SUMMARY
Maternal obesity during pregnancy has been associated with increased risk
of neurodevelopmental disorders, including autism spectrum disorder (ASD), in
offspring. Here we report that maternal high fat diet (MHFD) induces a shift in
microbial ecology that negatively impacts offspring social behavior. Social
deficits and gut microbiota dysbiosis in MHFD offspring are prevented by
co-housing with offspring of mothers on a regular diet (MRD) and transferable to
germ-free mice. In addition, social interaction induces synaptic potentiation
(LTP) in the ventral tegmental area (VTA) of MRD, but not MHFD offspring.
Moreover, MHFD offspring had fewer oxytocin immunoreactive neurons in the
hypothalamus. Using metagenomics and precision microbiota reconstitution, we
identified a single commensal strain that corrects oxytocin levels, LTP, and
social deficits in MHFD offspring. Our findings causally link maternal diet, gut
microbial imbalance, VTA plasticity and behavior, and suggest that probiotic
treatment may relieve specific behavioral abnormalities associated with
neurodevelopmental disorders.
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
Activity-dependent changes in the strength of synaptic connections are fundamental to the formation and maintenance of memory. The mechanisms underlying persistent changes in synaptic strength in the hippocampus, specifically long-term potentiation and depression, depend on new protein synthesis. Such changes are thought to be orchestrated by engaging the signaling pathways that regulate mRNA translation in neurons. In this review, we discuss the key regulatory pathways that govern translational control in response to synaptic activity and the mRNA populations that are specifically targeted by these pathways. The critical contribution of regulatory control over new protein synthesis to proper cognitive function is underscored by human disorders associated with either silencing or mutation of genes encoding proteins that directly regulate translation. In light of these clinical implications, we also consider the therapeutic potential of targeting dysregulated translational control to treat cognitive disorders of synaptic dysfunction.
At hippocampal synapses, activation of group I metabotropic glutamate receptors (mGluRs) induces long-term depression (LTD), which requires new protein synthesis. However, the underlying mechanism remains elusive. Here we describe the translational program that underlies mGluR-LTD and identify the translation factor eIF2α as its master effector. Genetically reducing eIF2α phosphorylation, or specifically blocking the translation controlled by eIF2α phosphorylation, prevented mGluR-LTD and the internalization of surface AMPA receptors (AMPARs). Conversely, direct phosphorylation of eIF2α, bypassing mGluR activation, triggered a sustained LTD and removal of surface AMPARs. Combining polysome profiling and RNA sequencing, we identified the mRNAs translationally upregulated during mGluR-LTD. Translation of one of these mRNAs, oligophrenin-1, mediates the LTD induced by eIF2α phosphorylation. Mice deficient in phospho-eIF2α–mediated translation are impaired in object-place learning, a behavioral task that induces hippocampal mGluR-LTD in vivo. Our findings identify a new model of mGluR-LTD, which promises to be of value in the treatment of mGluR-LTD-linked cognitive disorders.
The axon initial segment (AIS) is the site of action potential initiation in neurons. Recent studies have demonstrated activity-dependent regulation of the AIS, including homeostatic changes in AIS length, membrane excitability, and the localization of voltage-gated Na + channels. The neurodevelopmental disorder Angelman syndrome (AS) is usually caused by the deletion of small portions of the maternal copy of chromosome 15, which includes the UBE3A gene. A mouse model of AS has been generated and these mice exhibit multiple neurological abnormalities similar to those observed in humans. We examined intrinsic properties of pyramidal neurons in hippocampal area CA1 from AS model mice and observed alterations in resting membrane potential, threshold potential, and action potential amplitude. The altered intrinsic properties in the AS mice were correlated with significant increases in the expression of the α1 subunit of Na/K-ATPase (α1-NaKA), the Na +channel NaV1.6, and the AIS anchoring protein ankyrin-G, as well as an increase in length of the AIS. These findings are the first evidence for pathology of intrinsic membrane properties and AIS-specific changes in AS, a neurodevelopmental disorder associated with autism.
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