<i>Gtf2i</i> and <i>Gtf2ird1</i> mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

Kopp, Nathan; McCullough, Katherine; Se, Maloney; Dougherty, Joseph D.

doi:10.1101/558544

Cited by 3 publications

(2 citation statements)

References 87 publications

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“…The marble burying test was chosen based on results previously obtained in the WBS model [32][33][34]. An open test arena (26 × 26 cm) was filled with bedding to a depth of 5 cm, and 20 glass marbles were placed on the surface following a regular pattern (5 rows of 4 marbles).…”

Section: Behavior: Marble-burying Testmentioning

confidence: 99%

Altered Neocortical Dynamics in a Mouse Model of Williams–Beuren Syndrome

et al. 2019

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Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by moderate intellectual disability and learning difficulties alongside behavioral abnormalities such as hypersociability. Several structural and functional brain alterations are characteristic of this syndrome, as well as disturbed sleep and sleeping patterns. However, the detailed physiological mechanisms underlying WBS are mostly unknown. Here, we characterized the cortical dynamics in a mouse model of WBS previously reported to replicate most of the behavioral alterations described in humans. We recorded the laminar local field potential generated in the frontal cortex during deep anesthesia and characterized the properties of the emergent slow oscillation activity. Moreover, we performed micro-electrocorticogram recordings using multielectrode arrays covering the cortical surface of one hemisphere. We found significant differences between the cortical emergent activity and functional connectivity between wild-type mice and WBS model mice. Slow oscillations displayed Up states with diminished firing rate and lower high-frequency content in the gamma range. Lower firing rates were also recorded in the awake WBS animals while performing a marble burying task and could be associated with the decreased spine density and thus synaptic connectivity in this cortical area. We also found an overall increase in functional connectivity between brain areas, reflected in lower clustering and abnormally high integration, especially in the gamma range. These results expand previous findings in humans, suggesting that the cognitive deficits characterizing WBS might be associated with reduced excitability, plus an imbalance in the capacity to functionally integrate and segregate information.

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Section: Behavior: Marble-burying Testmentioning

confidence: 99%

Altered Neocortical Dynamics in a Mouse Model of Williams–Beuren Syndrome

et al. 2019

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“…Here we use time spent sniffing the social cylinder and time spent sniffing the nonsocial cylinder as the main dependent variables of interest. In the Supporting Information, we also present time spent in chambers; time spent sniffing the social cylinder minus the time spent sniffing the nonsocial cylinder (which we will refer to as the "delta sniffing" variable) to control for variability in sniffing times 74,[88][89][90] ; and distance traveled, a measure of locomotor activity.…”

Section: Novel Object and Novel Mouse Placement Side (Left Or Right Cmentioning

confidence: 99%

Sociability development in mice with cell‐specific deletion of the NMDA receptor NR1 subunit gene

Ferri

Pallathra

Kim

et al. 2019

Genes Brain and Behavior

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Social affiliative behavior is an important component of everyday life in many species and is likely to be disrupted in disabling ways in various neurodevelopmental and neuropsychiatric disorders. Therefore, determining the mechanisms involved in these processes is crucial. A link between N-methyl-D-aspartate (NMDA) receptor function and social behaviors has been clearly established. The cell types in which NMDA receptors are critical for social affiliative behavior, however, remain unclear. Here, we use mice carrying a conditional allele of the NMDA R1 subunit to address this question. Mice bearing a floxed NMDAR1 (NR1) allele were crossed with transgenic calcium/calmodulin-dependent kinase IIα (CaMKIIα)-Cre mice or parvalbumin (PV)-Cre mice targeting postnatal excitatory forebrain or PVexpressing interneurons, respectively, and assessed using the three-chambered Social Approach Test. We found that deletion of NR1 in PV-positive interneurons had no effect on social sniffing, but deletion of NR1 in glutamatergic pyramidal cells resulted in a significant increase in social approach behavior, regardless of age or sex. Therefore, forebrain excitatory neurons expressing NR1 play an important role in regulating social affiliative behavior.

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Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA-binding, and long term behavioral consequences

Kopp¹,

Nygaard²,

McCullough³

et al. 2019

Preprint

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AbstractGtf2ird1 and Gtf2i may mediate aspects of the cognitive and behavioral phenotypes of Williams Syndrome (WS) – a microdeletion syndrome encompassing these transcription factors (TFs). Knockout mouse models of each TF show behavioral phenotypes. Here we identify their genomic binding sites in the developing brain, and test for additive effects of their mutation on transcription and behavior. Both TFs target constrained chromatin modifier and synaptic protein genes, including a significant number of ASD genes. They bind promoters, strongly overlap CTCF binding and TAD boundaries, and moderately overlap each other, suggesting epistatic effects. We used single and double mutants to test whether mutating both TFs will modify transcriptional and behavioral phenotypes of single Gtf2ird1 mutants. Despite little difference in DNA-binding and transcriptome-wide expression, Gtf2ird1 mutation caused balance, marble burying, and conditioned fear phenotypes. However, mutating Gtf2i in addition to Gtf2ird1 did not further modify transcriptomic or most behavioral phenotypes, suggesting Gtf2ird1 mutation alone is sufficient.

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Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

Cited by 3 publications

References 87 publications

Altered Neocortical Dynamics in a Mouse Model of Williams–Beuren Syndrome

Altered Neocortical Dynamics in a Mouse Model of Williams–Beuren Syndrome

Sociability development in mice with cell‐specific deletion of the NMDA receptor NR1 subunit gene

Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA-binding, and long term behavioral consequences

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