Summary Experience alters cortical networks through neural plasticity mechanisms. During a developmental critical period, the most dramatic consequence of occluding vision through one eye (monocular deprivation) is a rapid loss of excitatory synaptic inputs to parvalbumin-expressing (PV) inhibitory neurons in visual cortex. Subsequent cortical disinhibition by reduced PV cell activity allows for excitatory ocular dominance plasticity. However, the molecular mechanisms underlying critical period synaptic plasticity are unclear. Here we show that brief monocular deprivation during the critical period down-regulates neuregulin-1(NRG1)/ErbB4 signaling in PV neurons, causing retraction of excitatory inputs to PV neurons. Exogenous NRG1 rapidly restores excitatory inputs onto deprived PV cells through downstream PKC-dependent activation and AMPA receptor exocytosis, thus enhancing PV neuronal inhibition to excitatory neurons. NRG1 treatment prevents the loss of deprived eye visual cortical responsiveness in vivo. Our findings reveal molecular, cellular and circuit mechanisms of NRG1/ErbB4 in regulating the initiation of critical period visual cortical plasticity.

Studies in rodent epilepsy models suggest that GABAergic interneuron progenitor grafts can reduce hyperexcitability and seizures in temporal lobe epilepsy (TLE). Although integration of the transplanted cells has been proposed as the underlying mechanism for these disease-modifying effects, prior studies have not explicitly examined cell types and synaptic mechanisms for long-term seizure suppression. To address this gap, we transplanted medial ganglionic eminence (MGE) cells from embryonic day 13.5 VGAT-Venus or VGATChR2-EYFP transgenic embryos into the dentate gyrus (DG) of adult mice 2 weeks after induction of TLE with pilocarpine. Beginning 3-4 weeks after status epilepticus, we conducted continuous video-electroencephalographic recording until 90 -100 d. TLE mice with bilateral MGE cell grafts in the DG had significantly fewer and milder electrographic seizures, compared with TLE controls. Immunohistochemical studies showed that the transplants contained multiple neuropeptide or calcium-binding protein-expressing interneuron types and these cells established dense terminal arborizations onto the somas, apical dendrites, and axon initial segments of dentate granule cells (GCs). A majority of the synaptic terminals formed by the transplanted cells were apposed to large postsynaptic clusters of gephyrin, indicative of mature inhibitory synaptic complexes. Functionality of these new inhibitory synapses was demonstrated by optogenetically activating VGAT-ChR2-EYFP-expressing transplanted neurons, which generated robust hyperpolarizations in GCs. These findings suggest that fetal GABAergic interneuron grafts may suppress pharmacoresistant seizures by enhancing synaptic inhibition in DG neural circuits.

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Background: Cryptotanshinone (CPT), as a major component of Salvia miltiorrhiza Bunge (Danshen), displays many pharmacological activities including anti-inflammatory effects. However, the exact cellular and molecular mechanisms of the anti-inflammatory activities of CPT remain to be elucidated. The present study was aimed to clarify its mechanisms on lipopolysaccharide (LPS)-induced inflammatory responses in mouse macrophages, RAW264.7 cells.Methods: In the current study, the anti-inflammatory properties of CPT were evaluated using LPS-stimulated RAW264.7 cell model. MTT assay was used to determine the viability of RAW264.7 cells. The anti-inflammatory effects of CPT were measured based on the detection of nitric oxide (NO) production (Griess and flow cytometry assay), and tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release (ELISA). Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) enzyme expressions were also determined by western blotting. Besides, by using flow cytometry, we also evaluated the effect of CPT on LPS-induced calcium influx. Finally, the underlying anti-inflammatory mechanisms of CPT were investigated using western blotting to assess the protein levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), phosphatidylinositol 3-kinase (PI3K)/AKT, nuclear factor erythroid 2 related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), and nuclear factor-kappa B (NF-κB) pathways. Results:Our data showed that CPT inhibited LPS-induced pro-inflammatory cytokine release like IL-6, and TNF-α, as well as NO production. It displayed a significant inhibitory effect on the protein expressions such as iNOS, COX-2, NF-κB pathway like inhibitor of kappa B kinase (IKK)α/β, inhibitor of kappa B (IκB)-α and NF-κB/p65, PI3K/AKT pathway like PI3K and AKT, and MAPK pathway like c-Jun N-terminal kinase (JNK)1/2, extracellular signal-regulated kinase (ERK)1/2, and p38, in LPS-stimulated RAW264.7 macrophages. Moreover, the immunofluorescence results indicated that CPT suppressed NF-κB/p65 translocation from the cytoplasm into the nucleus. Further investigations showed that CPT treatment increased NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1) expressions together with its upstream mediator, Nrf2. In addition, CPT inhibited LPS-induced toll-like receptor 4 (TLR4) and MyD88 expressions in RAW264.7 macrophages. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article' Conclusions: Collectively, we suggested that CPT exerted s...

BackgroundNutraceuticals containing traditional Chinese medicine (TCM) are promoted for use in the management of diabetes. The evidence to support such use is largely unknown. This study aimed to summarise and evaluate the literature reporting the results of randomized controlled trials (RCTs) investigating the effects of nutraceuticals in people living with diabetes.MethodsLiterature from four electronic databases (PubMed, Scopus, CINAHL and Web of Science) was searched following PRISMA guidelines to yield RCT publications on nutraceutical for diabetes management published since 2009. The quality of reporting was assessed using the CONSORT 2010 checklist statement. Risk-of-bias for each study was assessed using the Cochrane risk of bias tool.ResultsOut of 1978 records identified in the initial search, 24 randomized, double/triple-blinded, controlled trials that investigated the effect of nutraceuticals covering 17 different TCM herbs for diabetes management were selected. Participants included people who were diabetic (n = 16), pre-diabetic (n = 3) or predisposed to diabetes (n = 5). Sample sizes ranged between 23 and 117 for 2 arms, or 99–165 for 3 arms. Comparisons were made against placebo (n = 22), conventional medicine (n = 1), or regular diet (n = 1) for a duration between 4 and 24 weeks. All but one study tested the effect on fasting blood glucose levels (n = 23) or glycated haemoglobin levels (n = 18), and/or postprandial 2-h blood glucose levels (n = 4) as the primary outcomes. Nineteen studies reported some statistically significant reductions in the respective measures while 5 studies showed no effect on primary or secondary outcomes. None of the included studies met all the criteria for the CONSORT guidelines. Incomplete reporting about randomization and blinding, and a lack of ancillary analyses to explore other influential factors and potential harms associated with the use were repeatedly noted. Based on the Cochrane risk-of-bias tool, 19 studies were deemed to have a high risk of bias mainly attributed to sponsor bias.ConclusionsThere is some evidence to suggest positive clinical outcomes in response to the administration of a range of nutraceuticals containing TCM in the management of diabetes. However, these results must be interpreted with caution due to the overall low quality of the trials.

Yang et al. (2016) show that transplantation of GABAergic inhibitory neurons into the amygdala boosts the persistence of fear extinction in mice. Transplantation was found to degrade perineuronal nets on endogenous inhibitory neurons and enhance synaptic plasticity in host amygdala.