De novo heterozygous mutations in STXBP1 cause early infantile epileptic encephalopathy. Kovačević et al. analyse the underlying disease mechanisms in silico, in vitro and in vivo, and show that protein instability, haploinsufficiency and cortical hyperexcitability explain STXBP1-encephalopathy. In addition, they demonstrate the construct, face and predictive validity of Stxbp1+/- mice.

Many psychiatric disorders emerge during adolescence. The study of executive functions in animal models of these disorders critically requires short-duration tasks measuring these functions before the animal ages. Here, a novel 5-choice serial reaction time task (5-CSRTT) protocol is presented, to measure attention and impulsivity within one week, without scheduled food deprivation and with little animal handling. Mice were allowed 24-h/day task access from their home-cage, during which they could self-pace task progression and earn unlimited food rewards depending on task performance. Manipulation of task parameters in this self-paced 5-CSRTT protocol (SP-5C) affected attentional performance and impulsivity to a similar extent as previously observed in the 5-CSRTT. Task activity followed intrinsic circadian rhythm, distinctive for the SP-5C protocol, with task performance stable over the day. The sensitivity of the SP-5C protocol to detect strain differences between C57BL/6J, DBA/2 J, BXD16 and BXD62 mice was demonstrated as well as its suitability for testing adolescent mice. Acute administration of the muscarinic acetylcholine receptor antagonist scopolamine impaired attentional performance, providing initial pharmacological validation of the task. The SP-5C substantially shortens the assessment of impulsivity and attention, increases test efficiency and enables the assessment of adolescent mouse models of psychiatric disorders.

Many neurological and psychiatric disorders are characterized by deficits in cognitive flexibility. Modeling cognitive flexibility in mice enables the investigation of mechanisms underlying these deficits. The majority of currently available behavioral tests targeting this cognitive domain are reversal learning tasks that require scheduled food restriction, extended training periods and labor-intensive, and stress-inducing animal handling. Here, we describe a novel 4-day (4-d) continuously running task measuring discrimination-and reversal learning in an automated home cage (CognitionWall DL/RL task) that largely eliminates these limitations. In this task, mice can earn unlimited number of food rewards by passing through the correct hole of the three-holed CognitionWall. To assess the validity and sensitivity of this novel task, the performance of C57BL/6J mice, amyloid precursor protein/presenilin1 transgenic (APP/PS1) mice, a-calmodulin kinase-II (aCaMKII) T305D knock-in mice, and mice with an orbitofrontal cortex lesion were examined. We found that C57BL/6J mice reach stable performance levels within the 4 d of the task, while experiencing only slight reductions in weight and no major effects on circadian rhythm. The task detected learning deficits in APP/PS1 transgenic and aCaMKII T305D mutant mice. Additionally, we established that the orbitofrontal cortex underlies reversal learning performance in our task. Because of its short duration and the absence of food deprivation and concurrent weight loss, this novel automated home-cage task substantially improves comprehensive preclinical assessment of cognitive functions in mouse models of psychiatric and neurological disorders and also enables analysis during specific developmental stages.