Miranda N. Reed

Dietary selenium protects against selected signs of aging and methylmercury exposure

Acute or short-term exposure to high doses of methylmercury (MeHg) causes a well-characterized syndrome that includes sensory and motor deficits. The environmental threat from MeHg, however, comes from chronic, low-level exposure, the consequences of which are poorly understood. Selenium (Se), an essential nutrient, both increases deposition of mercury (Hg) in neurons and mitigates some of MeHgs neurotoxicity in the short term, but it is unclear whether this deposition produces long-term adverse consequences. To investigate these issues, adult Long-Evans rats were fed a diet containing 0.06 or 0.6 ppm of Se as sodium selenite. After 100 days on these diets, the subjects began consuming 0.0, 0.5, 5.0, or 15 ppm of Hg as methylmercuric chloride in their drinking water for 16 months. Somatosensory sensitivity, grip strength, hindlimb cross (clasping reflex), flexion, and voluntary wheel-running in overnight sessions were among the measures examined. MeHg caused a dose- and time-dependent impairment in all measures. No effects appeared in rats consuming 0 or 0.5 ppm of Hg. Somatosensory function, grip strength, and flexion were among the earliest signs of exposure. Selenium significantly delayed or blunted MeHgs effects. Selenium also increased running in unexposed animals as they aged, a novel finding that may have important clinical implications. Nerve pathology studies revealed axonal atrophy or mild degeneration in peripheral nerve fibers, which is consistent with abnormal sensorimotor function in chronic MeHg neurotoxicity. Lidocaine challenge reproduced the somatosensory deficits but not hindlimb cross or flexion. Together, these results quantify the neurotoxicity of long-term MeHg exposure, support the safety and efficacy of Se in ameliorating MeHgs neurotoxicity, and demonstrate the potential benefits of Se during aging.

Gestational methylmercury exposure selectively increases the sensitivity of operant behavior to cocaine.

Developmental methylmercury (MeHg) exposure alters dopamine neurotransmitter systems, but the selectivity of this and the effects of low, environmentally relevant MeHg exposure regimens are poorly understood. In previous reports, some including littermates of animals studied here, chronic, low-level exposures affected performance on reversal tasks and enhanced reinforcer efficacy. Using high- and low-rate operant behavior under a fixed interval (FI) schedule, sensitivity was examined to drugs that target noradrenergic and dopaminergic neurotransmitter systems. Female rats were exposed in utero to 0, 0.5, or 5 ppm of mercury, as MeHg, via maternal drinking water. Selenium (Se) is thought to attenuate MeHgs neurotoxicity, so animals consumed a diet containing 0.06 or 0.6 ppm of Se. At 11 months, they lever-pressed under a FI 120 schedule of sucrose reinforcement. Acute dose-effect curves were generated with cocaine, desipramine, SKF-38393, quinpirole, SCH-23390, and sulpiride. As compared with unexposed animals, those exposed to 5 ppm mercury, regardless of Se exposure, were 2 to 3 times more sensitive to the rate-reducing effects of high doses of cocaine and did not show increased responding earlier in the interval following moderate cocaine doses. Cocaines effects in the 0.5 ppm Hg groups depended on dietary Se: low Se diet resulted in a rightward shift in the DEC compared to controls, whereas a high Se diet did not. No differential effects of MeHg were seen with the other drugs. Gestational MeHg exposure produces irreversible sensitivity to dopamine, but not norepinephrine, reuptake inhibitors and not to drugs that target D1 or D2 receptors.

Altered AMPA receptor expression plays an important role in inducing bidirectional synaptic plasticity during contextual fear memory reconsolidation

HighlightsAltered AMPA receptor expression contributes to LTP and LTD during reconsolidation.New protein synthesis also plays an important role in memory reconsolidation.Interruption in AMPA receptor expression cause altered plasticity pattern. Abstract Retrieval of a memory appears to render it unstable until the memory is once again re‐stabilized or reconsolidated. Although the occurrence and consequences of reconsolidation have received much attention in recent years, the specific mechanisms that underlie the process of reconsolidation have not been fully described. Here, we present the first electrophysiological model of the synaptic plasticity changes underlying the different stages of reconsolidation of a conditioned fear memory. In this model, retrieval of a fear memory results in immediate but transient alterations in synaptic plasticity, mediated by modified expression of the glutamate receptor subunits GluA1 and GluA2 in the hippocampus of rodents. Retrieval of a memory results in an immediate impairment in LTP, which is enhanced 6 h following memory retrieval. Conversely, memory retrieval results in an immediate enhancement of LTD, which decreases with time. These changes in plasticity are accompanied by decreased expression of GluA2 receptor subunits. Recovery of LTP and LTD correlates with progressive overexpression of GluA2 receptor subunits. The contribution of the GluA2 receptor was confirmed by interfering with receptor expression at the postsynaptic sites. Blocking GluA2 endocytosis restored LTP and attenuated LTD during the initial portion of the reconsolidation period. These findings suggest that altered GluA2 receptor expression is one of the mechanisms that controls different forms of synaptic plasticity during reconsolidation.

Peripherally restricted viral challenge elevates extracellular glutamate and enhances synaptic transmission in the hippocampus

Peripheral infections increase the propensity and severity of seizures in susceptible populations. We have previously shown that intraperitoneal injection of a viral mimic, polyinosinic‐polycytidylic acid (PIC), elicits hypersusceptibility of mice to kainic acid (KA)‐induced seizures. This study was undertaken to determine whether this seizure hypersusceptibility entails alterations in glutamate signaling. Female C57BL/6 mice were intraperitoneally injected with PIC, and after 24 h, glutamate homeostasis in the hippocampus was monitored using the enzyme‐based microelectrode arrays. PIC challenge robustly increased the level of resting extracellular glutamate. While pre‐synaptic potassium‐evoked glutamate release was not affected, glutamate uptake was profoundly impaired and non‐vesicular glutamate release was augmented, indicating functional alterations of astrocytes. Electrophysiological examination of hippocampal slices from PIC‐challenged mice revealed a several fold increase in the basal synaptic transmission as compared to control slices. PIC challenge also increased the probability of pre‐synaptic glutamate release as seen from a reduction of paired‐pulse facilitation and synaptic plasticity as seen from an enhancement of long‐term potentiation. Altogether, our results implicate a dysregulation of astrocytic glutamate metabolism and an alteration of excitatory synaptic transmission as the underlying mechanism for the development of hippocampal hyperexcitability, and consequently seizure hypersusceptibility following peripheral PIC challenge.

Targeted inhibition of RAGE reduces amyloid-β influx across the blood-brain barrier and improves cognitive deficits in db/db mice

Aims: To investigate restorative effects of the receptor for advanced glycation end products (RAGE)‐specific inhibitor FPS‐ZM1 on abnormal amyloid &bgr; (A&bgr;) influx across the blood brain‐barrier (BBB) and cognitive deficits in db/db mice. Methods: A&bgr; influx across the BBB was determined by intra‐arterial infusion of 125I‐A&bgr;1‐40. Receptor for advanced glycation end products (RAGE), A&bgr;, NF‐&kgr;B p65, caspase‐3, Bax, Bcl‐2, PSD‐95 and synaptophysin were assayed by Western blot, immunohistochemistry or RT‐PCR. Apoptosis was quantified by TUNEL assay. In vivo hippocampal long term potentiation (LTP) recording, Golgi Staining, Morris water maze (MWM) task and Y‐maze test were performed. Results: FPS‐ZM1 (1.0 mg/kg i.p.) inhibited A&bgr; influx across the BBB and expression of RAGE participating in A&bgr; influx, consequently decreased hippocampal A&bgr;1‐40 and A&bgr;1‐42 in db/db mice. After FPS‐ZM1 treatment, NF‐&kgr;B signaling was inhibited, and neuronal apoptosis was reduced, which revealed by less TUNEL + cells, reduced caspase‐3 activity and higher ratio of Bcl‐2/Bax. In addition, FPS‐ZM1 improved hippocampal plasticity evidenced by enhanced in vivo LTP and the restoration of spine deficit and increased PSD‐95 expression in hippocampal neuron. Further studies found that FPS‐ZM1 treatment alleviated cognitive deficits shown by better performance in behavioral tests, without significant metabolic effects on blood glucose, insulin and cerebral AGEs. Conclusion: Downregulation of abnormal A&bgr; influx across the BBB by FPS‐ZM1 at higher dosage contributes to reduced neuronal apoptosis, improved hippocampal plasticity and cognitive impairment in db/db mice. HighlightsTargeted inhibition of RAGE restores abnormal transport of A&bgr; across the BBB.Targeted inhibition of RAGE reduces A&bgr; levels in brain of db/db mice.Targeted inhibition of RAGE ameliorates memory impairment in db/db mice.Targeted inhibition of RAGE inhibits neuronal apoptosis and improve hippocampal plasticity.

Riluzole rescues alterations in rapid glutamate transients in the hippocampus of rTg4510 mice

Those at risk for Alzheimer’s disease (AD) often exhibit hippocampal hyperexcitability in the years preceding diagnosis. Our previous work with the rTg(TauP301L)4510 tau mouse model of AD suggests that this increase in hyperexcitability is likely mediated by an increase in depolarization-evoked glutamate release and a decrease in glutamate uptake, alterations of which correlate with learning and memory deficits. Treatment with riluzole restored glutamate regulation and rescued memory deficits in the TauP301L model. Here, we used enzyme-based ceramic microelectrode array technology to measure real-time phasic glutamate release and uptake events in the hippocampal subregions of TauP301L mice. For the first time, we demonstrate that perturbations in glutamate transients (rapid, spontaneous bursts of glutamate) exist in a tau mouse model of AD mouse model and that riluzole mitigates these alterations. These results help to inform our understanding of how glutamate signaling is altered in the disease process and also suggest that riluzole may serve as a clinically applicable therapeutic approach in AD.

Antidepressant-like effect of zileuton is accompanied by hippocampal neuroinflammation reduction and CREB/BDNF upregulation in lipopolysaccharide-challenged mice

BACKGROUNDnRecent studies demonstrated beneficial effects of zileuton, a 5-lipoxygenase (5LO) inhibitor, on some brain diseases in animal models, but the role of zileuton in the depression remains unknown.nnnMETHODSnWe investigated the effects of zileuton on depressive behaviors using tail suspension test (TST), forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice injected with lipopolysaccharide (LPS). The 5LO level, activation of microglia, NF-κB p65, TNF-α, IL-1β, brain-derived neurotrophic factor (BDNF), and c-AMP response element-binding protein (CREB) were determined in the mouse hippocampus.nnnRESULTSnWe firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and was reversed by fluoxetine administration. Zileuton significantly suppressed LPS-induced depressive behaviors, evidenced by the decreases in immobility time in TST and FST, as well as the latency to feed in NSFT. This treatment pronouncedly alleviated LPS-induced neuroinflammatory response, characterized by decreased 5LO, suppressed activation of microglia, decreased NF-κB p65, TNF-α and IL-1β, and significantly increased the ratio of p-CREB/CREB or mBDNF/proBDNF in the hippocampus of the LPS-challenged mice.nnnCONCLUSIONSnZileuton abrogates LPS-induced depressive-like behaviors and neuroinflammation, and enhances CREB/BDNF signaling in the hippocampus, suggesting that zileuton could have potential therapeutic value for depression.

Inhibitory effect of INT-777 on lipopolysaccharide-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice.

Abstract Neuroinflammation plays an important role in the pathophysiology of Alzheimers disease (AD) and memory impairment. Herein, we evaluated the neuroprotective effects of 6‐ethyl‐23(S)‐methyl‐cholic acid (INT‐777), a specific G‐protein coupled bile acid receptor 1 (TGR5) agonist, in the LPS‐treated mouse model of acute neurotoxicity. Single intracerebroventricular (i.c.v.) injection of LPS remarkably induced mouse behavioral impairments in Morris water maze, novel object recognition, and Y‐maze avoidance tests, which were ameliorated by INT‐777 (1.5 or 3.0 &mgr;g/mouse, i.c.v.) treatment. Importantly, INT‐777 treatment reversed LPS‐induced TGR5 down‐regulation, suppressed the increase of nuclear NF‐&kgr;B p65, and mitigated neuroinflammation, evidenced by lower proinflammatory cytokines, less activation of microglia, and increased the ratio of p‐CREB/CREB or mBDNF/proBDNF in the hippocampus and frontal cortex. In addition, INT‐777 treatment also suppressed neuronal apoptosis, as indicated by the reduction of TUNEL‐positive cells, decreased activation of caspase‐3, increased the ratio of Bcl‐2/Bax, and ameliorated synaptic dysfunction as evidenced by the upregulation of PSD95 and synaptophysin in the hippocampus and frontal cortex. Taken together, this study showed the potential neuroprotective effects of INT‐777 against LPS‐induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice. HighlightsTGR5 agonist INT‐777 ameliorates LPS‐induced cognitive impairment.TGR5 agonist INT‐777 protects against neuroinflammation, apoptosis, and synaptic dysfunction induced by LPS.These effects are associated with the change of TGR5 expression.

6.11 – Neurotransmitter Receptors☆

Neurotransmitter receptors play a vital role in the normal functioning of the nervous system. Controlled modulation of neurotransmitter receptors is critical for proper signaling between nerve cells and effector organs. Factors that disrupt normal neurotransmitter signaling can alter the homeostasis of the cells or tissues, leading to adverse effects. The release of neurotransmitters at the presynaptic neuron and the subsequent activation of postsynaptic receptors lead to stimulation or inhibition of neuronal transmission. The excitatory neurotransmission involves depolarization of the postsynaptic neuron or cell due to a decrease in the polarity of the cells by the influx of cations such as sodium ions. The excitatory neurotransmission is mainly carried out by glutamate receptors in the mammalian nervous system. The inhibitory neurotransmission is due to hyperpolarization of the cells by either influx of anions such as chloride ions or efflux of cations such as potassium ions. The GABA and glycine receptors serve as major inhibitory neurotransmitter receptors. Toxins and toxicants can interfere with neuronal transmission by directly binding receptors and modulating their function or by altering transmitter synthesis, release, and reuptake mechanisms. Therefore, neurotoxins can impair neuronal transmission at the synapse by either presynaptic modulation or postsynaptic modifications. Due to the intricate network of the nervous system, impairment of the receptor functions in the synapse can lead to regional network dysfunction, eventually resulting in adverse cellular effects and behavioral deficits. Therefore, a thorough knowledge of neurotransmitter receptor modulation by toxins and toxicants is essential for future development of therapies against adverse effects of these neurotoxic substances.

Role of Adiponectin in Central Nervous System Disorders

Adiponectin, the most abundant plasma adipokine, plays an important role in the regulation of glucose and lipid metabolism. Adiponectin also possesses insulin-sensitizing, anti-inflammatory, angiogenic, and vasodilatory properties which may influence central nervous system (CNS) disorders. Although initially not thought to cross the blood-brain barrier, adiponectin enters the brain through peripheral circulation. In the brain, adiponectin signaling through its receptors, AdipoR1 and AdipoR2, directly influences important brain functions such as energy homeostasis, hippocampal neurogenesis, and synaptic plasticity. Overall, based on its central and peripheral actions, recent evidence indicates that adiponectin has neuroprotective, antiatherogenic, and antidepressant effects. However, these findings are not without controversy as human observational studies report differing correlations between plasma adiponectin levels and incidence of CNS disorders. Despite these controversies, adiponectin is gaining attention as a potential therapeutic target for diverse CNS disorders, such as stroke, Alzheimers disease, anxiety, and depression. Evidence regarding the emerging role for adiponectin in these disorders is discussed in the current review.