Brain Lateralization in Mice Is Associated with Zinc Signaling and Altered in Prenatal Zinc Deficient Mice That Display Features of Autism Spectrum Disorder

Grabrucker, Stefanie; Haderspeck, Jasmin; Sauer, Ann Katrin; Kittelberger, Nadine; Asoglu, Harun; Abaei, Alireza; Rasche, Volker; Schön, Michael P.; Boeckers, Tobias M.; Grabrucker, Andreas M.

doi:10.3389/fnmol.2017.00450

Cited by 33 publications

(31 citation statements)

References 74 publications

(111 reference statements)

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“…Peça et al (2011) reported an enlarged striatum earlier in the same model. An increased striatal volume in the PZD model was already reported by us earlier with a different analysis method (Grabrucker et al, 2018). It can be concluded that basal ganglia enlargement is a common phenomenon in PZD mice and SHANK3 deficiency, however, it might be dosage-dependent of the remaining isoforms.…”

Section: Discussionsupporting

confidence: 73%

“…The PZD model has been shown to display a reduction of excitatory synapses in this area (Grabrucker et al, 2014), where zinc was also shown to interact with SHANK3 at the postsynaptic density. Further, an altered brain lateralization, which among others, affects the dopaminergic transmission in the striatum of these mice was reported (Grabrucker et al, 2018). On behavioral level, this correlates with stereotyped repetitive behaviors such as abnormal circling and altered marble burying that has been reported in PZD mice (Grabrucker et al, 2016), but also other ASD mouse models.…”

Section: Discussionmentioning

confidence: 90%

“…TBV and striatum in PZD mice were already analyzed by Grabrucker et al (2018) however, with a different anaylsis tool, which resulted in slightly different anatomical boundaries.…”

Section: Methodsmentioning

confidence: 99%

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Shank3 Transgenic and Prenatal Zinc-Deficient Autism Mouse Models Show Convergent and Individual Alterations of Brain Structures in MRI

Schoen

Asoglu

Bauer

et al. 2019

Front. Neural Circuits

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Research efforts over the past decades have unraveled both genetic and environmental factors, which contribute to the development of autism spectrum disorders (ASD). It is, to date, largely unknown how different underlying causes result in a common phenotype. However, the individual course of development and the different comorbidities might reflect the heterogeneous genetic and non-genetic contributions. Therefore, it is reasonable to identify commonalities and differences in models of these disorders at the different hierarchical levels of brain function, including genetics/environment, cellular/synaptic functions, brain regions, connectivity, and behavior. To that end, we investigated Shank3 transgenic mouse lines and compared them with a prenatal zinc-deficient (PZD) mouse model of ASD at the level of brain structural alterations in an 11,7 T small animal magnetic resonance imaging (MRI). Animals were measured at 4 and 9 weeks of age. We identified a decreased total brain volume (TBV) and hippocampal size of Shank3 −/− mice but a convergent increase of basal ganglia (striatum and globus pallidus) in most mouse lines. Moreover, Shank3 transgenic mice had smaller thalami, whereas PZD mice had this region enlarged. Intriguingly, Shank3 heterozygous knockout mice mostly showed minor abnormalities to full knockouts, which might reflect the importance of proper Shank3 dosage in neuronal cells. Most reported volume changes seemed to be more pronounced at younger age. Our results indicate both convergent and divergent brain region abnormalities in genetic and non-genetic models of ASD. These alterations of brain structures might be mirrored in the reported behavior of both models, which have not been assessed in this study.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 90%

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Shank3 Transgenic and Prenatal Zinc-Deficient Autism Mouse Models Show Convergent and Individual Alterations of Brain Structures in MRI

Schoen

Asoglu

Bauer

et al. 2019

Front. Neural Circuits

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“…Our finding in WT mice that shows mostly bilateral CAPs is in line with this observation. On the other hand, in mouse models of autism spectrum disorder, brain lateralization, especially in the striatum, has been reported using MRI and immunohistochemistry (Grabrucker et al 2018). Therefore, right-lateralization of prominent CAPs in TG mice is an interesting finding that needs to be further investigated.…”

Section: Resting-state Markers Of Alzheimer's Diseasementioning

confidence: 98%

Resting-state Co-activation Patterns as Accurate Predictors of Alzheimer’s Disease in Aged Mice

Adhikari

Belloy

Linden

et al. 2020

Preprint

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Alzheimer′s disease (AD), a neurodegenerative disorder marked by accumulation of extracellular amyloid-beta plaques leads to progressive loss of memory and cognitive function. Resting state fMRI (RS-fMRI) studies have provided links between these two observations in terms of disruption of default mode and task positive resting state networks (RSNs). Important insights underlying these disruptions were recently obtained by investigating dynamic fluctuations in RS-fMRI signals in old TG2576 mice (mouse model of amyloidosis) using a set of quasi-periodic patterns (QPP). QPPs represent repeating spatiotemporal patterns of neural activity of predefined temporal length. In this article, we used an alternative methodology of co-activation patterns (CAPs) that represent instantaneous and transient brain configurations that are likely contributors to the emergence of commonly observed resting state networks (RSNs) and QPPs. We followed a recently published approach for obtaining CAPs that divided all time frames, instead of those corresponding to supra-threshold activations of a seed region as done traditionally, to extract CAPs from RS-fMRI recordings in 10 TG2576 female mice and 8 wild type littermates at 18 months of age. Subsequently, we matched the CAPs from the two groups using the Hungarian method and compared the temporal (duration, occurrence rate) and the spatial (lateralization of significantly activated voxels) properties of matched CAPs. We found robust differences in the spatial components of matched CAPs. Finally, we used supervised learning to train a classifier using either the temporal or the spatial component of CAPs to distinguish the transgenic mice from the WT. We found that while duration and occurrence rates of all CAPs performed the classification with significantly higher accuracy than the chance-level, blood oxygen level dependent (BOLD) signals of significantly activated voxels from individual CAPs turned out to be a significantly better predictive feature demonstrating a near perfect classification accuracy. Our results demonstrate resting-state co-activation patterns are a promising candidate for a diagnostic, and potentially, prognostic biomarker of Alzheimer′s disease.

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“…Two animal models of ASD involved abnormalities in Zn metabolism and demonstrate abnormalities in brain development. The prenatal Zn-deficient mouse model of ASD demonstrates enlargement of the thalamus 43 and striatum 44 , and an absence of lateralization of dopamine receptor 1 in the striatum 44 . Male Zn transporter 3 null mice demonstrate ASD-type behaviors and increased cortical volume and neurite density 45 .…”

Section: The Importance Of Copper and Zinc Metabolismmentioning

confidence: 99%

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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Brain Lateralization in Mice Is Associated with Zinc Signaling and Altered in Prenatal Zinc Deficient Mice That Display Features of Autism Spectrum Disorder

Cited by 33 publications

References 74 publications

Shank3 Transgenic and Prenatal Zinc-Deficient Autism Mouse Models Show Convergent and Individual Alterations of Brain Structures in MRI

Shank3 Transgenic and Prenatal Zinc-Deficient Autism Mouse Models Show Convergent and Individual Alterations of Brain Structures in MRI

Resting-state Co-activation Patterns as Accurate Predictors of Alzheimer’s Disease in Aged Mice

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

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