Prefrontal cortical network dysfunction from acute neurotoxicant exposure.

Prefrontal cortical (PFC) dysfunction has been linked to disorders exhibiting deficits in cognitive performance, attention, motivation, and impulse control. Neurons of the PFC are susceptible to glutamatergic excitotoxicity, an effect associated with cortical degeneration in frontotemporal disorders (FTDs). PFC susceptibility to environmental toxicant exposure, one possible contributor to sporadic FTD, has not been systematically studied. Here, we tested the ability of a well-known environmental neurotoxicant, methylmercury (MeHg), to induce hyperexcitability in medial prefrontal cortex (mPFC) excitatory pyramidal neurons, using whole cell patch-clamp recording. Acute MeHg exposure (20 µM) produced significant mPFC dysfunction, with a shift in the excitatory to inhibitory (E-I) balance toward increased excitability. Both excitatory postsynaptic current (EPSC) and inhibitory postsynaptic current (IPSC) charges were significantly increased after MeHg exposure. MeHg increased EPSC frequency, but there was no observable effect on IPSC frequency, EPSC amplitude or IPSC amplitude. Neither evoked AMPA receptor- nor NMDA receptor-mediated EPSC amplitudes were affected by MeHg. However, excitatory synapses experienced a significant reduction in paired-pulse depression and probability of release. In addition, MeHg induced temporal synchrony in spontaneous IPSCs, reflecting mPFC inhibitory network dysfunction. MeHg exposure also produced increased intrinsic excitability in mPFC neurons, with an increase in action potential firing rate. The observed effects of MeHg on mPFC reflect key potential mechanisms for neuropsychological symptoms from MeHg poisoning. Therefore, MeHg has a significant effect on mPFC circuits known to contribute to cognitive and emotional function and might contribute to etiology of neurodegenerative diseases, such as FTD.NEW & NOTEWORTHY Prefrontal cortical neurons are highly susceptible to glutamatergic excitotoxicity associated with neuronal degeneration in frontal dementia and to environmental toxicant exposure, one potential contributor to FTD. However, this has not been systematically studied. Our results demonstrate that methylmercury exposure leads to hyperexcitability of prefrontal cortical neurons by shifting excitatory to inhibitory (E-I) balance and raising sensitivity for spiking. Our results provide a mechanism by which environmental neurotoxicants may contribute to pathogenesis of diseases such as FTD.

Neuronal Nitric Oxide Synthase Regulates Cerebellar Parallel Fiber Slow EPSC in Purkinje Neurons by Modulating STIM1-Gated TRPC3-Containing Channels.

Responding to burst stimulation of parallel fibers (PFs), cerebellar Purkinje neurons (PNs) generate a convolved synaptic response displaying a fast excitatory postsynaptic current (EPSCFast) followed by a slow EPSC (EPSCSlow). The latter is companied with a rise of intracellular Ca2+ and critical for motor coordination. The genesis of EPSCSlow in PNs results from activation of metabotropic type 1 glutamate receptor (mGluR1), oligomerization of stromal interaction molecule 1 (STIM1) on the membrane of endoplasmic reticulum (ER) and opening of transient receptor potential canonical 3 (TRPC3) channels on the plasma membrane. Neuronal nitric oxide synthase (nNOS) is abundantly expressed in PFs and granule neurons (GNs), catalyzing the production of nitric oxide (NO) hence regulating PF-PN synaptic function. We recently found that nNOS/NO regulates the morphological development of PNs through mGluR1-regulated Ca2+-dependent mechanism. This study investigated the role of nNOS/NO in regulating EPSCSlow. Electrophysiological analyses showed that EPSCSlow in cerebellar slices of nNOS knockout (nNOS-/-) mice was significantly larger than that in wildtype (WT) mice. Activation of mGluR1 in cultured PNs from nNOS-/- mice evoked larger TRPC3-channel mediated currents and intracellular Ca2+ rise than that in PNs from WT mice. In addition, nNOS inhibitor and NO-donor increased and decreased, respectively, the TRPC3-current and Ca2+ rise in PNs. Moreover, the NO-donor effectively decreased TRPC3 currents in HEK293 cells expressing WT STIM1, but not cells expressing a STIM1 with cysteine mutants. These novel findings indicate that nNOS/NO inhibits TRPC3-containig channel mediated cation influx during EPSCSlow, at least in part, by S-nitrosylation of STIM1.

Variance analysis as a method to predict the locus of plasticity at populations of non-uniform synapses.

Our knowledge on synaptic transmission in the central nervous system has often been obtained by evoking synaptic responses to populations of synapses. Analysis of the variance in synaptic responses can be applied as a method to predict whether a change in synaptic responses is a consequence of altered presynaptic neurotransmitter release or postsynaptic receptors. However, variance analysis is based on binomial statistics, which assumes that synapses are uniform. In reality, synapses are far from uniform, which questions the reliability of variance analysis when applying this method to populations of synapses. To address this, we used an in silico model for evoked synaptic responses and compared variance analysis outcomes between populations of uniform versus non-uniform synapses. This simulation revealed that variance analysis produces similar results irrespectively of the grade of uniformity of synapses. We put this variance analysis to the test with an electrophysiology experiment using a model system for which the loci of plasticity are well established: the effect of amyloid-ß on synapses. Variance analysis correctly predicted that postsynaptically produced amyloid-ß triggered predominantly a loss of synapses and a minor reduction of postsynaptic currents in remaining synapses with little effect on presynaptic release probability. We propose that variance analysis can be reliably used to predict the locus of synaptic changes for populations of non-uniform synapses.

Synaptic variance and action potential firing of cerebellar output neurons during motor learning in larval zebrafish.

The cerebellum regulates both reflexive and acquired movements. Here, by recording voltage-clamped synaptic currents and spiking in cerebellar output (eurydendroid) neurons in immobilized larval zebrafish, we investigated synaptic integration during reflexive movements and throughout associative motor learning. Spiking coincides with the onset of reflexive fictive swimming but precedes learned swimming, suggesting that eurydendroid signals may facilitate the initiation of acquired movements. Although firing rates increase during swimming, mean synaptic inhibition greatly exceeds mean excitation, indicating that learned responses cannot result solely from changes in synaptic weight or upstream excitability that favor excitation. Estimates of spike threshold crossings based on measurements of intrinsic properties and the time course of synaptic currents demonstrate that noisy excitation can transiently outweigh noisy inhibition enough to increase firing rates at swimming onset. Thus, the millisecond-scale variance of synaptic currents can regulate cerebellar output, and the emergence of learned cerebellar behaviors may involve a time-based code.

Group I metabotropic glutamate receptor-triggered temporally patterned action potential-dependent spontaneous synaptic transmission in mouse MNTB neurons.

Rhythmic action potentials (AP) are generated via intrinsic ionic mechanisms in pacemaking neurons, producing synaptic responses of regular inter-event intervals (IEIs) in their targets. In auditory processing, evoked temporally patterned activities are induced when neural responses timely lock to a certain phase of the sound stimuli. Spontaneous spike activity, however, is a stochastic process, rendering the prediction of the exact timing of the next event completely based on probability. Furthermore, neuromodulation mediated by metabotropic glutamate receptors (mGluRs) is not commonly associated with patterned neural activities. Here, we report an intriguing phenomenon. In a subpopulation of medial nucleus of the trapezoid body (MNTB) neurons recorded under whole-cell voltage-clamp mode in acute mouse brain slices, temporally patterned AP-dependent glycinergic sIPSCs and glutamatergic sEPSCs were elicited by activation of group I mGluRs with 3,5-DHPG (200 µM). Auto-correlation analyses revealed rhythmogenesis in these synaptic responses. Knockout of mGluR5 largely eliminated the effects of 3,5-DHPG. Cell-attached recordings showed temporally patterned spikes evoked by 3,5-DHPG in potential presynaptic VNTB cells for synaptic inhibition onto MNTB. The amplitudes of sEPSCs enhanced by 3,5-DHPG were larger than quantal size but smaller than spike-driven calyceal inputs, suggesting that non-calyceal inputs to MNTB might be responsible for the temporally patterned sEPSCs. Finally, immunocytochemical studies identified expression and localization of mGluR5 and mGluR1 in the VNTB-MNTB inhibitory pathway. Our results imply a potential central mechanism underlying the generation of patterned spontaneous spike activity in the brainstem sound localization circuit.

Establishing extended pluripotent stem cells from human urine cells.

BACKGROUND: Extended pluripotent stem cells (EPSCs) can contribute to both embryonic and trophectoderm-derived extraembryonic tissues. Therefore, EPSCs have great application significance for both research and industry. However, generating EPSCs from human somatic cells remains inefficient and cumbersome. RESULTS: In this study, we established a novel and robust EPSCs culture medium OCM175 with defined and optimized ingredients. Our OCM175 medium contains optimized concentration of L-selenium-methylcysteine as a source of selenium and ROCK inhibitors to maintain the single cell passaging ability of pluripotent stem cells. We also used Matrigel or the combination of laminin 511 and laminin 521(1:1) to bypass the requirement of feeder cells. With OCM175 medium, we successfully converted integration-free iPSCs from easily available human Urine-Derived Cells (hUC-iPSCs) into EPSCs (O-IPSCs). We showed that our O-IPSCs have the ability to form both intra- and extra- embryonic chimerism, and could contribute to the trophoblast ectoderm lineage and three germ layer cell lineages. CONCLUSIONS: In conclusion, our novel OCM175 culture medium has defined, optimized ingredients, which enables efficient generation of EPSCs in a feeder free manner. With the robust chimeric and differentiation potential, we believe that this system provides a solid basis to improve the application of EPSCs in regenerative medicine.

4-EA-NBOMe, an amphetamine derivative, alters glutamatergic synaptic transmission through 5-HT1A receptors on cortical neurons from SpragueDawley rat and pyramidal neurons from C57BL/6 mouse.

New psychoactive substances (NPSs) are compounds designed to mimic illegal recreational drugs. In particular, there are difficulties in legal restrictions because there is no fast NPS detection method to suppress the initial spread of NPS with criminal records; thus, they expose the public to serious health threats, including toxicity and dependence. However, the effects of NPSs on the brain and the related cellular mechanisms are well unknown. One of the recently emerging drugs is 4-ethylamphetamine-NBOMe (4-EA-NBOMe), a member of the 2 C phenylalanine family with a similar structure to methamphetamine (methA). In this study, we tested the effect of methA analogs on the glutamatergic synaptic transmission on primary cultured cortical neurons of SpragueDawley (SD) rats and C57BL/6 mice, and also layer 2/3 pyramidal neurons of the medial prefrontal cortex (mPFC) of C57BL/6 mice. We found that acute treatment with 4-EA-NBOMe inhibits spontaneous excitatory postsynaptic currents (EPSCs) and that withdrawal after chronic inhibition by 4-EA-NBOMe augments glutamatergic synaptic transmission. These modifications of synaptic responses are mediated by 5-HT1A receptors. These findings suggest that 4-EA-NBOMe directly affects the central nervous system by changing the efficacy of glutamatergic synaptic transmission.

Ventromedial hypothalamus relays chronic stress inputs and exerts bidirectional regulation on anxiety state and related sympathetic activity.

Chronic stress can induce negative emotion states, including anxiety and depression, leading to sympathetic overactivation and disturbed physiological homeostasis in peripheral tissues. While anxiety-related neural circuitry integrates chronic stress information and modulates sympathetic nervous system (SNS) activity, the critical nodes linking anxiety and sympathetic activity still need to be clarified. In our previous study, we demonstrated that the ventromedial hypothalamus (VMH) is involved in integrating chronic stress inputs and exerting influence on sympathetic activity. However, the underlying synaptic and electrophysiological mechanisms remain elusive. In this study, we combined in vitro electrophysiological recordings, behavioral tests, optogenetic manipulations, and SNS activity analyses to explore the role of VMH in linking anxiety emotion and peripheral SNS activity. Results showed that the VMH played an important role in bidirectionally regulating anxiety-like behavior and peripheral sympathetic excitation. Chronic stress enhanced excitatory inputs into VMH neurons by strengthening the connection with the paraventricular hypothalamus (PVN), hence promoting anxiety and sympathetic tone outflow, an important factor contributing to the development of metabolic imbalance in peripheral tissues and cardiovascular diseases.

Human early syncytiotrophoblasts are highly susceptible to SARS-CoV-2 infection.

Direct in vivo investigation of human placenta trophoblast's susceptibility to SARS-CoV-2 is challenging. Here we report that human trophoblast stem cells (hTSCs) and their derivatives are susceptible to SARS-CoV-2 infection, which reveals heterogeneity in hTSC cultures. Early syncytiotrophoblasts (eSTBs) generated from hTSCs have enriched transcriptomic features of peri-implantation trophoblasts, express high levels of angiotensin-converting enzyme 2 (ACE2), and are productively infected by SARS-CoV-2 and its Delta and Omicron variants to produce virions. Antiviral drugs suppress SARS-CoV-2 replication in eSTBs and antagonize the virus-induced blockage of STB maturation. Although less susceptible to SARS-CoV-2 infection, trophoblast organoids originating from hTSCs show detectable viral replication reminiscent of the uncommon placental infection. These findings implicate possible risk of COVID-19 infection in peri-implantation embryos, which may go unnoticed. Stem cell-derived human trophoblasts such as eSTBs can potentially provide unlimited amounts of normal and genome-edited cells and facilitate coronavirus research and antiviral discovery.

Patch-clamp analysis of nicotinic synapses whose strength straddles the firing threshold of rat sympathetic neurons.

Neurons in paravertebral sympathetic ganglia are innervated by converging nicotinic synapses of varying strength. Based upon intracellular recordings of excitatory postsynaptic potentials (EPSPs) with sharp microelectrodes these synapses were classified in the past as either primary (strong) or secondary (weak) by their ability to trigger postsynaptic action potentials. Here we present an analysis of 22 synapses whose strength straddled threshold, thereby distinguishing them from the original classification scheme for primary and secondary synapses. Recordings at 36°C were made from intact superior cervical ganglia isolated from 13 male and 3 female Sprague-Dawley rats and from 4 male spontaneously hypertensive (SHR) rats. Ganglia were pretreated with collagenase to permit patch recording. By dissecting a 1 cm length of the presynaptic cervical sympathetic nerve as part of the preparation and through use of graded presynaptic stimulation it was possible to fractionate synaptic inputs by their distinct latencies and magnitudes, and by the presynaptic stimulus threshold for each component. Comparison of cell-attached extracellular recordings with intracellular recordings of synaptic potentials and synaptic currents indicated that straddling EPSPs are not an artifact of shunting damage caused by intracellular recording. The results also showed that in cells where a single presynaptic shock elicits multiple action potentials, the response is driven by multiple synapses and not by repetitive postsynaptic firing. The conductance of straddling synapses also provides a direct estimate of the threshold synaptic conductance (9.8 nS ± 7.6 nS, n = 22, mean ± SD). The results are discussed in terms of their implications for ganglionic integration and an existing model of synaptic amplification.

Insulin-like growth factor 1 regulates excitatory synaptic transmission in pyramidal neurons from adult prefrontal cortex.

Insulin-like growth factor 1 (IGF1) influences synaptic function in addition to its role in brain development and aging. Although the expression levels of IGF1 and IGF1 receptor (IGF1R) peak during development and decline with age, the adult brain has abundant IGF1 or IGF1R expression. Studies reveal that IGF1 regulates the synaptic transmission in neurons from young animals. However, the action of IGF1 on neurons in the adult brain is still unclear. Here, we used prefrontal cortical (PFC) slices from adult mice (∼8 weeks old) to characterize the role of IGF1 on excitatory synaptic transmission in pyramidal neurons and the underlying molecular mechanisms. We first validated IGF1R expression in pyramidal neurons using translating ribosomal affinity purification assay. Then, using whole-cell patch-clamp recording, we found that IGF1 attenuated the amplitude of evoked excitatory postsynaptic current (EPSC) without affecting the frequency and amplitude of miniature EPSC. Furthermore, this decrease in excitatory neurotransmission was blocked by pharmacological inhibition of IGF1R or conditional knockdown of IGF1R in PFC pyramidal neurons. In addition, we determined that IGF1-induced decrease of EPSC amplitude was due to postsynaptic effect (internalization of a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptors [AMPAR]) rather than presynaptic glutamate release. Finally, we found that inhibition of metabotropic glutamate receptor subtype-1 (mGluR1) abolished IGF1-induced attenuation of evoked EPSC amplitude and decrease of AMPAR expression at synaptic membrane, suggesting mGluR1-mediated endocytosis of AMPAR was involved. Taken together, these data provide the first evidence that IGF1 regulates excitatory synaptic transmission in adult PFC via the interaction between IGF1R-dependent signaling pathway and mGluR1-mediated AMPAR endocytosis.

Methylphenidate Restores Behavioral and Neuroplasticity Impairments in the Prenatal Nicotine Exposure Mouse Model of ADHD: Evidence for Involvement of AMPA Receptor Subunit Composition and Synaptic Spine Morphology in the Hippocampus.

In ADHD treatment, methylphenidate (MPH) is the most frequently used medication. The present work provides evidence that MPH restored behavioral impairments and neuroplasticity due to changes in AMPAR subunit composition and distribution, as well as maturation of dendritic spines, in a prenatal nicotine exposure (PNE) ADHD mouse model. PNE animals and controls were given a single oral dose of MPH (1 mg/kg), and their behavior was tested for attention, hyperactivity, and working memory. Long-term potentiation (LTP) was induced and analyzed at the CA3/CA1 synapse in hippocampal slices taken from the same animals tested behaviorally, measuring fEPSPs and whole-cell patch-clamp EPSCs. By applying crosslinking and Western blots, we estimated the LTP effects on AMPAR subunit composition and distribution. The density and types of dendritic spines were quantified by using the Golgi staining method. MPH completely restored the behavioral impairments of PNE mice. Reduced LTP and AMPA-receptor-mediated EPSCs were also restored. EPSC amplitudes were tightly correlated with numbers of GluA1/GluA1 AMPA receptors at the cell surface. Finally, we found a lower density of dendritic spines in hippocampal pyramidal neurons in PNE mice, with a higher fraction of thin-type immature spines and a lower fraction of mushroom mature spines; the latter effect was also reversed by MPH.

DISEMM: a tool for the investigation of elasto-plastic behaviour on polycrystalline samples using X-ray and neutron diffraction.

The software DISEMM is designed to analyse diffraction data from in situ loading experiments on polycrystalline samples for the determination of single-crystal elastic constants (SECs) and elasto-plastic self-consistent (EPSC) modelling of lattice strains. The SECs can be obtained from powder-diffraction elastic constants using a variety of grain-to-grain interaction models, namely Voigt, Reuss, Hill, Kröner, de Wit and Matthies approaches. The texture of the polycrystalline sample can be taken into account using the orientation distribution function of the grains. For the analysis of two-phase materials, an approach was implemented to calculate the stress transfer between the phases and its impact on the apparent elastic properties. The calculated SECs can then be used as input into the EPSC model, which allows the user to predict the elasto-plastic behaviour for comparison with experimental lattice strain data and to investigate the activation of individual slip systems. For this purpose, critical resolved shear stresses and hardening parameters are adapted iteratively.

The electric power supply chain network design and emission reduction policy: a comprehensive review.

Electrical energy is unique because it must sustain a consistent production and consumption balance. This guarantees that the "generation-transmission-distribution-consumption-storage" electric power supply chain (EPSC) continues to be connected and inseparable through the power system's complete operation. This paper is a type of secondary study. According to the nature of the article which is qualitative, the grounded theory (GT) method for reviewing the literature has been used. A systematic review of existing literature is carried out over 12 years (2010-2022) by classifying it based on several dimensions such as phase sources of production, the total fixed cost of the real variable, and criteria of decision-making and emissions. The literature is further divided into categories based on the year of publication and the journals in which it was published. The study shows a direction for future studies in the electric power domain of the supply chain while utilizing an operations strategy approach.

The ß2V287L nicotinic subunit linked to sleep-related epilepsy differently affects fast-spiking and regular spiking somatostatin-expressing neurons in murine prefrontal cortex.

Mutant subunits of the neuronal nicotinic ACh receptor (nAChR) can cause Autosomal Dominant Sleep-related Hypermotor Epilepsy (ADSHE), characterized by frontal seizures during non-rapid eye movement (NREM) sleep. We studied the cellular bases of the pathogenesis in brain slices from mice conditionally expressing the ADSHE-linked ß2V287L nAChR subunit. ß2V287L mice displayed minor structural alterations, except for a ~10% decrease of prefrontal cortex thickness. However, they showed a substantial decrease of the excitatory input to layer V fast-spiking (FS) interneurons, despite a concomitant increase in the number of glutamatergic terminals around the cell soma. Hence, prefrontal hyperexcitability may depend on a permanent impairment of surround inhibition. The effect disappeared when ß2V287L was silenced until postnatal day 15th, suggesting that the transgene selectively affects the maturation of glutamatergic synapses on FS neurons. The other main population of interneurons in layer V was constituted by somatostatin-expressing regular spiking cells. When tested with 10 µM nicotine, these displayed larger somatic nicotinic currents in transgenic mice. Thus, during wakefulness, activation of ß2V287L-containing nAChRs by the high cholinergic tone may counteract hyperexcitability by promoting local inhibition by somatostatin-expressing cells and decreasing the effect of glutamatergic deficit in FS neurons. This interpretation was tested in networks disinhibited by 2 µM bicuculline. Slices expressing ß2V287L were more susceptible to develop synchronized activity in the absence of nicotine. Addition of the drug boosted excitability in the controls, but had little effect in ß2V287L. Our findings suggest why NREM sleep favors ADSHE seizures and nicotine can be palliative in patients.

The Relapse of Psoriasis: Mechanisms and Mysteries.

Over the past decades, tremendous success in the treatment of psoriasis has been achieved using biologics, such as neutralizing antibodies against TNF/TNFR, IL-23, and IL-17A/IL-17RA. Although psoriatic skin lesions appear to resolve after treatment with these biologics, lesions often recur after therapy is discontinued or during therapy. Memory T cells residing in the skin have been considered as the major driver of psoriasis relapse. However, whether structural cells in the skin such as keratinocytes and fibroblasts are involved in the relapse of psoriasis is unknown. In this review, we outline the therapeutic rationale of biologics used in the treatment of psoriasis, summarize different clinical features of psoriasis relapse on the basis of preclinical and clinical data, and specifically discuss how memory T cells and structural cells in the skin are involved in psoriasis relapse. Finally, we discuss the future challenges in the basic or clinical research on psoriasis.

Synapsin II Directly Suppresses Epileptic Seizures In Vivo.

The synapsin family offers a strong linkage between synaptic mechanisms and the epileptic phenotype. Synapsins are phosphoproteins reversibly associated with synaptic vesicles. Synapsin deficiency can cause epilepsy in humans, and synapsin II (SynII) in knockout (KO) mice causes generalized epileptic seizures. To differentiate between the direct effect of SynII versus its secondary adaptations, we used neonatal intracerebroventricular injections of the adeno-associated virus (AAV) expressing SynII. We found that SynII reintroduction diminished the enhanced synaptic activity in Syn2 KO hippocampal slices. Next, we employed the epileptogenic agent 4-aminopyridine (4-AP) and found that SynII reintroduction completely rescued the epileptiform activity observed in Syn2 KO slices upon 4-AP application. Finally, we developed a protocol to provoke behavioral seizures in young Syn2 KO animals and found that SynII reintroduction balances the behavioral seizures. To elucidate the mechanisms through which SynII suppresses hyperexcitability, we injected the phospho-incompetent version of Syn2 that had the mutated protein kinase A (PKA) phosphorylation site. The introduction of the phospho-incompetent SynII mutant suppressed the epileptiform and seizure activity in Syn2 KO mice, but not to the extent observed upon the reintroduction of native SynII. These findings show that SynII can directly suppress seizure activity and that PKA phosphorylation contributes to this function.

Activation of microglial GPR109A alleviates thermal hyperalgesia in female lupus mice by suppressing IL-18 and glutamatergic synaptic activity.

Many patients with systemic lupus erythematosus (SLE) live with chronic pain despite advances in medical management in reducing mortality related to SLE. Few animal studies have addressed mechanisms and treatment for chronic pain caused by SLE. In this study, we provide the first evidence for the analgesic effects of a GPR109A specific agonist (MK1903) and its action mechanisms in thermal hyperalgesia in female MRL/lpr mice, an SLE mouse model. Specifically, we show that MRL/lpr mice had a higher sensitivity to thermal stimuli at age 11-16 weeks, which was accompanied with significantly microglial and astrocytic activation, increases in p38 MAPK and glutamatergic synaptic activities in the spinal dorsal horn. We demonstrate that thermal hyperalgesia in MRL/lpr mice was significantly attenuated by intrathecal injection of MK1903. GPR109A was expressed in spinal microglia but not astrocytes or neurons. Its expression was significantly increased in MRL/lpr mice with thermal hyperalgesia. Activation of GPR109A receptors in microglia attenuated glutamatergic synaptic activity via suppressing production of interleukin-18 (IL-18). We provide evidence that activation of GPR109A attenuated thermal hyperalgesia in the SLE animal model via suppressing p38 MAPK activity and production of IL-18. Our study suggests that targeting the microglial GPR109A is a potent approach for reversing spinal neuroinflammation, abnormal excitatory synaptic activity, and management of thermal hyperalgesia caused by SLE.

Input-dependent synaptic suppression by pregabalin in the central amygdala in male mice with inflammatory pain.

Pregabalin (PGB) is a synthetic amino acid compound most widely prescribed for chronic peripheral and central neuropathic pain. PGB is a ligand for the α2δ1 subunit of voltage-dependent calcium channels, and its binding reduces neurotransmitter release and thus inhibits synaptic transmission. The central nucleus of the amygdala (CeA) is a kernel site for the enhanced nociception-emotion link in chronic pain. The nociceptive information is conveyed to the CeA via the following two pathways: 1) the pathway arising from the basolateral amygdala (BLA), which carries nociceptive information mediated by the thalamocortical system, and 2) that arising from the external part of the pontine lateral parabrachial nucleus (LPB), that forms the final route of the spino-parabrachio-amygdaloid pathway that conveys nociceptive information directly from the superficial layer of the spinal dorsal horn. We compared the effects of PGB on the excitatory postsynaptic currents of neurons in the right CeA in response to electrical stimulation of BLA and LPB pathways using the whole-cell patch-clamp technique. Inflammatory pain was induced by intraplantar injection of formalin solution at the left hind paw. At eight hours post-formalin, PGB reduced EPSCs amplitude of the BLA-to-CeA synaptic transmission, accompanied by a significant increase in the PPR, suggesting a decreased release probability from the presynaptic terminals. In addition, these effects of PGB were only seen in inflammatory conditions. PGB did not affect the synaptic transmission at the LPB-to-CeA pathway, even in formalin-treated mice. These results suggest PGB improves not simply the aberrantly enhanced nociception but also various pain-associated cognitive and affective consequences in patients with chronic nociplastic pain.

Fibroblast Growth Factor 19 Increases the Excitability of Pre-Motor Glutamatergic Dorsal Vagal Complex Neurons From Hyperglycemic Mice.

Intracerebroventricular administration of the protein hormone fibroblast growth factor 19 (FGF19) to the hindbrain produces potent antidiabetic effects in hyperglycemic mice that are likely mediated through a vagal parasympathetic mechanism. FGF19 increases the synaptic excitability of parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) from hyperglycemic, but not normoglycemic, mice but the source of this synaptic input is unknown. Neurons in the area postrema (AP) and nucleus tractus solitarius (NTS) express high levels of FGF receptors and exert glutamatergic control over the DMV. This study tested the hypothesis that FGF19 increases glutamate release in the DMV by increasing the activity of glutamatergic AP and NTS neurons in hyperglycemic mice. Glutamate photoactivation experiments confirmed that FGF19 increases synaptic glutamate release from AP and NTS neurons that connect to the DMV in hyperglycemic, but not normoglycemic mice. Contrary to expectations, FGF19 produced a mixed effect on intrinsic membrane properties in the NTS with a trend towards inhibition, suggesting that another mechanism was responsible for the observed effects on glutamate release in the DMV. Consistent with the hypothesis, FGF19 increased action potential-dependent glutamate release in the NTS in hyperglycemic mice only. Finally, glutamate photoactivation experiments confirmed that FGF19 increases the activity of glutamatergic AP neurons that project to the NTS in hyperglycemic mice. Together, these results support the hypothesis that FGF19 increases glutamate release from AP and NTS neurons that project to the DMV in hyperglycemic mice. FGF19 therefore modifies the local vago-vagal reflex circuitry at several points. Additionally, since the AP and NTS communicate with several other metabolic regulatory nuclei in the brain, FGF19 in the hindbrain may alter neuroendocrine and behavioral aspects of metabolism, in addition to changes in parasympathetic output.