Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice

Molenhuis, Remco T.; Bruining, Hilgo; Remmelink, Esther; Visser, Leonie de; Loos, Maarten; Burbach, J. Peter H.; Kas, Martien

doi:10.1186/s11689-016-9140-2

Cited by 17 publications

(15 citation statements)

References 31 publications

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“…In this study, we compared cell surface expression levels of several glutamate and GABA receptors in ASD related brain region of three different ASD mouse models ( Shank2 −/− , Shank3 αβ −/− and Cntn4 −/− ) aiming on unraveling molecular abnormalities in excitatory and/or inhibitory signaling components which are common to all three mouse models. It is important to note that the mouse models used in this study differ with respect to their ASD-related behavior: Shank2 −/− and Shank3 αβ −/− mice clearly show repetitive, stereotyped behavior and deficits in social interactions, though in varying degrees (Schmeisser et al, 2012 ; Vicidomini et al, 2017 ; Monteiro and Feng, 2017 ), whereas ASD-related behavior in Cntn4 −/− has been less well characterized but appears to be much less pronounced (Molenhuis et al, 2016 ). Our data suggest that—as might have been expected—genetic deficiency of Shank2 and Shank3 yields relatively similar changes in cell surface glutamate and GABA receptor expression levels: on the whole, a downregulation of cell surface ionotropic glutamate receptor subunits (GluN1, GluA2 and GluA1) could be observed in several ASD-related brain regions (especially in the striatum and thalamus) whereas almost no changes in the expression of cell surface ionotropic GABA receptors was seen.…”

Section: Discussionmentioning

confidence: 84%

Heterogeneity of Cell Surface Glutamate and GABA Receptor Expression in Shank and CNTN4 Autism Mouse Models

Heise

Preuss

Schroeder

et al. 2018

Front. Mol. Neurosci.

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Autism spectrum disorder (ASD) refers to a large set of neurodevelopmental disorders, which have in common both repetitive behavior and abnormalities in social interactions and communication. Interestingly, most forms of ASD have a strong genetic contribution. However, the molecular underpinnings of this disorder remain elusive. The SHANK3 gene (and to a lesser degree SHANK2) which encode for the postsynaptic density (PSD) proteins SHANK3/SHANK2 and the CONTACTIN 4 gene which encodes for the neuronal glycoprotein CONTACTIN4 (CNTN4) exhibit mutated variants which are associated with ASD. Like many of the other genes associated with ASD, both SHANKs and CNTN4 affect synapse formation and function and are therefore related to the proper development and signaling capability of excitatory and inhibitory neuronal networks in the adult mammal brain. In this study, we used mutant/knock-out mice of Shank2 (Shank2−/−), Shank3 (Shank3αβ−/−), and Cntn4 (Cntn4−/−) as ASD-models to explore whether these mice share a molecular signature in glutamatergic and GABAergic synaptic transmission in ASD-related brain regions. Using a biotinylation assay and subsequent western blotting we focused our analysis on cell surface expression of several ionotropic glutamate and GABA receptor subunits: GluA1, GluA2, and GluN1 were analyzed for excitatory synaptic transmission, and the α1 subunit of the GABAA receptor was analyzed for inhibitory synaptic transmission. We found that both Shank2−/− and Shank3αβ−/− mice exhibit reduced levels of several cell surface glutamate receptors in the analyzed brain regions—especially in the striatum and thalamus—when compared to wildtype controls. Interestingly, even though Cntn4−/− mice also show reduced levels of some cell surface glutamate receptors in the cortex and hippocampus, increased levels of cell surface glutamate receptors were found in the striatum. Moreover, Cntn4−/− mice do not only show brain region-specific alterations in cell surface glutamate receptors but also a downregulation of cell surface GABA receptors in several of the analyzed brain regions. The results of this study suggest that even though mutations in defined genes can be associated with ASD this does not necessarily result in a common molecular phenotype in surface expression of glutamatergic and GABAergic receptor subunits in defined brain regions.

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Section: Discussionmentioning

confidence: 84%

Heterogeneity of Cell Surface Glutamate and GABA Receptor Expression in Shank and CNTN4 Autism Mouse Models

Heise

Preuss

Schroeder

et al. 2018

Front. Mol. Neurosci.

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“…Deficiency of ASD-risk gene Cntn4 in mice was found to cause no aberrations in autism-like behavior, but did affect sensory behavior and cognitive performance. 33 Elaboration of the set of behavioral experiments and including a set of experiments during the development, may bring a subtle behavioral phenotype to view. These data suggests that disruption of Cntn5 has no or limited influence on social, explorative and repetitive behavior in our mouse model.…”

Section: Discussionmentioning

confidence: 99%

Structural abnormalities in the primary somatosensory cortex and a normal behavioral profile in Contactin-5 deficient mice

Kleijer

Nieuwenhuize

Spierenburg

et al. 2017

Cell Adhesion & Migration

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Contactin-5 (Cntn5) is an immunoglobulin cell adhesion molecule that is exclusively expressed in the central nervous system. In view of its association with neurodevelopmental disorders, particularly autism spectrum disorder (ASD), this study focused on Cntn5-positive areas in the forebrain and aimed to explore the morphological and behavioral phenotypes of the Cntn5 null mutant (Cntn5−/−) mouse in relation to these areas and ASD symptomatology. A newly generated antibody enabled us to elaborately describe the spatial expression pattern of Cntn5 in P7 wild type (Cntn5+/+) mice. The Cntn5 expression pattern included strong expression in the cerebral cortex, hippocampus and mammillary bodies in addition to described previously brain nuclei of the auditory pathway and the dorsal thalamus. Thinning of the primary somatosensory (S1) cortex was found in Cntn5−/− mice and ascribed to a misplacement of Cntn5-ablated cells. This phenotype was accompanied by a reduction in the barrel/septa ratio of the S1 barrel field. The structure and morphology of the hippocampus was intact in Cntn5−/− mice. A set of behavioral experiments including social, exploratory and repetitive behaviors showed that these were unaffected in Cntn5−/− mice. Taken together, these data demonstrate a selective role of Cntn5 in development of the cerebral cortex without overt behavioral phenotypes.

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“… Molenhuis et al (2016) analyzed the development of neurological phenotypes in Cntn4-deficient mice at various developmental ages through an extended SHIRPA battery of tests. This study also included assessments for ASD-related behaviors such as the juvenile social interaction test, three-chamber social interaction test, novel object investigation task and the Barnes maze; however, Cntn4-deficiency was not observed to affect ASD-related behaviors ( Molenhuis et al, 2016 ). Compared to wild-type littermates, Cntn4-deficient mice did not show any further changes in grooming behavior, social interaction, sensorimotor coordination, or cognitive flexibility ( Molenhuis et al, 2016 ).…”

Section: Neurophysiological Roles Of Chl1 Cntn6 mentioning

confidence: 99%

“…This study also included assessments for ASD-related behaviors such as the juvenile social interaction test, three-chamber social interaction test, novel object investigation task and the Barnes maze; however, Cntn4-deficiency was not observed to affect ASD-related behaviors ( Molenhuis et al, 2016 ). Compared to wild-type littermates, Cntn4-deficient mice did not show any further changes in grooming behavior, social interaction, sensorimotor coordination, or cognitive flexibility ( Molenhuis et al, 2016 ). No defects in olfaction were observed in Cntn4-deficient mice, which is unexpected since Cntn4 has been found to play a role in the establishment of odor maps ( Kaneko-Goto et al, 2008 ).…”

Section: Neurophysiological Roles Of Chl1 Cntn6 mentioning

confidence: 99%

Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion Syndrome and Autism Spectrum Disorder

Gandawijaya

Bamford

Burbach

et al. 2021

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) is characterized by impaired social interaction, language delay and repetitive or restrictive behaviors. With increasing prevalence, ASD is currently estimated to affect 0.5–2.0% of the global population. However, its etiology remains unclear due to high genetic and phenotypic heterogeneity. Copy number variations (CNVs) are implicated in several forms of syndromic ASD and have been demonstrated to contribute toward ASD development by altering gene dosage and expression. Increasing evidence points toward the p-arm of chromosome 3 (chromosome 3p) as an ASD risk locus. Deletions occurring at chromosome 3p result in 3p-deletion syndrome (Del3p), a rare genetic disorder characterized by developmental delay, intellectual disability, facial dysmorphisms and often, ASD or ASD-associated behaviors. Therefore, we hypothesize that overlapping molecular mechanisms underlie the pathogenesis of Del3p and ASD. To investigate which genes encoded in chromosome 3p could contribute toward Del3p and ASD, we performed a comprehensive literature review and collated reports investigating the phenotypes of individuals with chromosome 3p CNVs. We observe that high frequencies of CNVs occur in the 3p26.3 region, the terminal cytoband of chromosome 3p. This suggests that CNVs disrupting genes encoded within the 3p26.3 region are likely to contribute toward the neurodevelopmental phenotypes observed in individuals affected by Del3p. The 3p26.3 region contains three consecutive genes encoding closely related neuronal immunoglobulin cell adhesion molecules (IgCAMs): Close Homolog of L1 (CHL1), Contactin-6 (CNTN6), and Contactin-4 (CNTN4). CNVs disrupting these neuronal IgCAMs may contribute toward ASD phenotypes as they have been associated with key roles in neurodevelopment. CHL1, CNTN6, and CNTN4 have been observed to promote neurogenesis and neuronal survival, and regulate neuritogenesis and synaptic function. Furthermore, there is evidence that these neuronal IgCAMs possess overlapping interactomes and participate in common signaling pathways regulating axon guidance. Notably, mouse models deficient for these neuronal IgCAMs do not display strong deficits in axonal migration or behavioral phenotypes, which is in contrast to the pronounced defects in neuritogenesis and axon guidance observed in vitro. This suggests that when CHL1, CNTN6, or CNTN4 function is disrupted by CNVs, other neuronal IgCAMs may suppress behavioral phenotypes by compensating for the loss of function.

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Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice

Cited by 17 publications

References 31 publications

Heterogeneity of Cell Surface Glutamate and GABA Receptor Expression in Shank and CNTN4 Autism Mouse Models

Heterogeneity of Cell Surface Glutamate and GABA Receptor Expression in Shank and CNTN4 Autism Mouse Models

Structural abnormalities in the primary somatosensory cortex and a normal behavioral profile in Contactin-5 deficient mice

Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion Syndrome and Autism Spectrum Disorder

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