism spectrum disorder

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