The Glutathione Metabolite γ-Glutamyl-Glutamate Partially Activates Glutamate NMDA Receptors in Central Neurons With Higher Efficacy for GluN2B-Containing Receptors

Gamma-L-glutamyl-L-glutamate (γ-Glu-Glu) was synthetized and further characterized for its activity on cultured neurons. We observed that γ-Glu-Glu elicited excitatory effects on neurons likely by activating mainly the N-methyl-D-aspartate (NMDA) receptors. These effects were dependent on the integrity of synaptic transmission as they were blocked by tetrodotoxin (TTX). We next evaluated its activity on NMDA receptors by testing it on cells expressing these receptors. We observed that γ-Glu-Glu partially activated NMDA receptors and exhibited better efficacy for NMDA receptors containing the GluN2B subunit. Moreover, at low concentration, γ-Glu-Glu potentiated the responses of glutamate on NMDA receptors. Finally, the endogenous production of γ-Glu-Glu was measured by LC-MS on the extracellular medium of C6 rat astroglioma cells. We found that extracellular γ-Glu-Glu concentration was, to some extent, directly linked to GSH metabolism as γ-Glu-Glu can be a by-product of glutathione (GSH) breakdown after γ-glutamyl transferase action. Therefore, γ-Glu-Glu could exert excitatory effects by activating neuronal NMDA receptors when GSH production is enhanced.

Mutations in DISC1 alter IP3R and Voltage-Gated Ca2+ Channel Functioning: Implications for Major Mental Illness

Disrupted in Schizophrenia 1 (DISC1) participates in a wide variety of developmental processes of central neurons. It also serves critical roles that underlie cognitive functioning in adult central neurons. Here we summarize DISC1’s general properties and discuss its use as a model system for understanding major mental illnesses. We then discuss the cellular actions of DISC1 that involve or regulate Ca2+ signaling in adult central neurons. In particular, we focus on the tethering role DISC1 plays in transporting RNA particles containing Ca2+ channel subunit RNAs, including IP3R1, CACNA1C and CACNA2D1, and in transporting mitochondria into dendritic and axonal processes. We also review DISC1’s role in modulating IP3R1 activity within mitochondria-associated ER membrane. Finally, we discuss DISC1-GSK3b signaling that regulates functional expression at voltage-gated Ca2+ channel at central synapses. In each case, DISC1 regulates the movement of molecules that impact Ca2+ signaling in neurons.

Decoding the olfactory map: targeted transcriptomics link olfactory receptors to glomeruli

Sensory processing in olfactory systems is organized across olfactory bulb glomeruli, wherein axons of peripheral sensory neurons expressing the same olfactory receptor co-terminate to transmit receptor-specific activity to central neurons. Understanding how receptors map to glomeruli is therefore critical to understanding olfaction. High-throughput spatial transcriptomics is a rapidly advancing field, but low-abundance olfactory receptor expression within glomeruli has previously precluded high-throughput mapping of receptors to glomeruli. Here we combined sequential sectioning along the anteroposterior, dorsoventral, and mediolateral axes with target capture enrichment sequencing to overcome low-abundance target expression. This strategy allowed us to spatially map 86% of olfactory receptors across the olfactory bulb and uncover a relationship between OR sequence and glomerular position.

Analgesic Effects of the Cressa Cretica Extract on Induced Neuropathic Pain in Rats, and the Potential Role of Opioid Receptors

Background: Damages to the peripheral fibers of sensory nerve cells and central neurons cause neuropathic pain. Manifestations of neuropathic pain occur in various conditions, including diabetes mellitus, chemotherapy, and as the side effects of some medications. Cressa cretica has long been used in traditional medicine for pain control. This study was conducted to determine the role of opioid receptors in the analgesic effect of the hydroalcoholic extract of C. cretica in an experimental model of neuropathic pain. Methods: The hydroalcoholic extract of C. cretica was prepared, and its total phenolic and flavonoid contents were standardized. Painful peripheral neuropathy was induced in rats by Chronic Constriction Injury (CCI) of the sciatic nerve. To evaluate the effects of the extract, the animals were orally given C. cretica extract (300 mg/kg), gabapentin (70 mg/kg) or normal saline (4 mL/kg) on days 3, 7, 14, and 21 after surgery, and behavioral tests were performed 45 minutes after taking the medications. To evaluate the role of the opioid receptors, Naloxone (1 mg/kg, IP) was given to rats treated with the extract 30 minutes after the extract and then the behavioral tests were performed after 15 minutes. Results: The hydroalcoholic extract of C. cretica attenuates neuropathic pain induced by CCI in rats. The extract works acutely and chronically, depending on the dosage and duration of use. Conclusion: The hydroalcoholic extract of C. cretica reduces CCI-induced neuropathic pain in rats, and Naloxone, as an opioid receptor antagonist, inhibits this effect.

Decoding the olfactory map: targeted transcriptomics link olfactory sensory neurons to glomeruli

Sensory processing in vertebrate olfactory systems is organized across olfactory bulb glomeruli, wherein axons of peripheral sensory neurons expressing the same olfactory receptor co-terminate to transmit receptor-specific activity to central neurons. Understanding how receptors map to glomeruli is therefore critical to understanding olfaction. High-throughput spatial transcriptomics is a rapidly advancing field, but low-abundance olfactory receptor expression within glomeruli has previously precluded high-throughput mapping of receptors to glomeruli. Here we combined spatial sectioning along the anteroposterior, dorsoventral, and mediolateral axes with target capture enrichment sequencing to overcome low-abundance target expression. This strategy allowed us to spatially map 86% of olfactory receptors across the olfactory bulb and uncover a relationship between OR sequence and glomerular position.

Characterization of Toxicological and Neurophysiological Effects of Natural Product Based Chromenes to Fall Armyworm, Spodoptera frugiperda

We previously extracted and purified a chromene amide from Amyris texana and found this scaffold is moderately insecticidal and thus, this study aimed to test the insecticidal properties of 13 synthetically derived chromene analogs to the fall armyworm (FAW, Spodoptera frugiperda). Microinjection of chromenes with alcohol or aldehydes substitutions at the meta position on the benzopyran moiety led to moderate toxicity that was approximately 2- to 3-fold less toxic when compared to permethrin, yet microinjection of differently substituted chromenes exhibited little to no toxicity. Similarly, chromenes with alcohol or aldehydes substitutions at the meta position on the benzopyran moiety were among the most toxic chromenes studied through ingested exposure. In addition to acute toxicity, select chromenes significantly increased the percentage of developmental defects upon eclosion that prevented adult moths from being capable of flight, suggesting these compounds alter development. Interestingly, microinjection yielded differing signs of intoxication between alcohol and aldehyde substitutions where the alcohol resulted in flaccid paralysis and lethargy whereas aldehyde led to tonic contractions and hyperactivity. These contrasting signs of intoxication were also observed in electrophysiological assays where alcohol substitutions led to the depression of central neuron firing activity and aldehyde substitutions led to hyperexcitation of central neurons. In summary, the chromene amides led to acute lethality and/or altered developmental trajectories of FAW, yet the high doses required for acute mortality suggest these scaffolds hold relatively little promise for development into FAW-directed insecticides but may represent novel growth regulators for FAW.

Nicotinic acetylcholine receptor redux: Discovery of accessories opens therapeutic vistas

The neurotransmitter acetylcholine (ACh) acts in part through a family of nicotinic ACh receptors (nAChRs), which mediate diverse physiological processes including muscle contraction, neurotransmission, and sensory transduction. Pharmacologically, nAChRs are responsible for tobacco addiction and are targeted by medicines for hypertension and dementia. Nicotinic AChRs were the first ion channels to be isolated. Recent studies have identified molecules that control nAChR biogenesis, trafficking, and function. These nAChR accessories include protein and chemical chaperones as well as auxiliary subunits. Whereas some factors act on many nAChRs, others are receptor specific. Discovery of these regulatory mechanisms is transforming nAChR research in cells and tissues ranging from central neurons to spinal ganglia to cochlear hair cells. Nicotinic AChR–specific accessories also enable drug discovery on high-confidence targets for psychiatric, neurological, and auditory disorders.

Continuous, multidimensional coding of 3D complex tactile stimuli by primary sensory neurons of the vibrissal system

Across all sensory modalities, first-stage sensory neurons are an information bottleneck: they must convey all information available for an animal to perceive and act in its environment. Our understanding of coding properties of primary sensory neurons in the auditory and visual systems has been aided by the use of increasingly complex, naturalistic stimulus sets. By comparison, encoding properties of primary somatosensory afferents are poorly understood. Here, we use the rodent whisker system to examine how tactile information is represented in primary sensory neurons of the trigeminal ganglion (Vg). Vg neurons have long been thought to segregate into functional classes associated with separate streams of information processing. However, this view is based on Vg responses to restricted stimulus sets which potentially underreport the coding capabilities of these neurons. In contrast, the current study records Vg responses to complex three-dimensional (3D) stimulation while quantifying the complete 3D whisker shape and mechanics, thereby beginning to reveal their full representational capabilities. The results show that individual Vg neurons simultaneously represent multiple mechanical features of a stimulus, do not preferentially encode principal components of the stimuli, and represent continuous and tiled variations of all available mechanical information. These results directly contrast with proposed codes in which subpopulations of Vg neurons encode select stimulus features. Instead, individual Vg neurons likely overcome the information bottleneck by encoding large regions of a complex sensory space. This proposed tiled and multidimensional representation at the Vg directly constrains the computations performed by more central neurons of the vibrissotrigeminal pathway.

Effects of Multi-Component Backgrounds of Volatile Plant Compounds on Moth Pheromone Perception

The volatile plant compounds (VPC) alter pheromone perception by insects but mixture effects inside insect olfactory landscapes are poorly understood. We measured the activity of receptor neurons tuned to Z7-12Ac (Z7-ORN), a pheromone component, in the antenna and central neurons in male Agrotis ipsilon while exposed to simple or composite backgrounds of a panel of VPCs representative of the odorant variety encountered by a moth. Maps of activities were built using calcium imaging to visualize which areas in antennal lobes (AL) were affected by VPCs. We compared the VPC activity and their impact as backgrounds at antenna and AL levels, individually or in blends. At periphery, VPCs showed differences in their capacity to elicit Z7-ORN firing response that cannot be explained by differences in stimulus intensities because we adjusted concentrations according to vapor pressures. The AL neuronal network, which reformats the ORN input, did not improve pheromone salience. We postulate that the AL network evolved to increase sensitivity and to encode for fast changes of pheromone at some cost for signal extraction. Comparing blends to single compounds indicated that a blend shows the activity of its most active component. VPC salience seems to be more important than background complexity.

Mechanotransduction channel Piezo is widely expressed in the spider, Cupiennius salei, mechanosensory neurons and central nervous system

Mechanosensory neurons use mechanotransduction (MET) ion channels to detect mechanical forces and displacements. Proteins that function as MET channels have appeared multiple times during evolution and occur in at least four different families: the DEG/ENaC and TRP channels, as well as the TMC and Piezo proteins. We found twelve putative members of MET channel families in two spider transcriptomes, but detected only one, the Piezo protein, by in situ hybridization in their mechanosensory neurons. In contrast, probes for orthologs of TRP, ENaC or TMC genes that code MET channels in other species did not produce any signals in these cells. An antibody against C. salei Piezo detected the protein in all parts of their mechanosensory cells and in many neurons of the CNS. Unspecific blockers of MET channels, Ruthenium Red and GsMTx4, had no effect on the mechanically activated currents of the mechanosensory VS-3 neurons, but the latter toxin reduced action potential firing when these cells were stimulated electrically. The Piezo protein is expressed throughout the spider nervous system including the mechanosensory neurons. It is possible that it contributes to mechanosensory transduction in spider mechanosensilla, but it must have other functions in peripheral and central neurons.