G protein-coupled receptors strongly modulate neuronal excitability but there has been little evidence for G protein mechanisms in genetic epilepsies. Recently, four patients with epileptic encephalopathy (EIEE17) were found to have mutations in GNAO1, the most abundant G protein in brain, but the mechanism of this effect is not known. The GNAO1 gene product, Gαo, negatively regulates neurotransmitter release. Here, we report a dominant murine model of Gnao1-related seizures and sudden death. We introduced a genomic gain-of-function knock-in mutation (Gnao1+/G184S) that prevents Go turnoff by Regulators of G protein signaling proteins. This results in rare seizures, strain-dependent death between 15 and 40 weeks of age, and a markedly increased frequency of interictal epileptiform discharges. Mutants on a C57BL/6J background also have faster sensitization to pentylenetetrazol (PTZ) kindling. Both premature lethality and PTZ kindling effects are suppressed in the 129SvJ mouse strain. We have mapped a 129S-derived modifier locus on Chromosome 17 (within the region 41–70 MB) as a Modifer of G protein Seizures (Mogs1). Our mouse model suggests a novel gain-of-function mechanism for the newly defined subset of epileptic encephalopathy (EIEE17). Furthermore, it reveals a new epilepsy susceptibility modifier Mogs1 with implications for the complex genetics of human epilepsy as well as sudden death in epilepsy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-014-9509-z) contains supplementary material, which is available to authorized users.

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Effective curiosity-driven learning requires recognizing that the value of evidence for testing hypotheses depends on what other hypotheses are under consideration. Do we intuitively represent the discriminability of hypotheses? Here we show children alternative hypotheses for the contents of a box and then shake the box (or allow children to shake it themselves) so they can hear the sound of the contents. We find that children are able to compare the evidence they hear with imagined evidence they do not hear but might have heard under alternative hypotheses. Children (N = 160; mean: 5 years and 4 months) prefer easier discriminations (Experiments 1-3) and explore longer given harder ones (Experiments 4-7). Across 16 contrasts, children’s exploration time quantitatively tracks the discriminability of heard evidence from an unheard alternative. The results are consistent with the idea that children have an “intuitive psychophysics”: children represent their own perceptual abilities and explore longer when hypotheses are harder to distinguish.

From minimal observable action, humans make fast, intuitive judgments about what other people think, want, and feel (Heider & Simmel, 1944). Even when no agent is visible, children can infer the presence of intentional agents based on the environmental traces that only agents could leave behind (Saxe et al., 2005; Newman et al., 2010). Here we show that, beyond inferring the presence of agents, four- to six-year-olds can also determine the mental states that best explain an environmental trace. Participants (N = 35, M: 5.6 years, range:4.0 − 6.8 years) saw pairs of dresser drawers with different numbers and orientations of open drawers, and they were asked to de- termine which static scenes was generated by an agent with a given knowledge state (whether the agent wasn’t searching at all but was just playing, knew exactly where an object was hidden, knew the approximate location, had no idea where it was hidden, or at first didn’t know and then remembered). We compare children’s performance to a computational model that extends models of mental-state attribution to consider cases where the behavior is not observed but must be inferred from the structure of the environment. We find that children’s graded pattern of responded shows quantitative similarity to the predictions made by our model