Explore the vast range of titles available.

Rapid and precise neuronal communication is enabled through a highly synchronous release of signaling molecules neurotransmitters within just milliseconds of the action potential. Yet neurotransmitter release lacks a theoretical framework that is both phenomenologically accurate and mechanistically realistic. Here, we present an analytic theory of the action-potential-triggered neurotransmitter release at the chemical synapse. The theory is demonstrated to be in detailed quantitative agreement with existing data on a wide variety of synapses from electrophysiological recordings in vivo and fluorescence experiments in vitro . Despite up to ten orders of magnitude of variation in the release rates among the synapses, the theory reveals that synaptic transmission obeys a simple, universal scaling law, which we confirm through a collapse of the data from strikingly diverse synapses onto a single master curve. This universality is complemented by the capacity of the theory to readily extract, through a fit to the data, the kinetic and energetic parameters that uniquely identify each synapse. The theory provides a means to detect cooperativity among the SNARE complexes that mediate vesicle fusion and reveals such cooperativity in several existing data sets. The theory is further applied to establish connections between molecular constituents of synapses and synaptic function. The theory allows competing hypotheses of short-term plasticity to be tested and identifies the regimes where particular mechanisms of synaptic facilitation dominate or, conversely, fail to account for the existing data for the paired-pulse ratio. The derived trade-off relation between the transmission rate and fidelity shows how transmission failure can be controlled by changing the microscopic properties of the vesicle pool and SNARE complexes. The established condition for the maximal synaptic efficacy reveals that no fine tuning is needed for certain synapses to maintain near-optimal transmission. We discuss the limitations of the theory and propose possible routes to extend it. These results provide a quantitative basis for the notion that the molecular-level properties of synapses are crucial determinants of the computational and information-processing functions in synaptic transmission.

Fezf2 (Fezl) is a transcription factor that specifies corticospinal motor neurons (CSMN) originating from cortical layer 5b. Lodato et al . use cortical progenitor isolation from developing mouse brain and gene expression profiling to identify genes downstream of Fezf2 and demonstrate co-regulation of CSMN gene ensembles by Fezf2 in establishing CSMN cell identity. The neocortex contains an unparalleled diversity of neuronal subtypes, each defined by distinct traits that are developmentally acquired under the control of subtype-specific and pan-neuronal genes. The regulatory logic that orchestrates the expression of these unique combinations of genes is unknown for any class of cortical neuron. Here, we report that Fezf2 is a selector gene able to regulate the expression of gene sets that collectively define mouse corticospinal motor neurons (CSMN). We find that Fezf2 directly induces the glutamatergic identity of CSMN via activation of Vglut1 ( Slc17a7 ) and inhibits a GABAergic fate by repressing transcription of Gad1 . In addition, we identify the axon guidance receptor EphB1 as a target of Fezf2 necessary to execute the ipsilateral extension of the corticospinal tract. Our data indicate that co-regulated expression of neuron subtype–specific and pan-neuronal gene batteries by a single transcription factor is one component of the regulatory logic responsible for the establishment of CSMN identity.

Rationale Neuroactive derivatives of steroid hormones, neurosteroids, can act on GABA A receptors (GABA A Rs) to potentiate the effects of GABA on these receptors. Neurosteroids become elevated to physiologically relevant levels under conditions characterized by increased steroid hormones. There is considerable evidence for plasticity of GABA A Rs associated with altered levels of neurosteroids which may counteract the fluctuations in the levels of these allosteric modulators. Objectives The objective of this review is to summarize the current literature on GABA A R plasticity under conditions characterized by alterations in neurosteroid levels, such as over the estrous cycle, during puberty, and throughout pregnancy and the postpartum period. Results The expression of specific GABA A R subunits is altered over the estrous cycle, at puberty, and throughout pregnancy and the postpartum period. Inability to regulate δ subunit-containing GABA A Rs throughout pregnancy and the postpartum period is associated with depression-like behavior restricted to the postpartum period. Conclusions GABA A R plasticity associated with alterations in neurosteroid levels represents a homeostatic compensatory mechanism to maintain an ideal level of inhibition to offset the potentiating effects of neurosteroids on GABAergic inhibition. Failure to properly regulate GABA A Rs under conditions of altered neurosteroid levels may increase vulnerability to mood disorders, such as premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and postpartum depression.

Gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter that is known to be synthesized and released from GABAergic neurons in the brain. However, recent studies have shown that not only neurons but also astrocytes contain a considerable amount of GABA that can be released and activate GABA receptors in neighboring neurons. These exciting new findings for glial GABA raise further interesting questions about the source of GABA, its mechanism of release and regulation and the functional role of glial GABA. In this review, we highlight recent studies that identify the presence and release of GABA in glial cells, we show several proposed potential pathways for accumulation and modulation of glial intracellular and extracellular GABA content, and finally we discuss functional roles for glial GABA in the brain.

d -Aspartate ( d -Asp) is an endogenous amino acid in the central nervous and reproductive systems of vertebrates and invertebrates. High concentrations of d -Asp are found in distinct anatomical locations, suggesting that it has specific physiological roles in animals. Many of the characteristics of d -Asp have been documented, including its tissue and cellular distribution, formation and degradation, as well as the responses elicited by d -Asp application. d -Asp performs important roles related to nervous system development and hormone regulation; in addition, it appears to act as a cell-to-cell signaling molecule. Recent studies have shown that d -Asp fulfills many, if not all, of the definitions of a classical neurotransmitter—that the molecule’s biosynthesis, degradation, uptake, and release take place within the presynaptic neuron, and that it triggers a response in the postsynaptic neuron after its release. Accumulating evidence suggests that these criteria are met by a heterogeneous distribution of enzymes for d -Asp’s biosynthesis and degradation, an appropriate uptake mechanism, localization within synaptic vesicles, and a postsynaptic response via an ionotropic receptor. Although d -Asp receptors remain to be characterized, the postsynaptic response of d -Asp has been studied and several l -glutamate receptors are known to respond to d -Asp. In this review, we discuss the current status of research on d -Asp in neuronal and neuroendocrine systems, and highlight results that support d -Asp’s role as a signaling molecule.

The mononuclear pterin-dependent nonheme iron enzymes catalyze the rate-limiting step in neurotransmitter biosynthesis and are essential in maintaining proper brain function. These enzymes utilize molecular oxygen, a redox active pterin cofactor, and a ferrous active site to generate an Fe IV -oxo intermediate that catalyzes substrate oxidation. This study demonstrates that the pterin cofactor directly coordinates to the iron center before oxygen activation and also coordinates to a kinetically generated peroxy-Fe II intermediate that is transiently observed in Fe IV -oxo formation. The direct coordination of the pterin cofactor to the iron center enables facile electron transfer to promote rapid oxygen reduction that facilitates the biological function of this family of enzymes and thus defines a unified oxygen activation mechanism for the cofactor-dependent nonheme iron enzymes. The pterin-dependent nonheme iron enzymes hydroxylate aromatic amino acids to perform the biosynthesis of neurotransmitters to maintain proper brain function. These enzymes activate oxygen using a pterin cofactor and an aromatic amino acid substrate bound to the Fe II active site to form a highly reactive Fe IV = O species that initiates substrate oxidation. In this study, using tryptophan hydroxylase, we have kinetically generated a pre-Fe IV = O intermediate and characterized its structure as a Fe II -peroxy-pterin species using absorption, Mössbauer, resonance Raman, and nuclear resonance vibrational spectroscopies. From parallel characterization of the pterin cofactor and tryptophan substrate–bound ternary Fe II active site before the O 2 reaction (including magnetic circular dichroism spectroscopy), these studies both experimentally define the mechanism of Fe IV = O formation and demonstrate that the carbonyl functional group on the pterin is directly coordinated to the Fe II site in both the ternary complex and the peroxo intermediate. Reaction coordinate calculations predict a 14 kcal/mol reduction in the oxygen activation barrier due to the direct binding of the pterin carbonyl to the Fe II site, as this interaction provides an orbital pathway for efficient electron transfer from the pterin cofactor to the iron center. This direct coordination of the pterin cofactor enables the biological function of the pterin-dependent hydroxylases and demonstrates a unified mechanism for oxygen activation by the cofactor-dependent nonheme iron enzymes.

Agriculture surplus were used as substrates to synthesize γ-aminobutyric acid (GABA) by Lactobacillus plantarum DSM19463 for the manufacture of a functional beverage or as a novel application for dermatological purposes. Dilution of the grape must to 1 or 4% (w/v) of total carbohydrates favored higher cell yield and synthesis of GABA with respect to whey milk. Optimal conditions for synthesizing GABA in grape must were: initial pH 6.0, initial cell density of Log 7.0 cfu/mL, and addition of 18.4 mM l-glutamate. L. plantarum DSM19463 synthesized 4.83 mM of GABA during fermentation at 30°C for 72 h. The fermented grape must also contain various levels of niacin, free minerals, and polyphenols, and Log 10.0 cfu/g of viable cells of L. plantarum DSM19463. Freeze dried preparation of grape must was applied to the SkinEthic® Reconstructed Human Epidermis or multi-layer human skin model (FT-skin tissue). The effect on transcriptional regulation of human beta-defensin-2 (HBD-2), hyaluronan synthase (HAS1), filaggrin (FGR), and involucrin genes was assayed through RT-PCR. Compared to GABA used as pure chemical compound, the up-regulation HBD-2 was similar while the effect on the expression of HAS1 and FGR genes was higher.

Background The American lobster, Homarus americanus , is an important species as an economically valuable fishery, a key member in marine ecosystems, and a well-studied model for central pattern generation, the neural networks that control rhythmic motor patterns. Despite multi-faceted scientific interest in this species, currently our genetic resources for the lobster are limited. In this study, we de novo assemble a transcriptome for Homarus americanus using central nervous system (CNS), muscle, and hybrid neurosecretory tissues and compare gene expression across these tissue types. In particular, we focus our analysis on genes relevant to central pattern generation and the identity of the neurons in a neural network, which is defined by combinations of genes distinguishing the neuronal behavior and phenotype, including ion channels, neurotransmitters, neuromodulators, receptors, transcription factors, and other gene products. Results Using samples from the central nervous system (brain, abdominal ganglia), abdominal muscle, and heart (cardiac ganglia, pericardial organs, muscle), we used RNA-Seq to characterize gene expression patterns across tissues types. We also compared control tissues with those challenged with the neuropeptide proctolin in vivo . Our transcriptome generated 34,813 transcripts with known protein annotations. Of these, 5,000-10,000 of annotated transcripts were significantly differentially expressed (DE) across tissue types. We found 421 transcripts for ion channels and identified receptors and/or proteins for over 20 different neurotransmitters and neuromodulators. Results indicated tissue-specific expression of select neuromodulator (allostatin, myomodulin, octopamine, nitric oxide) and neurotransmitter (glutamate, acetylcholine) pathways. We also identify differential expression of ion channel families, including kainite family glutamate receptors, inward-rectifying K + (IRK) channels, and transient receptor potential (TRP) A family channels, across central pattern generating tissues. Conclusions Our transcriptome-wide profiles of the rhythmic pattern generating abdominal and cardiac nervous systems in Homarus americanus reveal candidates for neuronal features that drive the production of motor output in these systems.

Glutamate accumulation into synaptic vesicles is a pivotal step in glutamate transmission. This process is achieved by a vesicular glutamate transporter (VGLUT) coupled to v-type proton ATPase. Normal synaptic transmission, in particular during intensive neuronal firing, would demand rapid transmitter re-filling of emptied synaptic vesicles. We have previously shown that isolated synaptic vesicles are capable of synthesizing glutamate from α-ketoglutarate (not from glutamine) by vesicle-bound aspartate aminotransferase for immediate uptake, in addition to ATP required for uptake by vesicle-bound glycolytic enzymes. This suggests that local synthesis of these substances, essential for glutamate transmission, could occur at the synaptic vesicle. Here we provide evidence that synaptosomes (pinched-off nerve terminals) also accumulate α-ketoglutarate-derived glutamate into synaptic vesicles within, at the expense of ATP generated through glycolysis. Glutamine-derived glutamate is also accumulated into synaptic vesicles in synaptosomes. The underlying mechanism is discussed. It is suggested that local synthesis of both glutamate and ATP at the presynaptic synaptic vesicle would represent an efficient mechanism for swift glutamate loading into synaptic vesicles, supporting maintenance of normal synaptic transmission.

Background This study explored the possible mechanism of flavones from Vitis vinifera L. (VTF) on neurotransmitters, synaptic transmission and related learning and memory in rats with Alzheimer disease (AD). Methods The researchers injected amyloid-β (25–35) into the hippocampus to establish AD model rats. The Sprague-Dawley (SD) rats were divided into a control group, a donepezil group, an AD model group, a VTF low-dose group, a VTF medium-dose group and a VTF high-dose group. The researchers detected the activity of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) according to kit instructions. The protein expression of brain-derived neurotrophic factor (BDNF), synaptotagmin-1 (SYT1) and cyclic adenosine monophosphate response element binding protein (CREB) in the rats’ hippocampi was detected by immunohistochemistry and Western blot, and the gene expression of cAMP-regulated enhancer (CRE) was detected by real-time quantitative polymerase chain reaction (PCR). Results VTF may enhance the protein expression of p-CREB, BDNF and SYT1 in rat hippocampi, depending on dose. The messenger RNA (mRNA) level of CREB was significantly higher in the VTF high-dose group than in the model group, which was consistent with the results of Western blotting. VTF may reduce the activity of AChE and increase that of ChAT in rat hippocampi. Finally, VTF effectively improved the learning and memory abilities of AD rats. Conclusions VTF can promote synaptic plasticity and indirectly affect the expression of cholinergic neurotransmitters, which may be one mechanism of VTF protection in AD rats.