Gaba Subscript Alpha Receptor Properties That Shape Neuronal Inhibition

GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABAA and GABAB receptors. Recently, a novel form of GABAA receptor-mediated inhibition, termed “tonic” inhibition, has been described. Whereas synaptic GABAA receptors underlie classical “phasic” GABAA receptor-mediated inhibition (inhibitory postsynaptic currents), tonic GABAA receptor-mediated inhibition results from the activation of extrasynaptic receptors by low concentrations of ambient GABA. Extrasynaptic GABAA receptors are composed of receptor subunits that convey biophysical properties ideally suited to the generation of persistent inhibition and are pharmacologically and functionally distinct from their synaptic counterparts. This book highlights ongoing work examining the properties of recombinant and native extrasynaptic GABAA receptors and their preferential targeting by endogenous and clinically relevant agents. In addition, it emphasizes the important role of extrasynaptic GABAA receptors in GABAergic inhibition throughout the CNS and identifies them as a major player in both physiological and pathophysiological processes.

The auditory thalamus or medial geniculate body (MGB) is the final brain structure for acoustic information processing prior to, and functioning in reciprocity with, auditory cortex. MGB neurons process and gate aspects of acoustic stimuli, functions which depend partly on GABAergic inhibition. To characterize these properties, the inhibitory neurotransmitters involved and how they may be altered in the aged MGB, specific aims sought to: 1) determine the presence of functional high affinity GABA A receptors (GABA A Rs) in the MGB, 2) determine whether GABAA R function is altered with age and 3) determine to what degree MGB neurons of awake young and aged rats display stimulus-specific adaptation (SSA). Inhibitory neurotransmission is essential for accurate coding of acoustic information in the central auditory system, but appears disrupted in the aged. The present study required the development of a slice preparation that permitted whole cell recordings from juvenile, young adult and aged rat MGB neurons. The presence of high affinity GABA A Rs and the impact of aging on synaptic and high affinity GABAA R function were examined. Low concentrations of gaboxadol (GABAA R agonist) activated a gabazine-sensitive (GABA A R antagonist) tonic current, providing support for the expression of functional high affinity GABAA Rs in the MGB. Activation of high affinity GABAA Rs expressed by MGB neurons decreased input resistance, hyperpolarized resting membrane potential, reduced evoked firing rates and induced a transition from tonic to burst firing mode. In aged MGB neurons there was a significant 50.4% reduction in GABAA R-mediated tonic Cl- current. Synaptic GABAA R inhibition appeared differentially affected by age in lemniscal and non-lemniscal auditory thalamus although gramicidin perforated patch-clamp recordings indicated neuronal Cl- homeostasis was unaltered with age. Anesthetized rodent MGB single units show SSA, during which the firing rate in response to repetitive stimuli decreases/adapts over time but low probability stimuli (i.e. novel) continue to elicit robust responses. To examine the presence of SSA in the MGB of awake rats, a multichannel single unit recording preparation was implemented. This approach involved implanting young and aged rats with an array of four individually-advanceable tetrodes in order to evaluate SSA by recording responses to a frequency oddball paradigm and a random/non-random frequency range paradigm. Single units in the MGB of awake FBN rats were found to display SSA, which was stronger in the non-lemniscal than lemniscal regions of the MGB. SSA was most dramatic at lower intensities where 27 of 57 (47%) young adult single units and 28 of 54 (52%) aged single units displayed SSA. However, there were no significant age-related differences in average magnitude or time course of SSA of MGB single units studied. Data from aims 1 and 2 provide the initial description of functional high affinity GABAA Rs in the rodent MGB and the plasticity of these receptors with age. These data suggest that GABAA R subtype-selective agonists or modulators could be used to augment MGB inhibitory neurotransmission, possibly improving speech understanding for a subset of elderly individuals. Findings from aim 3 were the first to show that SSA by MGB neurons is not dependent on arousal level nor on the anesthetized state, but is a common response in the MGB of awake rats. SSA did not appear to be overtly altered in the aged auditory thalamus of awake rats.

Highlighting the current developments and future directions in GABA research, the ambitious aim of this topical volume is to cover GABA from the molecular mechanisms of its transmission to new targets for pharmaceutical research. Distinguished scientists at the forefront of GABA research were invited to contribute reviews on glutamate decarboxylase and autoimmunity, molecular structure and functional regulation of GABA transporters, transmitter release and GABA receptor regulation, GABA receptor subtypes and functional regulation, and GABA receptor ligands and their therapeutic application. Describing the latest advances in what has become a rapidly-evolving field, this volume will prove immensely valuable to neuroscientists, pharmacologists, biochemists, and physiologists working in the field of GABA research.

Neural Engineering, 2nd Edition, contains reviews and discussions of contemporary and relevant topics by leading investigators in the field. It is intended to serve as a textbook at the graduate and advanced undergraduate level in a bioengineering curriculum. This principles and applications approach to neural engineering is essential reading for all academics, biomedical engineers, neuroscientists, neurophysiologists, and industry professionals wishing to take advantage of the latest and greatest in this emerging field.

The improved understanding of ion channel structure, achieved through the use of molecular biology techniques, has opened the way for the development of new drugs targeted at specific types of ion channels. This book provides a comprehensive, single-volume overview of the effects of different drugs and toxins on ionic channels. The first part of the book deals with the development of ion channels, while subsequent chapters detail the electrophysiological properties and pharmacology of eight different types of ion channels, including intracellular, cyclic nucleotide-gated, and receptor operated channels. Drug effects in various cell types, along with the potential use of channels in therapeutics, are discussed for each channel type. Comprehensive and up-to-date, Ion Channel Pharmacology is an essential reference for every investigator in this fast-growing area of research.

Functional Magnetic Resonance Imaging (fMRI) is a common technique for imaging brain activity in humans. However, the fMRI signal stems from local changes in oxygen level rather than from neuronal excitation. The change in oxygen level is referred to as the Blood Oxygen Level Dependent (BOLD) response, and is connected to neuronal excitation and the BOLD response are connected by the neurovascular coupling. The neurons affect the oxygen metabolism, blood volume and blood flow, and this in turn controls the shape of the BOLD response. This interplay is complex, and therefore fMRI analysis often relies on models. However, none of the previously existing models are based on the intracellular mechanisms of the neurovascular coupling. Systems biology is a relatively new field where mechanistic models are used to integrate data from many different parts of a system in order to holistically analyze and predict system properties. This thesis presents a new framework for analysis of fMRI data, based on mechanistic modelling of the neurovascular coupling, using systems biology methods. Paper I presents the development of the first intracellular signaling model of the neurovascular coupling. Using models, a feed-forward and a feedback hypothesis are tested against each other. The resulting model can mechanistically explain both the initial dip, the main response and the post-peak undershoot of the BOLD response. It is also fitted to estimation data from the visual cortex and validated against variations in frequency and intensity of the stimulus. In Paper II, I present a framework for separating activity from noise by investigating the influence of the astrocytes on the blood vessels via release of vasoactive sub- stances, using observability analysis. This new method can recognize activity in both measured and simulated data, and separate differences in stimulus strength in simulated data. Paper III investigates the effects of the positive allosteric GABA modulator diazepam on working memory in healthy adults. Both positive and negative BOLD was measured during a working memory task, and activation in the cingulate cortex was negatively correlated to the plasma concentration of diazepam. In this area, the BOLD response had decreased below baseline in test subjects with >0.01 mg/L diazepam in the blood. Paper IV expands the model presented in Paper I with a GABA mechanism so that it can describe neuronal inhibition and the negative BOLD response. Sensitization of the GABA receptors by diazepam was added, which enabled the model to explain how changes to the BOLD response described in Paper III could occur without a change in the balance between the GABA and glutamate concentrations. The framework presented herein may serve as the basis for a new method for identification of both brain activity and useful potential biomarkers for brain diseases and disorders, which will bring us a deeper understanding of the functioning of the human brain.

Many advances have been made in the last decade in the understanding of the computational principles underlying olfactory system functioning. Neuromorphic Olfaction is a collaboration among European researchers who, through NEUROCHEM (Fp7-Grant Agreement Number 216916)-a challenging and innovative European-funded project-introduce novel computing p

The complexity of the brain and the protean nature of behavior remain the most elusive area of science, but also the most important. van Hemmen and Sejnowski invited 23 experts from the many areas--from evolution to qualia--of systems neuroscience to formulate one problem each. Although each chapter was written independently and can be read separately, together they provide a useful roadmap to the field of systems neuroscience and will serve as a source of inspirations for future explorers of the brain.

Drug-Acceptor Interactions: Modeling theoretical tools to test and evaluate experimental equilibrium effects suggests novel theoretical tools to test and evaluate drug interactions seen with combinatorial drug therapy. The book provides an in-depth, yet controversial, exploration of existing tools for analysis of dose-response studies at equilibrium or steady state. The book is recommended reading for post-graduate students and researchers engaged in the study of systems biology, networks, and the pharmacodynamics of natural or industrial drugs, as well as for medical clinicians interested in drug application and combinatorial drug therapy. Even people without mathematical skills will be able to follow the pros and cons of reaction schemes and their related distribution equations. Chapter 9 is a hands-on guide for software to plot, fit and analyze one’s own data.