Williams syndrome (WS) is a neurodevelopmental disorder caused by a 1.5–1.8 Mbp deletion on chromosome 7q11.23, affecting the copy number of 26–28 genes. Phenotypes of WS include cardiovascular problems, craniofacial dysmorphology, deficits in visual–spatial cognition and a characteristic hypersocial personality. There are still no genes in the region that have been consistently linked to the cognitive and behavioral phenotypes, although human studies and mouse models have led to the current hypothesis that the general transcription factor 2 I family of genes, GTF2I and GTF2IRD1, are responsible. Here we test the hypothesis that these two transcription factors are sufficient to reproduce the phenotypes that are caused by deletion of the WS critical region (WSCR). We compare a new mouse model with loss of function mutations in both Gtf2i and Gtf2ird1 to an established mouse model lacking the complete WSCR. We show that the complete deletion (CD) model has deficits across several behavioral domains including social communication, motor functioning and conditioned fear that are not explained by loss of function mutations in Gtf2i and Gtf2ird1. Furthermore, transcriptome profiling of the hippocampus shows changes in synaptic genes in the CD model that are not seen in the double mutants. Thus, we have thoroughly defined a set of molecular and behavioral consequences of complete WSCR deletion and shown that genes or combinations of genes beyond Gtf2i and Gtf2ird1 are necessary to produce these phenotypic effects.
Williams Syndrome results in distinct behavioral phenotypes, which include learning deficits, anxiety, increased phobias and hypersociability. While the underlying mechanisms driving this subset of phenotypes is unknown, oxytocin (OT) dysregulation is hypothesized to be involved as some studies have shown elevated blood OT and altered OT receptor expression in patients. A “Complete Deletion” (CD) mouse, modeling the hemizygous deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These CD mice also exhibit impaired fear responses in the conditioned fear task. Here, we address whether OT dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an OT receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in CD mice. Thus, increased OT signaling is not acutely responsible for this phenotype. We also evaluated OT receptor and serotonin transporter availability in regions related to fear learning, memory and sociability using autoradiography in wild type and CD mice. While no differences withstood correction, we identified regions that may warrant further investigation. There was a nonsignificant decrease in OT receptor expression in the lateral septal nucleus and nonsignificant lowered serotonin transporter availability in the striatum and orbitofrontal cortex. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus.
more » « less- NSF-PAR ID:
- 10445930
- Publisher / Repository:
- Wiley-Blackwell
- Date Published:
- Journal Name:
- Genes, Brain and Behavior
- Volume:
- 21
- Issue:
- 1
- ISSN:
- 1601-1848
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract -
more » « less
Abstract Williams syndrome is a rare neurodevelopmental disorder exhibiting cognitive and behavioral abnormalities, including increased social motivation, risk of anxiety and specific phobias along with perturbed motor function. Williams syndrome is caused by a microdeletion of 26–28 genes on chromosome 7, including
GTF2IRD1 , which encodes a transcription factor suggested to play a role in the behavioral profile of Williams syndrome. Duplications of the full region also lead to frequent autism diagnosis, social phobias and language delay. Thus, genes in the region appear to regulate social motivation in a dose‐sensitive manner. A “complete deletion” mouse, heterozygously eliminating the syntenic Williams syndrome region, has been deeply characterized for cardiac phenotypes, but direct measures of social motivation have not been assessed. Furthermore, the role ofGtf2ird1 in these behaviors has not been addressed in a relevant genetic context. Here, we have generated a mouse overexpressingGtf2ird1 , which can be used both to model duplication of this gene alone and to rescueGtf2ird1 expression in the complete deletion mice. Using a comprehensive behavioral pipeline and direct measures of social motivation, we provide evidence that the Williams syndrome critical region regulates social motivation along with motor and anxiety phenotypes, but thatGtf2ird1 complementation is not sufficient to rescue most of these traits, and duplication does not decrease social motivation. However,Gtf2ird1 complementation does rescue light‐aversive behavior and performance on select sensorimotor tasks, perhaps indicating a role for this gene in sensory processing or integration. -
more » « less
Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα−/−mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα−/−mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα−/−microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB–related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα−/−mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα–deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα−/−mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.
-
more » « less
Background Dysregulation of the corticotropin‐releasing factor (
CRF ) system has been observed in rodent models of binge drinking, with a large focus onCRF receptor 1 (CRF ‐R1). The role ofCRF ‐binding protein (CRF ‐BP ), a key regulator ofCRF activity, in binge drinking is less well understood. In humans, single‐nucleotide polymorphisms inCRHBP CRF ‐BP in vulnerability to alcohol addiction.Methods The role and regulation of
CRF ‐BP in binge drinking were examined in mice exposed to the drinking in the dark (DID ) paradigm. Using in situ hybridization, the regulation ofCRF ‐BP ,CRF ‐R1, andCRF mRNA expression was determined in the stress and reward systems of C57BL /6J mice after repeated cycles ofDID . To determine the functional role ofCRF ‐BP in binge drinking,CRF ‐BP knockout (CRF ‐BP KO ) mice were exposed to 6 cycles ofDID , during which alcohol consumption was measured and compared to wild‐type mice.Results CRF ‐BP mRNA expression was significantly decreased in the prelimbic (PL ) and infralimbic medial prefrontal cortex (mPFC ) of C57BL /6J mice after 3 cycles and in thePL mPFC after 6 cycles ofDID . No significant changes inCRF orCRF ‐R1 mRNA levels were observed in mPFC , ventral tegmental area, bed nucleus of the stria terminalis, or amygdala after 3 cycles ofDID .CRF ‐BP KO mice do not show significant alterations in drinking compared to wild‐type mice across 6 cycles of DID.Conclusions These results reveal that repeated cycles of binge drinking alter
CRF ‐BP mRNA expression in the mPFC , a region responsible for executive function and regulation of emotion and behavior, including responses to stress. We observed a persistent decrease inCRF ‐BP mRNA expression in the mPFC after 3 and 6DID cycles, which may allow for increasedCRF signaling atCRF ‐R1 and contribute to excessive binge‐like ethanol consumption. -
more » « less
Key points Dravet syndrome mice (
Scn1a +/−) demonstrate a marked strain dependence for the severity of seizures which is correlated with GABAAreceptor α2subunit expression.The α2/α3subunit selective positive allosteric modulator (PAM) AZD7325 potentiates inhibitory postsynaptic currents (IPSCs) specifically in perisomatic synapses.
AZD7325 demonstrates stronger effects on IPSCs in the seizure resistant mouse strain, consistent with higher α2subunit expression.
AZD7325 demonstrates seizure protective effects in
Scn1a +/−mice without apparent sedative effectsin vivo .Abstract GABAAreceptor potentiators are commonly used for the treatment of epilepsy, but it is not clear whether targeting distinct GABAAreceptor subtypes will have disproportionate benefits over adverse effects. Here we demonstrate that the α2/α3selective positive allosteric modulator (PAM) AZD7325 preferentially potentiates hippocampal inhibitory responses at synapses proximal to the soma of CA1 neurons. The effect of AZD7325 on synaptic responses was more prominent in mice on the 129S6/SvEvTac background strain, which have been demonstrated to be seizure resistant in the model of Dravet syndrome (
Scn1a+/− ), and in which the α2GABAAreceptor subunits are expressed at higher levels relative to in the seizure prone C57BL/6J background strain. Consistent with this, treatment ofScn1a+/− mice with AZD7325 elevated the temperature threshold for hyperthermia‐induced seizures without apparent sedative effects. Our results in a model system indicate that selectively targeting α2is a potential therapeutic option for Dravet syndrome.
