Synaptic inhibition and γ-aminobutyric acid in the mammalian central nervous system

Signal transmission through synapses connecting two neurons is mediated by release of neurotransmitter from the presynaptic axon terminals and activation of its receptor at the postsynaptic neurons. γ-Aminobutyric acid (GABA), non-protein amino acid formed by decarboxylation of glutamic acid, is a principal neurotransmitter at inhibitory synapses of vertebrate and invertebrate nervous system. On one hand glutamic acid serves as a principal excitatory neurotransmitter. This article reviews GABA researches on; (1) synaptic inhibition by membrane hyperpolarization, (2) exclusive localization in inhibitory neurons, (3) release from inhibitory neurons, (4) excitatory action at developmental stage, (5) phenotype of GABA-deficient mouse produced by gene-targeting, (6) developmental adjustment of neural network and (7) neurological/psychiatric disorder. In the end, GABA functions in simple nervous system and plants, and non-amino acid neurotransmitters were supplemented.     

The catecholamine system in health and disease —Relation to tyrosine 3-monooxygenase and other catecholamine-synthesizing enzymes—

Catecholamines [dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine); CAs] are neurotransmitters in the central and peripheral nervous systems as well as hormones in the endocrine system. CAs in the brain play a central role in versatile functions as slow-acting neurotransmitters functioning in synaptic neurotransmission, modulating the effects of fast-acting neurotransmitters such as glutamate and γ-aminobutyric acid (GABA). In this review, I focus on recent advances in the biochemistry and molecular biology of the CA system in humans in health and disease, especially in neuropsychiatric diseases such as Parkinson’s disease (PD), in relation to the biosynthesis of CAs regulated by a pteridine-dependent monooxygenase, tyrosine 3-monooxygenase (tyrosine hydroxylase, TH) and its pteridine cofactor, tetrahydrobiopterin (BH4).     

Ralph A. Alpher, Robert C. Herman, and the Cosmic Microwave Background Radiation

Much of the literature on the history of the prediction and discovery of the Cosmic Microwave Background Radiation (CMBR) is incorrect in some respects. I focus on the early history of the CMBR, from its prediction in 1948 to its measurement in 1964, basing my discussion on the published literature, the private papers of Ralph A. Alpher, and interviews with several of the major figures involved in the prediction and measurement of the CMBR. I show that the early prediction of the CMBR continues to be widely misunderstood.     

Reminiscence of 40-year research on nitrogen metabolism

This article summarizes my research over 40 years. The main theme of my work is nitrogen metabolism of amino acids, though later I focused on protein turnover in the cell. In the first years of my research work, I was busy dissecting the pathways involved in the metabolism of certain amino acids and their related enzymes. Then I became interested in the physiology and regulation of matabolism of these amino acids. For that, I used primary cultured hepatocytes, which contain many liver-specific enzymes. However, this play field was very rough around 1970 and hence I had to smooth them (differentiated) first. We discovered a specific growth factor (hepatocyte growth factor, HGF) in rat platelets. Exceptionally, I also worked on branched chain amino acids (valine, leucine and isoleucine). These amino acids are not efficiently metabolized in the liver, so I had to consider the physiology of extrahepatic tissues as well. Finally, I came across a huge protease complex, the proteasome. Whether these players, small amino acid metabolizing enzymes and the huge protease complex, danced well in harmony on my playground or not, I still do not know.     

ESR of Reacting Radicals

This paper represents a review of my research that was presented upon receiving the 2012 Zavoisky Award given by the Zavoisky Physical-Technical Institute in Kazan, Tatarstan, Russia. It is my belief that my early experiences gave an important background for experimental research and success in the area of ESR (electron spin resonance). I will describe some of these. In addition, I will give some of my educational experience that displayed how random chance was also important as to what research area I adopted. Much of my research has been with ESR of radicals produced by ionizing radiation and some of the more important observations are described. Among them is the initial discovery of chemically induced dynamic electron polarization (CIDEP). Also mentioned are a treatment of second-order hyperfine splittings and a number of issues regarding radical structure. This work also contributed to spectrometer design for time-resolved experiments. Modified Bloch equations were developed to describe the ESR time dependence. A number of observations on the hydrated electron, e _aq ^? , are described, including the finding of an “inverse” CIDEP when e _aq ^? is present with certain counter radicals. Several more recent studies finally explained this behavior. Two topics not used in the presentation are also included: a determination of the relaxation time of e _aq ^? and a determination of relative radical yields in pulse radiolysis. Finally, two other applications of microwave absorption are described, including a new method for determining the dipole moments of photo-excited molecules.     

A neurochemical map of the developing amphioxus nervous system

ABSTRACT: BACKGROUND: Amphioxus, representing the most basal group of living chordates, is the best available proxy for the last invertebrate ancestor of the chordates. Although the central nervous system (CNS) of amphioxus comprises only about 20,000 neurons (as compared to billions in vertebrates), the developmental genetics and neuroanatomy of amphioxus are strikingly vertebrate-like. In the present study, we mapped the distribution of amphioxus CNS cells producing distinctive neurochemicals. To this end, we cloned genes encoding biosynthetic enzymes and/or transporters of the most common neurotransmitters and assayed their developmental expression in the embryo and early larva. RESULTS: By single and double in situ hybridization experiments, we identified glutamatergic, GABAergic/glycinergic, serotonergic and cholinergic neurons in developing amphioxus. In addition to characterizing the distribution of excitatory and inhibitory neurons in the developing amphioxus CNS, we observed that cholinergic and GABAergic/glycinergic neurons are segmentally arranged in the hindbrain, whereas serotonergic, glutamatergic and dopaminergic neurons are restricted to specific regions of the cerebral vesicle and the hindbrain. We were further able to identify a discrete group of GABAergic and glutamatergic interneurons and cholinergic motoneurons at level of the primary motor center (PMC), the major integrative center of sensory and motor stimuli of the amphioxus nerve cord. CONCLUSIONS: In this study, we assessed neuronal differentiation in the developing amphioxus nervous system and compiled the first neurochemical map of the amphioxus CNS. This map is a first step towards a full characterization of the neurotransmitter signature of previously described nerve cell types in the amphioxus CNS, such as motoneurons and interneurons. The most striking discovery was that sub-populations of neurons become differentiated for producing distinctive neurochemicals well before the outgrowth of neurites establishes the definite neurocircuitry.     

Reflections on Manoj Banerjee and his early contributions to nuclear physics

I highlight some of the scientific contributions of Manoj Banerjee during the years 1957 to 1969. This is more a personalised account than a complete review. Choice of material is influenced by my own bias.     

The discovery of polyacetylene film – the dawning of an era of conducting polymers

This lecture is not directly related to our discovery and development of conducting polymers to which the Nobel Prize in Chemistry 2000 was awarded. However, I would like to present my previous work that I had carried out just before we reached the discovery of chemical doping. I do hope my talk will be of use for you the audience to deepen your understandings by learning what had happened before and how we did reach the idea of chemical doping.     

Gerson Goldhaber: A Life in Science

I draw on my interviews in 2005–2007 with Gerson Goldhaber (1924–2010), his wife Judith, and his colleagues at Lawrence Berkeley National Laboratory. I discuss his childhood, early education, marriage to his first wife Sulamith (1923–1965), and his further education at the Hebrew University in Jerusalem (1942–1947) and his doctoral research at University of Wisconsin at Madison (1947–1950). He then was appointed to an instructorship in physics at Columbia University (1950–1953) before accepting a position in the physics department at the University of California at Berkeley and the Radiation Laboratory (later the Lawrence Berkeley Laboratory, today the Lawrence Berkeley National Laboratory), where he remained for the rest of his life. He made fundamental contributions to physics, including to the discovery of the antiproton in 1955, the GGLP effect in 1960, the psi particle in 1974, and charmed mesons in 1977, and to cosmology, including the discovery of the accelerating universe and dark energy in 1998. Beginning in the late 1960s, he also took up art, and he and his second wife Judith, whom he married in 1969, later collaborated in illustrating and writing two popular books. Goldhaber died in Berkeley, California, on July 19, 2010, at the age of 86.     

NMR studies of protein structure and dynamics - a look backwards and forwards

NMR spectroscopy has evolved to become one of the most powerful tools for the study of protein structure and dynamics. Advances over the past decade have greatly extended the methodology to studies of molecules of ever increasing complexity. Herein I provide a short perspective relating the circumstances that led to some of the contributions from my laboratory in this area and highlight how these original experiments, summarized in a Journal of Magnetic Resonance article in 2005 (JMR, 173 193–207), have influenced the current focus of my research.     

A Personal Perspective on the Last Half-Century of Critical Phenomena

One of the crowning achievements of mathematical, statistical physics over the past half century has been the discovery of the many aspects of structure of the critical point. It has been an exciting time and was only possible through the combined efforts of many excellent people. This article contains brief reviews of some of the parts in which I have been most interested and to which I have made some contributions.     

Tetrodotoxin: a brief history

Tetrodotoxin (TTX), contained in puffer, has become an extremely popular chemical tool in the physiological and pharmacological laboratories since our discovery of its channel blocking action in the early 1960s. This brief review describes the history of discovery of TTX action on sodium channels, and represents a story primarily of my own work. TTX inhibits voltage-gated sodium channels in a highly potent and selective manner without effects on any other receptor and ion channel systems. TTX blocks the sodium channel only from outside of the nerve membrane, and is due to binding to the selectivity filter resulting in prevention of sodium ion flow. It does not impairs the channel gating mechanism. More recently, the TTX-resistant sodium channels have been discovered in the nervous system and received much attention because of their role in pain sensation. TTX is now known to be produced not by puffer but by bacteria, and reaches various species of animals via food chain.(Communicated by Masanori OTSUKA, M.J.A.).     

First Protein Crystallography Experiments on a Synchrotron

My story started in the winter of 1973/1974. I was a graduate student at UCLA, my thesis work was going nowhere, and my wife was expecting a baby in the early summer, while we had no health insurance that would pay for this happy event. It was clearly time to find a place other than Los Angeles to continue work in protein crystallography. Since I wanted to study crystal structure of the nerve growth factor (NGF), and the West Coast expert in that field was Eric Shooter at Stanford, I asked him if he would be willing to accept me as a postdoc. He was, but had no funds. However, somehow he contacted Keith Hodgson and the two of them managed to find some money, to the best of my recollection in the Department of Psychiatry. Although Keith agreed to let me work on the structure of NGF and a few other proteins, he stipulated that my primary objective should be to help in setting up the first in the world beamline devoted to the use of synchrotron radiation for single-crystal diffraction from protein crystals. To tell the truth, I initially had some problems understanding what exactly he had in mind—somehow my undergraduate degree in physics did not cover that particular subject. Thus, in the late spring of 1974, the team was established—Keith at the lead, two postdocs (Margueritte Yevitz Bernheim and myself) and a graduate student, James Phillips. We were joined by Julia Goodfellow (now Dame Julia) a year later. And the Stanford Synchrotron Radiation Project also officially commenced at about the same time.     

Myelin contributes to the parallel orientation of axonal growth on white matter in vitro

Background  

The fly visual system is a highly ordered brain structure with well-established physiological and behavioral functions. A large number of interneurons in the posterior part of the third visual neuropil, the lobula plate tangential cells (LPTCs), respond to visual motion stimuli. In these cells the mechanism of motion detection has been studied in great detail. Nevertheless, the cellular computations leading to their directionally selective responses are not yet fully understood. Earlier studies addressed the neuropharmacological basis of the motion response in lobula plate interneurons. In the present study we investigated the distribution of the respective neurotransmitter receptors in the fly visual system, namely nicotinic acetylcholine receptors (nAChRs) and GABA receptors (GABARs) demonstrated by antibody labeling.     

Fokker action principles with self-action. II. Applications of the general theory to a single particle in uniform circular motion; modified Maxwell-Lorentz interaction; a model of the electron

Fokker action principles with self-action are studied. A program is outlined that offers long-odds hope for the construction of classical models of some elementary particles. Part I [31] gave an outline of the general theory, its possibilities, and its difficulties. Part II gives applications of the theory to circular motions of a single particle interacting with itself under modified Maxwell-Lorentz interaction. A specific, but ugly, model that arose in a thus-far unsuccessful attempt at a theory of the electron is discussed. Part III, which will be published shortly, will extend the results of Part II to a general interaction function Λ.     

Adventures of a Theoretical Physicist, Part I: Europe

I was born in Budapest, Hungary, on July 7, 1907, and this first part of my interview with Andor Frenkel focuses on my life and work in Europe. After my elementary and secondary education I studied mathematics at the University of Budapest for two years. I went to the University of G?ttingen in 1928 where I attended Max Born’s lectures on quantum mechanics, which influenced me to change from mathematics to physics, and as a consequence I focused on filling the gaps in my physics background. When ready to turn to research work I followed the advice of my friend Edward Teller and spent three months in Werner Heisenberg’s group at the University of Leipzig in the summer of 1930. That fall I returned to the University of Budapest, where I received my Ph.D.degree in the summer of 1932. Two months later, because I had become entangled in the illegal Communist Party, I was arrested and sentenced to fourteen months in prison. Fifteen months after my release, I joined Lev Landau’s group at the Ukrainian Physical-Technical Institute in Kharkov, passed Landau’s so-called “theorminimum” program on my second attempt, began research on the theory of liquid helium, and lost my faith in communism following Stalin’s repressive measures. I obtained an exit visa through the Hungarian Legation and returned to Budapest in June 1937. That September, again with the help of my friend Edward Teller, I attended a conference in Paris where I met Fritz London and Edmond Bauer, who arranged for me a small scholarship and an association with the Langevin laboratory at the Collège de France. Four months later, in January 1938 Kapitza, and John F. Allen and A. Donald Misener reported their independent discovery of the superfluidity of helium, which London and I explored theoretically and I explained with my two-fluid theory later in 1938. Following the German invasion of France, my wife and I left Paris for Toulouse in June 1940, obtained exit visas to enter Spain and Portugal in February 1941, and boarded a Portuguese ship for New York the following month. The second part of this interview, covering my life and work in America, will appear in the next issue.     

The role of the t-SNARE SNAP-25 in action potential-dependent calcium signaling and expression in GABAergic and glutamatergic neurons

Background  

The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, comprised of SNAP-25, syntaxin 1A, and VAMP-2, has been shown to be responsible for action potential (AP)-dependent, calcium-triggered release of several neurotransmitters. However, this basic fusogenic protein complex may be further specialized to suit the requirements for different neurotransmitter systems, as exemplified by neurons and neuroendocrine cells. In this study, we investigate the effects of SNAP-25 ablation on spontaneous neuronal activity and the expression of functionally distinct isoforms of this t-SNARE in GABAergic and glutamatergic neurons of the adult brain.     

Summary talk

To summarize something like 28 plenary talks and about 100 presentations, distributed over 9 parallel sessions, is not a challenge, it is a “mission impossible”. Following my personal taste, I will mention only a small sample of all that material, and apologize from the start to all the speakers (the overwhelming majority) whose contributions I will not quote.     

An evaluation of the reproducibility of 1H-MRS GABA and GSH levels acquired in healthy volunteers with J-difference editing sequences at varying echo times

Recent advances in J-difference-edited proton magnetic resonance spectroscopy (¹H MRS) data acquisition and processing have led to the development of Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) techniques, which enable the simultaneous measurement of ɣ-aminobutyric acid (GABA), the primary inhibitory amino acid neurotransmitter in the central nervous system, and of glutathione (GSH), the most abundant antioxidant in living tissue, at the commonly available magnetic field strength of 3 T. However, the reproducibility of brain levels of GABA and GSH measured across multiple scans in human subjects using HERMES remains to be established. In the present study, twelve healthy volunteers completed two consecutive HERMES scans of the dorsal anterior cingulate cortex (dACC) to assess the test-retest reproducibility of the technique for GABA and GSH measurements at TE = 80 ms. Eleven of the twelve participants additionally completed two consecutive MEGA-PRESS scans at TE = 120 ms, with editing pulses configured for GSH acquisition, to compare the reliability of GSH in the same voxel measured using the standard MEGA-PRESS at TE = 120 ms. The primary findings of study were that, 1) the coefficient of variation (CV) of measuring GABA with HERMES was 16.7%, which is in agreement with the reliability we previously reported for measuring GABA using MEGA-PRESS; and 2) the reliability of measuring GSH with MEGA-PRESS at TE = 120 ms was more than twice as high as that for measuring the antioxidant with HERMES at TE = 80 ms (CV = 7.3% vs. 19.0% respectively). These findings suggest that HERMES and MEGA-PRESS offer similar reliabilities for measuring GABA, while MEGA-PRESS at TE = 120 ms is more reliable for measuring GSH relative to HERMES at TE = 80 ms.     

Polyamorphism in water

Water, the most common and important liquid, has peculiar properties like the density maximum at 4 °C. Such properties are thought to stem from complex changes in the bonding-network structure of water molecules. And yet we cannot understand water. The discovery of the high-density amorphous ice (HDA) in 1984 and the discovery of the apparently discontinuous change in volume of amorphous ice in 1985 indicated experimentally clearly the existence of two kinds of disordered structure (polyamorphism) in a one-component condensed-matter system. This fact has changed our viewpoint concerning water and provided a basis for a new explanation; when cooled under pressure, water would separate into two liquids. The peculiar properties of water would be explained by the existence of the separation point: the liquid-liquid critical point (LLCP). Presently, accumulating evidences support this hypothesis. Here, I describe the process of my experimental studies from the discovery of HDA to the search for LLCP together with my thoughts which induced these experiments.