Routine tail suspension husbandry facilitates onset of seizure susceptibility in el mice

Summary: Purpose: Tail suspension can elicit seizures in susceptible EL mice, a model of idiopathic, multifactorial epilepsy. Further, repeated tail suspension hastens the lifetime onset of seizure susceptibility in these mice. The present study tested the hypothesis that curtailing human handling during development would delay the onset of seizure susceptibility relative to EL mice handled regularly by using tail suspension for standard laboratory husbandry. Methods: Control mice were handled by the tail for bedding changes, whereas unhandled mice bedding was changed by using specially designed connector cages that allowed mice to transfer without handling to a cage containing clean bedding. Seizure susceptibility was tested beginning at 70, 80, 90, 100, or 140 days of age by using a handling-induced seizure-susceptibility paradigm. Results: Among handled mice, more than half of the sample exhibited seizures by age 80 days relative to fewer than one fourth of unhandled mice. In addition, each group was tested a second time 10 days after the initial seizure-susceptibility test to detect potential experience-induced increases in seizure susceptibility. Once again, a higher frequency of handled mice expressed seizures at significantly younger ages relative to unhandled mice. Conclusions: Although it was already known that repeated tail suspension could speed the onset of seizure susceptibility in EL mice, the present results are the first to demonstrate the converse finding that decreasing routine human handling can delay significantly the onset of seizure susceptibility. This suggests that removal of nonconsensual aspects of human\u96animal contact may delay or prevent the onset of seizure susceptibility

Ankyrin 3: genetic association with bipolar disorder and relevance to disease pathophysiology

Bipolar disorder (BD) is a multi-factorial disorder caused by genetic and environmental influences. It has a large genetic component, with heritability estimated between 59-93%. Recent genome-wide association studies (GWAS) using large BD patient populations have identified a number of genes with strong statistical evidence for association with susceptibility for BD. Among the most significant and replicated genes is ankyrin 3 (ANK3), a large gene that encodes multiple isoforms of the ankyrin G protein. This article reviews the current evidence for genetic association of ANK3 with BD, followed by a comprehensive overview of the known biology of the ankyrin G protein, focusing on its neural functions and their potential relevance to BD. Ankyrin G is a scaffold protein that is known to have many essential functions in the brain, although the mechanism by which it contributes to BD is unknown. These functions include organizational roles for subcellular domains in neurons including the axon initial segment and nodes of Ranvier, through which ankyrin G orchestrates the localization of key ion channels and GABAergic presynaptic terminals, as well as creating a diffusion barrier that limits transport into the axon and helps define axo-dendritic polarity. Ankyrin G is postulated to have similar structural and organizational roles at synaptic terminals. Finally, ankyrin G is implicated in both neurogenesis and neuroprotection. ANK3 and other BD risk genes participate in some of the same biological pathways and neural processes that highlight several mechanisms by which they may contribute to BD pathophysiology. Biological investigation in cellular and animal model systems will be critical for elucidating the mechanism through which ANK3 confers risk of BD. This knowledge is expected to lead to a better understanding of the brain abnormalities contributing to BD symptoms, and to potentially identify new targets for treatment and intervention approaches.Stanley Medical Research InstituteAvis and Clifford Barrus Medical FoundationMassachusetts General Hospital (Executive Committee on Research)Broad Institute (Stanley Center for Psychiatric Research

Ankyrin-G Regulates Neurogenesis and Wnt Signaling by Altering the Subcellular Localization of β-catenin

Ankyrin-G is a scaffolding protein required for the formation of the axon initial segment in neurons. Recent genome-wide association studies and whole-exome sequencing have identified ANK3, the gene coding for ankyrin-G, to be a risk gene for multiple neuropsychiatric disorders such as bipolar disorder (BD), schizophrenia, and autism spectrum disorder (ASD). Here, we describe a novel role for ankyrin-G in neural progenitor proliferation in the developing cortex. We found that ankyrin-G regulates canonical Wnt signaling by altering the subcellular localization and availability of β-catenin in proliferating cells. Ankyrin-G loss-of-function increases β-catenin levels in the nucleus, thereby promoting neural progenitor proliferation. Importantly, abnormalities in proliferation can be rescued by reducing Wnt pathway signaling. Together, these results suggest that ankyrin-G is required for proper brain development

Anxiety Associated Increased CpG Methylation in the Promoter of Asb1: A Translational Approach Evidenced by Epidemiological and Clinical Studies and a Murine Model

Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine model. In the KORA cohort, participants (n=1522, age 32–72 years) were administered the Generalized Anxiety Disorder (GAD-7) instrument, whole blood DNA methylation was measured (Illumina 450K BeadChip), and circulating levels of hs-CRP and IL-18 were assessed in the association between anxiety and methylation. DNA methylation was measured using the same instrument in a study of patients with anxiety disorders recruited at the Max Planck Institute of Psychiatry (MPIP, 131 non-medicated cases and 169 controls). To expand our mechanistic understanding, these findings were reverse translated in a mouse model of acute social defeat stress. In the KORA study, participants were classified according to mild, moderate, or severe levels of anxiety (29.4%/6.0%/1.5%, respectively). Severe anxiety was associated with 48.5% increased methylation at a single CpG site (cg12701571) located in the promoter of the gene encoding Asb1 (β-coefficient=0.56 standard error (SE)=0.10, p (Bonferroni)=0.005), a protein hypothetically involved in regulation of cytokine signaling. An interaction between IL-18 and severe anxiety with methylation of this CpG cite showed a tendency towards significance in the total population (p=0.083) and a significant interaction among women (p=0.014). Methylation of the same CpG was positively associated with Panic and Agoraphobia scale (PAS) scores (β=0.005, SE=0.002, p=0.021, n=131) among cases in the MPIP study. In a murine model of acute social defeat stress, Asb1 gene expression was significantly upregulated in a tissue-specific manner (p=0.006), which correlated with upregulation of the neuroimmunomodulating cytokine interleukin 1 beta. Our findings suggest epigenetic regulation of the stress-responsive Asb1 gene in anxiety-related phenotypes. Further studies are necessary to elucidate the causal direction of this association and the potential role of Asb1-mediated immune dysregulation in anxiety disorders