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.
Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social ...deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host’s gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction.
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•Treatment with L. reuteri rescues social deficits in several ASD mouse models•L. reuteri reverses social deficits via the vagus nerve•L. reuteri reverses social deficits even in germ-free mice•OXTR inhibition prevents L. reuteri’s effects on social behavior and VTA plasticity
Precision microbial-based therapy rescues social deficits in genetic, environmental, and idiopathic mouse models of ASD. This rescue depends upon the vagus nerve as well as the oxytocinergic and dopaminergic signaling in the brain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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•Maternal high-fat diet (MHFD) induces behavioral alterations in offspring•MHFD causes alterations in gut microbial ecology in offspring•MHFD offspring show deficient synaptic plasticity in the VTA and oxytocin production•L. reuteri treatment restores oxytocin levels, VTA plasticity and social behaviors
A maternal high-fat diet leads to changes in the gut microbiome of offspring and induces behavioral alterations that can be restored via selective reintroduction of a commensal bacterial strain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The core symptoms of many neurological disorders have traditionally been thought to be caused by genetic variants affecting brain development and function. However, the gut microbiome, another ...important source of variation, can also influence specific behaviors. Thus, it is critical to unravel the contributions of host genetic variation, the microbiome, and their interactions to complex behaviors. Unexpectedly, we discovered that different maladaptive behaviors are interdependently regulated by the microbiome and host genes in the Cntnap2−/− model for neurodevelopmental disorders. The hyperactivity phenotype of Cntnap2−/− mice is caused by host genetics, whereas the social-behavior phenotype is mediated by the gut microbiome. Interestingly, specific microbial intervention selectively rescued the social deficits in Cntnap2−/− mice through upregulation of metabolites in the tetrahydrobiopterin synthesis pathway. Our findings that behavioral abnormalities could have distinct origins (host genetic versus microbial) may change the way we think about neurological disorders and how to treat them.
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•Host genetics and microbiota differentially regulate behaviors in an ASD mouse model•Microbe therapy (L. reuteri) rescues Cntnap2−/− social deficits but not hyperactivity•Microbe-induced metabolite (BH4) selectively rescues Cntnap2−/− social deficits•L. reuteri and BH4 improves Cntnap2−/− social-reward-mediated synaptic transmission
Host genetics and the microbiome interdependently regulate maladaptive behaviors in a mouse model for neurodevelopmental disorders. Additionally, precise microbial therapy, or microbe-induced metabolite-based therapy, selectively rescues social deficits but not hyperactivity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The axon initial segment (AIS), with its dense clusters of voltage‐gated ion channels decorating the axonal membrane, regulates action potential initiation and modulation. The AIS also functions as a ...barrier to maintain axodendritic polarity, and its precise axonal location contributes to the fine‐tuning of neuronal excitability. Therefore, it is not surprising that mutations in AIS‐related genes, disruption of the molecular organization of the AIS and altered AIS ion channel expression, function, location and/or density are emerging as key players in neurological disorders. Here, we consider the role of the AIS in nervous system disease and injury.
The axon initial segment (AIS), with its dense clusters of voltage‐gated ion channels decorating the axonal membrane, regulates action potential initiation and modulation. The AIS also functions as a barrier to maintain axodendritic polarity, and its precise axonal location contributes to the fine‐tuning of neuronal excitability.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Inflammation has been associated with progression and complications of chronic heart failure (HF) but no effective therapy has yet been identified to treat this dysregulated immunologic state. The ...selective cytopheretic device (SCD) provides extracorporeal autologous cell processing to lessen the burden of inflammatory activity of circulating leukocytes of the innate immunologic system.
The objective of this study was to evaluate the effects of the SCD as an extracorporeal immunomodulatory device on the immune dysregulated state of HF. HF.
SCD treatment in a canine model of systolic HF or HF with reduced ejection fraction (HFrEF) diminished leukocyte inflammatory activity and enhanced cardiac performance as measured by left ventricular (LV) ejection fraction and stroke volume (SV) up to 4 weeks after treatment initiation. Translation of these observations in first in human, proof of concept clinical study was evaluated in a patient with severe HFrEFHFrEF ineligible for cardiac transplantation or LV LV assist device (LVAD) due to renal insufficiency and right ventricular dysfunction. Six hour SCD treatments over 6 consecutive days resulted in selective removal of inflammatory neutrophils and monocytes and reduction in key plasma cytokines, including tumor necrosis factor-alpha (TNF-α),), interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. These immunologic changes were associated with significant improvements in cardiac power output, right ventricular stroke work index, cardiac index and LVSV index…. Stabilization of renal function with progressive volume removal permitted successful LVAD implantation.
This translational research study demonstrates a promising immunomodulatory approach to improve cardiac performance in HFrEFHFrEF and supports the important role of inflammation in the progression of HFHF.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Increased arterial stiffness is associated with an impairment of ventricular–vascular coupling efficiency and increased risk of cardiovascular mortality. Recently, it has been suggested that ...an increase in arterial stiffness is associated with resistance exercise training. Therefore, the aims of this study were to compare augmentation index (AIx) and left ventricular wasted pressure energy (LV
EW
) as markers of arterial stiffness and ventricular–vascular coupling efficiency in young aerobic-trained (AT) and resistance (RT)-trained subjects. We also investigated the relationship of muscle sympathetic nerve activity (MSNA) and flow-mediated dilation (FMD) to AIx in both sets of subjects to determine if endothelial function or sympathetic outflow could explain any differences in arterial stiffness.
Method
To achieve our aims, we measured MSNA in 15 male subjects (8 RT, 7 AT) using microneurography. We also used applanation tonometry of the radial pressure waveform to noninvasively synthesize aortic pressure waveforms. FMD was calculated as percent dilation of the radial artery from baseline following a 5 min occlusion.
Result
RT subjects had an increased AIx (12 ± 3 vs. −7 ± 2;
P
< 0.01), LV
EW
(429 ± 111 vs. −360 ± 77;
P
< 0.01) and MSNA burst incidence (34 ± 4 vs. 26 ± 4;
P
< 0.01) when compared with AT subjects. There was no difference in FMD between groups. MSNA burst incidence was also significantly related to AIx in subjects (
R
2
= 0.61;
P
< 0.01) with a distinct demarcation between RT and AT subjects.
Conclusion
These results confirm previous reports of a positive association between MSNA and AIx in young male resistance-trained subjects. Furthermore, RT is associated with increased arterial stiffness and elevated sympathetic outflow.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The axon initial segment (AIS) and nodes of Ranvier are the sites of action potential initiation and regeneration in axons. Although the basic molecular architectures of AIS and nodes, characterized ...by dense clusters of Na(+) and K(+) channels, are similar, firing patterns vary among cell types. Neuronal firing patterns are established by the collective activity of voltage-gated ion channels and can be modulated through interaction with auxiliary subunits. Here, we report the neuronal expression pattern and subcellular localization of Navβ4, the modulatory Na(+) channel subunit thought to underlie resurgent Na(+) current. Immunostaining of rat tissues revealed that Navβ4 is strongly enriched at the AIS of a select set of neuron types, including many characterized by high-frequency firing, and at nodes of Ranvier in the PNS and some nodes in the CNS. By introducing full-length and mutant GFP-tagged Navβ4 into cultured neurons, we determined that the AIS and nodal localization of Navβ4 depends on its direct interaction with Na(+) channel α subunits through an extracellular disulfide bond. Based on these results, we propose that differences in the specific composition of the Na(+) channel complexes enriched at the AIS and nodes contribute to the diverse physiologies observed among cell types.
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.
Dysbiosis of the maternal gut microbiome during pregnancy is associated with adverse neurodevelopmental outcomes. We previously showed that maternal high-fat diet (MHFD) in mice induces gut ...dysbiosis, social dysfunction, and underlying synaptic plasticity deficits in male offspring (F1). Here, we reason that, if HFD-mediated changes in maternal gut microbiota drive offspring social deficits, then MHFD-induced dysbiosis in F1 female MHFD offspring would likewise impair F2 social behavior. Metataxonomic sequencing reveals reduced microbial richness among female F1 MHFD offspring. Despite recovery of microbial richness among MHFD-descendant F2 mice, they display social dysfunction. Post-weaning Limosilactobacillus reuteri treatment increases the abundance of short-chain fatty acid-producing taxa and rescues MHFD-descendant F2 social deficits. L. reuteri exerts a sexually dimorphic impact on gut microbiota configuration, increasing discriminant taxa between female cohorts. Collectively, these results show multigenerational impacts of HFD-induced dysbiosis in the maternal lineage and highlight the potential of maternal microbiome-targeted interventions for neurodevelopmental disorders.
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•MHFD reduces microbial richness in female offspring (F1)•Social deficits persist in MHFD-descendant F2, despite recovery of microbial richness•Post-weaning L. reuteri treatment rescues MHFD-descendant F2 social deficits•L. reuteri exerts a sexually dimorphic impact on host microbiota configuration
Di Gesù, Matz et al. find that maternal high-fat diet results in intergenerational (F1, F2), but not transgenerational (F3), descendant social dysfunction. Metataxonomic sequencing and fecal microbiota transplant data implicate dysbiosis of the maternal gut microbiome in intergenerational social deficits, which can be restored by post-weaning Limosilactobacillus reuteri-6475 supplementation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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