The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults.

S and full research articles published in SLEEP, the official journal of the APSS. Sleep and sleep disorder scientific findings.

It has been suggested that imprinted genes are important in the regulation of sleep. However, the fundamental question of whether genomic imprinting has a role in sleep has remained elusive up to now. In this work we show that REM and NREM sleep states are differentially modulated by the maternally expressed imprinted gene Gnas. In particular, in mice with loss of imprinting of Gnas, NREM and complex cognitive processes are enhanced while REM and REM–linked behaviors are inhibited. This is the first demonstration that a specific overexpression of an imprinted gene affects sleep states and related complex behavioral traits. Furthermore, in parallel to the Gnas overexpression, we have observed an overexpression of Ucp1 in interscapular brown adipose tissue (BAT) and a significant increase in thermoregulation that may account for the REM/NREM sleep phenotypes. We conclude that there must be significant evolutionary advantages in the monoallelic expression of Gnas for REM sleep and for the consolidation of REM–dependent memories. Conversely, biallelic expression of Gnas reinforces slow wave activity in NREM sleep, and this results in a reduction of uncertainty in temporal decision-making processes. REM and NREM sleep are two distinct stages of the sleeping brain that are involved in the modulation of metabolic, physiological, and cognitive processes. Clinical evidence suggests that epigenetic mechanisms, such as genomic imprinting, play a role in sleep. Here we show that REM and NREM brain states are differentially modulated by the maternally imprinted gene Gnas. In particular, a mutation resulting in loss of imprinted expression of Gnas enhances NREM–dependent physiologic and cognitive functions while repressing REM and REM-linked functions. This is the first experimental demonstration of a specific effect of genomic imprinting on sleep states and their associated effects on cognition.

An AT motif-dependent axis, modulated by the transcription factor Zfhx3, influences the circadian clock in mice. In particular, gain of function of Zfhx3 significantly shortens circadian rhythms and alters the transcriptional activity of an important class of neuropeptides that controls intercellular signaling in the suprachiasmatic nucleus (SCN) of the hypothalamus. The ZFHX3/AT axis revealed an important, largely cell-nonautonomous control of the circadian clock. Here, by studying the recently identified circadian mouse mutant Zfhx3(Sci/+), we identify significant effects on sleep homeostasis, a phenomenon that is outside the canonical circadian clock system and that is modulated by the activity of those neuropeptides at a circuit level. We show that the Zfhx3(Sci/+) mutation accelerates the circadian clock at both the hourly scale (i.e., advancing circadian rhythms) and the seconds-to-minutes scale (i.e., anticipating behavioral responses) in mice. The in vivo results are accompanied by a significant presence of sleep targets among protein-protein interactions of the Zfhx3(Sci/+)-dependent network.

Fast-spiking interneurons (FSIs) play a central role in organizing the output of striatal neural circuits, yet functional interactions between these cells are still largely unknown. Here we investigated the interplay of action potential firing between electrically connected pairs of identified FSIs in mouse striatal slices. In addition to a loose coordination of firing activity mediated by membrane potential coupling, gap junctions induced a frequency-dependent inhibition of spike discharge in coupled cells. At relatively low firing rates (2-20 Hz), some action potentials were tightly synchronized whereas others were inhibited. However, burst firing at intermediate frequencies (25-60 Hz) mostly induced spike inhibition, while at frequencies >50-60 Hz FSI pairs tended to synchronize. Spike silencing occurred even in the absence of GABAergic synapses or persisted after a complete block of GABAA receptors. Pharmacological suppression of presynaptic spike afterhyperpolarization caused postsynaptic spikelets to become more prone to trigger spikes at near-threshold potentials, leading to a mostly synchronous firing activity. The complex pattern of functional coordination mediated by gap junctions endows FSIs with peculiar dynamic properties that may be critical in controlling striatal-dependent behavior.