Highlights d Treatment with L. reuteri rescues social deficits in several ASD mouse models d L. reuteri reverses social deficits via the vagus nerve d L. reuteri reverses social deficits even in germ-free mice d OXTR inhibition prevents L. reuteri's effects on social behavior and VTA plasticity

Down syndrome (DS) is the most common genetic cause of intellectual disability. Protein homeostasis is essential for normal brain function, but little is known about its role in DS pathophysiology. In this study, we found that the integrated stress response (ISR)—a signaling network that maintains proteostasis—was activated in the brains of DS mice and individuals with DS, reprogramming translation. Genetic and pharmacological suppression of the ISR, by inhibiting the ISR-inducing double-stranded RNA–activated protein kinase or boosting the function of the eukaryotic translation initiation factor eIF2-eIF2B complex, reversed the changes in translation and inhibitory synaptic transmission and rescued the synaptic plasticity and long-term memory deficits in DS mice. Thus, the ISR plays a crucial role in DS, which suggests that tuning of the ISR may provide a promising therapeutic intervention.

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Why ketogenic diet (KD) effectively controls seizures in some people with epilepsy is unclear. In a recent issue of Cell, Olson et al. (2018) showed that KD prevents seizures by upregulating key bacterial species (Akkermansia muciniphila and Parabacteroides merdae). These bacteria synergize to decrease gammaglutamylation of amino acids, increase hippocampal GABA/Glutamate ratios, and, ultimately, prevent seizures.

Evolution of antibiotic resistance is a world health crisis, fueled by new mutations. Drugs to slow mutagenesis could, as cotherapies, prolong the shelf-life of antibiotics, yet evolution-slowing drugs and drug targets have been underexplored and ineffective. Here, we used a network-based strategy to identify drugs that block hubs of fluoroquinolone antibiotic-induced mutagenesis. We identify a U.S. Food and Drug Administration– and European Medicines Agency–approved drug, dequalinium chloride (DEQ), that inhibits activation of the Escherichia coli general stress response, which promotes ciprofloxacin-induced (stress-induced) mutagenic DNA break repair. We uncover the step in the pathway inhibited: activation of the upstream “stringent” starvation stress response, and find that DEQ slows evolution without favoring proliferation of DEQ-resistant mutants. Furthermore, we demonstrate stress-induced mutagenesis during mouse infections and its inhibition by DEQ. Our work provides a proof-of-concept strategy for drugs to slow evolution in bacteria and generally.