CALHM1 was recently demonstrated to be a voltage‐gated ATP‐permeable ion channel and to serve as a bona fide conduit for ATP release from sweet‐, umami‐, and bitter‐sensing type II taste cells. Calhm1 is expressed in taste buds exclusively in type II cells and its product has structural and functional similarities with connexins and pannexins, two families of channel protein candidates for ATP release by type II cells. Calhm1 knockout in mice leads to loss of perception of sweet, umami, and bitter (...) compounds and to impaired gustatory nerve responses to these tastants. These new studies validate the concept of ATP as the primary neurotransmitter from type II cells to gustatory neurons. Furthermore, they identify voltage‐gated ATP release through CALHM1 as an essential molecular mechanism of ATP release in taste buds. We discuss these new findings, as well as unresolved issues in peripheral taste signaling that we hope will stimulate future research. (shrink)

This argument map presents Paul Loewi’s crucial experiment in which he showed that neural transmissions of signals are chemical in nature, not electrical, in form of an argumentation. The map can be used in science education to show how the formulation of hypotheses should be related to a corresponding determination of experimental designs.

Graphical AbstractWhereas clathrin-mediated endocytosis (CME) exists in all eukaryotic cells, we first detect classical dynamin in Ichthyosporid, a single-cell, metazoan precursor. Based on a key functional residue in its pleckstrin homology domain, we speculate that the evolution of metazoan dynamin coincided with the specialized need for regulated CME during neurotransmission.

Thinkers from a variety of fields analyze the roles of imaging technologies in science and consider their implications for many issues, from our conception of selfhood to the authority of science. In what follows, I encourage scholars to develop an applied philosophy of imaging, that is, to collect these analyses of scientific imaging and to reflect on how they can be made useful for ongoing scientific work. As an example of this effort, I review concepts developed in Don Ihde’s phenomenology (...) of technology and refigure them for use in the analysis of scientific practice. These concepts are useful for drawing out the details of the interpretive frameworks scientists bring to laboratory images. Next, I apply these ideas to a contemporary debate in neurobiology over the interpretation of images of neurons which have been frozen at the moment of transmitter release. This reveals directions for further thought for the study of neurotransmission. (shrink)

Recently a number of complex electrophysiological responses to neurotransmitters have been observed that cannot be described as simple excitation or inhibition. These responses are often characterized as modulatory, although there is no consensus on what defines modulation. Morphological studies reveal certain neurotransmitters stored in what might be release sites without synaptic contact. There is no direct evidence for nonsynaptic release from CNS sites, although such release does occur in the periphery and in invertebrates. Nonsynaptic release might provide a basis for (...) diffuse one-cell-to-many communication, but it might also simply be a means of sending the transmitter to a broader area of a single neuron than occurs in typical synapses. Several kinds of macromolecules have been found to be transported in a retrograde direction – and in some cases transsynaptically. There have been suggestions that some neurons may release more than one type of transmitter. Particularly intriguing is the possibility of release of substances that modulate actions of a primary transmitter. Taken together this range of evidence suggests that neurons may use a variety of forms of molecular communication in addition to traditionally described synaptic transmission.Several authors have suggested modes of communication distinct from classical synaptic transmission and have classified released substances using terms such as neurohumor, neurohormone, neuroregulator, and modulator. These suggestions have the heuristic value of drawing together diverse kinds of data, but it remains to be established that the pieces fit together in that fashion – for example, that complex electrophysiological effects are associated with substances released nonsynaptically. In order to reduce confusion, a flexible, generic approach to nomenclature for substances released from neurons and for hypothetical modes of communication is recommended. Some behavioral implications of nonconventional transmission are considered. (shrink)

This book explores the relationship between schizophrenia and common sense. It approaches this theme from a multidisciplinary perspective. Coverage features contributions from phenomenology, cognitive neuroscience, philosophy of mind, psychology, and social cognition. -/- The contributors address the following questions: How relevant is the loss of common sense in schizophrenia? How can the study of schizophrenia contribute to the study of common sense? How to understand and explain this loss of common sense? -/- They also consider: What is the relationship of (...) practical reasoning and logical formal reasoning with schizophrenia? What is the relationship between the person with a diagnosis of schizophrenia and social values? -/- Chapters examine such issues as rationality, emotions, self, and delusion. In addition, one looks at brain structure and neurotransmission. Others explore phenomenological and Wittgensteinian theories. The book features papers from the Schizophrenia and Common Sense International Workshop, held at New University of Lisbon, November 2015. It offers new insights into this topic and will appeal to researchers, students, as well as interested general readers. (shrink)

Prevailing theories of the neural basis of at least a subset of individuals with autism spectrum disorder include an imbalance of excitatory and inhibitory neurotransmission. These circuitry imbalances are commonly probed in adults using auditory steady-state responses to elicit coherent electrophysiological responses from intact circuitry. Challenges to the ASSR methodology occur during development, where the optimal ASSR driving frequency may be unknown. An alternative approach is the amplitude-modulated sweep in which the amplitude of a tone is modulated as a (...) sweep from 10 to 100 Hz over the course of ∼15 s. Phase synchrony of evoked responses, measured via intra-trial coherence, is recorded as a function of frequency. We applied such AM sweep stimuli bilaterally to 40 typically developing and 80 children with ASD, aged 6–18 years. Diagnoses were confirmed by DSM-5 criteria as well as autism diagnostic observation schedule observational assessment. Stimuli were presented binaurally during MEG recording and consisted of 20 AM swept stimuli with a duration of ∼30 s each. Peak intra-trial coherence values and peak response frequencies of source modeled responses were examined. First, the phase synchrony or inter-trial coherence of the ASSR is diminished in ASD; second, hemispheric bias in the ASSR, observed in typical development, is maintained in ASD, and third, that the frequency at which the peak response is obtained varies on an individual basis, in part dependent on age, and with altered developmental trajectories in ASD vs. TD. Finally, there appears an association between auditory steady-state phase synchrony and clinical assessment of language ability/impairment. We concluded that the AM sweep stimulus provides a mechanism for probing ASSR in an unbiased fashion, during developmental maturation of peak response frequency, peak frequencies vary, in part due to developmental age, and importantly, ITC at this peak frequency is diminished in ASD, with the degree of ITC disturbance related to clinically assessed language impairment. (shrink)

Attention-deficit/hyperactivity disorder (ADHD) represents adaptation to defective neurotransmission – an adaptation seldom with benefit. The resulting behavioural style not only increases vulnerability to adverse experiences, but also creates a context in which encountering adversity is more likely. Furthermore, the fact that ADHD is a highly heritable condition increases the probability of a child with a compromised neurobiological disposition being raised by caregivers with suboptimal resources.

Elevations in brain stimulation reward (BSR) thresholds have been observed in rats undergoing nicotine withdrawal and have been proposed as a sensitive measure of the negative affective state associated with nicotine withdrawal. mGluR are presynaptic autoreceptors that decrease glutamate release when stimulated. The aim of this study was to examine the role of glutamate neurotransmission in nicotine dependence. The mGluR agonist LY314582 (2.5–7.5 mg/kg) precipitated nicotine withdrawal as measured by elevations in BSR thresholds in nicotine-treated rats but not in (...) controls. It was hypothesized that LY314582 precipitated nicotine withdrawal by decreasing glutamatergic tone at postsynaptic glutamate receptors. Therefore, the effects of MPEP (0.5–2 mg/kg), an mGluR antagonist, and MK-801 (0.01–1 mg/kg), an NMDA receptor antagonist, were examined. MPEP elevated BSR thresholds by an equal magnitude in control and nicotine-treated rats. At low doses, MK-801 (0.01–0.2 mg/kg) lowered BSR thresholds to a similar extent in control and nicotine-treated rats. At higher doses, MK-801 (0.25–1 mg/kg) disrupted performance in nicotine-treated and control rats. These data indicate that mGluR and NMDA receptors regulate BSR in opposite directions in non-dependent animals, and chronic nicotine treatment does not alter these effects. Most importantly, the data demonstrate that the mGluR is involved in nicotine dependence, but mGluR and NMDA receptors do not mediate mGluR actions in nicotine dependence. (shrink)

Adenosine 5′-triphosphate (ATP) was identified in 1970 as the transmitter responsible for non-adrenergic, non-cholinergic neurotransmission in the gut and bladder and the term ‘purinergic’ was coined. Purinergic cotransmission was proposed in 1976 and ATP is now recognized as a cotransmitter in all nerves in the peripheral and central nervous systems. P1 (adenosine) and P2 (ATP) receptors were distinguished in 1978. Cloning of these receptors in the early 1990s was a turning point in the acceptance of the purinergic signalling hypothesis. (...) There are both short-term purinergic signalling in neurotransmission, neuromodulation and secretion and long-term (trophic) purinergic signalling of cell proliferation, differentiation and death in development and regeneration. Much is known about the mechanisms of ATP release and its breakdown by ectonucleotidases. Recently, there has been emphasis on purinergic pathophysiology, including neurodegenerative and neuropsychiatric disorders. Purinergic therapeutic strategies are being developed for treatment of gut, kidney, bladder, lung, skeletal and reproductive system disorders, pain and cancer. (shrink)

The human brain does not use more energy than the smaller brains of animals of comparable corporal weight. Uniquely, human functions localized largely in parts of the human brain that show greatest size increase over other animals may be mediated primarily by nonsynaptic neurotransmission, with reduced energy cost per kilogram of brain. This may affect the energetic constraints on evolution.

Many biologically active compounds including neurotransmitters, metabolic precursors, and certain drugs are accumulated intracellularly by transporters that are coupled to the transmembrane Na+ gradient. Amino acid neurotransmitter transporters play a key role in the regulation of extracellular amino acid concentrations and termination of neurotransmission in the CNSAbbreviations: CNS, central nervous system; GABA, γ‐aminobutyric acid; cDNA, complementary deoxyribonucleic acid; mRNA, messenger ribonucleic acid; NMDA, N‐methyl‐D‐aspartate; PKC, protein kinase C; PMA, phorbol 12‐myristate 13‐acetate; DAG, diacyl glycerol; R59022, DAG kinase inhibitor; AA, (...) arachidonic acid; ACHC, cis‐3‐aminocyclohexanecarboxylic acid; GAT‐A, ACHC‐sensitive GABA transporter; GAT‐B, β‐alanine‐sensitive GABA transporter; GLY‐1 and GLYT‐1, glycine transporters; PROT‐1, proline transporter; BGT‐1, betaine transporter.. Transporters for the major amino acid neurotransmitters glutamate, GABA, and glycine are found in both neurons and glial cells. Recent work has resulted in the identification of cDNAs encoding several amino acid neurotransmitter transport proteins, all of which belong to the Na+‐and Cl−‐dependent transporter gene family. The diversity of this family suggests a degree of transporter heterogeneity that is greater than that indicated by biochemical and pharmacological studies. (shrink)

This book explores the relationship between schizophrenia and common sense. It approaches this theme from a multidisciplinary perspective. Coverage features contributions from phenomenology, cognitive neuroscience, philosophy of mind, psychology, and social cognition. The contributors address the following questions: How relevant is the loss of common sense in schizophrenia? How can the study of schizophrenia contribute to the study of common sense? How to understand and explain this loss of common sense? They also consider: What is the relationship of practical reasoning (...) and logical formal reasoning with schizophrenia? What is the relationship between the person with a diagnosis of schizophrenia and social values? Chapters examine such issues as rationality, emotions, self, and delusion. In addition, one looks at brain structure and neurotransmission. Others explore phenomenological and Wittgensteinian theories. The book features papers from the Schizophrenia and Common Sense International Workshop, held at New University of Lisbon, November 2015. It offers new insights into this topic and will appeal to researchers, students, as well as interested general readers. (shrink)

Substance P and related tachykinin peptides probably act as neurotransmitters or modulators of neurotransmission, and regulate biological processes as diverse as salivary secretion and transmission of pain signals. Substance P peptide sequences are expressed in three distinct mRNAs that are generated from one gene by differential RNA splicing. In addition to substance P, as many as three other tachykinin peptides can be generated from the polyprotein precursors by differential posttranslational processing. Three tachykinin receptor subtypes have been extensively characterized which (...) differentially interact with the naturally occurring tachykinin peptides. Therefore, the generation of diversity of tachykinin peptides results from differential precursor RNA splicing and differential posttranslational processing. The specificity of peptide responses is the result of selective receptor subtype expression. (shrink)

Determining the brain properties that make people ‘brainier’ has moved well beyond early demonstrations that increasing intelligence correlates with increasing grey and white matter volumes. Both structural and functional in vivo neuroimaging techniques delineate a distributed network of brain regions, perhaps with a focus in the lateral prefrontal cortex, which varies in extent and connectivity with individual differences in intelligence. Longitudinal studies further show that the neuroanatomic correlates of intelligence are dynamic, changing most rapidly in early childhood. Several promising candidate (...) genes affecting neuronal development and neurotransmission have been proposed that might begin to explain the marked genetic overlap between cortical morphology and intelligence. A major future challenge is to determine the cellular events that underpin the neuroanatomic differences correlated with intelligence. BioEssays 29:962–973, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The first clinical symptoms focused on the presentation of coronavirus disease 2019 have been respiratory failure, however, accumulating evidence also points to its presentation with neuropsychiatric symptoms, the exact mechanisms of which are not well known. By using a computational methodology, we aimed to explain the molecular paths of COVID-19 associated neuropsychiatric symptoms, based on the mimicry of the human protein interactions with SARS-CoV-2 proteins.Methods: Available 11 of the 29 SARS-CoV-2 proteins’ structures have been extracted from Protein Data Bank. HMI-PRED, (...) a recently developed web server for structural PREDiction of protein-protein interactions between host and any microbial species, was used to find the “interface mimicry” through which the microbial proteins hijack host binding surfaces. Classification of the found interactions was conducted using the PANTHER Classification System.Results: Predicted Human-SARS-CoV-2 protein interactions have been extensively compared with the literature. Based on the analysis of the molecular functions, cellular localizations and pathways related to human proteins, SARS-CoV-2 proteins are found to possibly interact with human proteins linked to synaptic vesicle trafficking, endocytosis, axonal transport, neurotransmission, growth factors, mitochondrial and blood-brain barrier elements, in addition to its peripheral interactions with proteins linked to thrombosis, inflammation and metabolic control.Conclusion: SARS-CoV-2-human protein interactions may lead to the development of delirium, psychosis, seizures, encephalitis, stroke, sensory impairments, peripheral nerve diseases, and autoimmune disorders. Our findings are also supported by the previous in vivo and in vitro studies from other viruses. Further in vivo and in vitro studies using the proteins that are pointed here, could pave new targets both for avoiding and reversing neuropsychiatric presentations. (shrink)

The role of acetylcholinesterase (AChE) in neurotransmission is well known. But long before synapses are formed in vertebrates, AChE is expressed in young postmitotic neuroblasts that are about to extend the first long tracts. AChE histochemistry can thus be used to map primary steps of brain differentiation. Preceding an possibly inducing AChE in avian brains, the closely related butyrylcholinesterase (BChE) spatially fore-shadows AChE-positive cell areas and the course of their axons. In particular, before spinal motor axons grow, their corresponding (...) rostral sclerotomes and myotomes express BChE, and both their neuronal source and myotomal target cells express AChE. Since axon growth has been found inhibited by acetylcholine, it is postulated that both cholinetsreases can attract neurite growth cones by neutralizing the inhibitor. Thus, the early expression of both cholinesterases that is at least partially independent from classical cholinergic synaptogenesis, sheds new light on the developmental and medical significance of these enzymes. (shrink)

From single‐cell organisms to complex neural networks, all evolved to provide control solutions to generate context‐ and goal‐specific actions. Neural circuits performing sensorimotor computation to drive navigation employ inhibitory control as a gating mechanism as they hierarchically transform (multi)sensory information into motor actions. Here, the focus is on this literature to critically discuss the proposition that prominent inhibitory projections form sensorimotor circuits. After reviewing the neural circuits of navigation across various invertebrate species, it is argued that with increased neural circuit (...) complexity and the emergence of parallel computations, inhibitory circuits acquire new functions. The contribution of inhibitory neurotransmission for navigation goes beyond shaping the communication that drives motor neurons, and instead includes encoding of emergent sensorimotor representations. A mechanistic understanding of the neural circuits performing sensorimotor computations in invertebrates will unravel the minimum circuit requirements driving adaptive navigation. (shrink)

Depue & Collins's (D&C's) work relies on extrapolation from data obtained through studies in experimental animals, and needs support from studies of the role of dopamine (DA) neurotransmission in human behaviour. Here we review evidence from two sources: (1) studies of patients with Parkinson's disease and (2) positron emission tomography (PET) studies of DA neurotransmission, which we believe lend support to Depue & Collins's theory, and which can potentially form the basis for a true neurochemistry of personality.

Secretion is a fundamental cellular process involving the regulated release of intracellular products from cells. Physiological functions such as neurotransmission, or the release of hormones and digestive enzymes, are all governed by cell secretion. Anomalies in the processes involved in secretion contribute to the development and progression of diseases such as diabetes and other hormonal disorders. To unravel the mechanisms that govern such diseases, it is essential to understand how hormones, growth factors and neurotransmitters are synthesized and processed, and (...) how their signals are recognized, amplified and transmitted by intracellular signaling pathways in the target cells. Here, we discuss diverse aspects of the detailed mechanisms involved in secretion based on mathematical models. The models range from stochastic ones describing the trafficking of secretory vesicles to deterministic ones investigating the regulation of cellular processes that underlie hormonal secretion. In all cases, the models are closely related to experimental results and suggest theoretical predictions for the secretion mechanisms. (shrink)

In the mammalian brain dopamine systems play a central role in the control of movement, hormone release, emotional balance and reward. Alteration of dopaminergic neurotransmission is involved in Parkinson's disease and other movement disorders, as well as in some psychotic syndromes. This review summarises recent findings, which shed some light on signals and cellular interactions involved in the specification and maturation of the dopaminergic function during neurogenesis. In particular we will focus on three major issues: (1) the differentiation of (...) dopaminergic neurones triggered by direct contact with the midbrain floor plate cells through the action of sonic hedgehog; (2) the neurotrophic factors acting on dopaminergic neurones; and (3) the role of target striatal cells on the survival and the axonal growth of developing or grafted dopaminergic neurones. (shrink)

This pioneering book explores in depth the role of neurotransmitters in conscious awareness. The central aim is to identify common neural denominators of conscious awareness, informed by the neurochemistry of natural, drug induced and pathological states of consciousness. Chemicals such as acetylcholine and dopamine, which bridge the synaptic gap between neurones, are the 'neurotransmitters in mind' that form the substance of the volume, which is essential reading for all who believe that unravelling mechanisms of consciousness must include these vital systems (...) of the brain.Up-to-date information is provided on: Psychological domains of attention, motivation, memory, sleep and dreaming that define normal states of consciousness. Effects of chemicals that alter or abolish consciousness, including hallucinogens and anaesthetics. Disorders of the brain such as dementia, schizophrenia and depression considered from the novel perspective of the way these affect consciousness, and how this might relate to disturbances in neurotransmission.(Series B). (shrink)

Technologies for deriving human neurons in vitro have transformed our ability to study cellular and molecular components of human neurotransmission. Three groups, including our own, have recently published methods for efficiently generating human serotonergic neurons in vitro. Remarkably, serotonergic neurons derived from each method robustly produce serotonin, express raphe genes, are electrically active, and respond to selective serotonin reuptake inhibitors in vitro. Two of the methods utilize transdifferentiation technology by overexpressing key serotonergic transcription factors. The third and most recent (...) method involves differentiating induced pluripotent stem cells (iPSCs) to serotonergic neurons using developmental patterning cues. In this mini‐review, we briefly describe the developmental programs governing serotonergic specification in vivo and how they have been harnessed to achieve serotonergic differentiation in vitro. We discuss the distinct and overlapping features of the recently published methodologies and their value in the context of in vitro disease modeling.Also see the video abstract here. (shrink)