Begell House Inc.
Critical Reviews™ in Neurobiology
CRN
0892-0915
13
2
1999
Knock-Out Mouse Models Used to Study Neurobiological Systems
103-149
10.1615/CritRevNeurobiol.v13.i2.10
Marina R.
Picciotto
Departments of Psychiatry and Pharmacology, Yale University School of Medicine, 34 Park St., New Haven, CT 06508
mutagenesis
mice
knockout
brain
inbred strains
pharmacology
behavior
The use of knock-out mice to examine problems relevant to neurobiology is rapidly expanding. Knock-out mice have been used to study the role of particular gene products in biochemical processes, in mediating the effects of neuropharmacological substances, and in complex behaviors. The advantages and disadvantages of using knock-out mice to study neurobiological problems are discussed here, and the current state of knock-out technology is reviewed briefly. The use of knock-out mice to elucidate the functions of molecules involved in signaling through various neurotransmitter systems is then examined. Approaches to complex neurobiological problems such as the biochemical basis of learning and memory and the molecular basis of drug abuse are also explored.
Lysophospholipid Receptors: Implications for Neural Signaling
151-168
10.1615/CritRevNeurobiol.v13.i2.20
Jerold
Chun
Department of Pharmacology, Neurosciences Program, Biomedical Sciences Program, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636
neurogenesis
myelination
GTPase
actin cytoskeleton
Rho
SRE
Lysophospholipids (LPs) such as lysophosphatidic acid (LPA) and sphingosine-1 -phosphate (SIP) represent quantitatively minor phospholipid species that nonetheless are capable of acting as extracellular signals. As an organ system dominated by lipids, the nervous system would seem a likely benefactor of this form of intercellular signaling. A major difficulty in determining the neurobiological importance of these lipids, however, has been a lack of cloned receptors. The unavailability, indeed, uncertain existence, of these receptors has been particularly problematic because of the absence of specific, competitive antagonists to block function. Further, these lipids have detergent-like chemical structures, raising the explanation that any observed effects of exogenously applied lysophospholipids could be due to nonspecific membrane perturbations. During studies of G-protein coupled receptor (GPCR) genes involved with cerebral cortical neurogenesis, the first lysophospholipid receptor gene (lpAI/vzg-l) was isolated (Hecht et al., J. Cell Biol., 135, 1071,1996), implicating receptor-mediated lysophospholipid signaling as potentially important components of nervous system development and function. Expression studies indicated roles in neurogenesis, cortical development, and effects on glia, particularly oligodendrocyte and Schwann cell development. Reviewed here are the molecular biology of LP receptors, relevant aspects of intracellular signaling, and their possible roles in the nervous system.
Expression Patterns and Regulation of Glutamate Transporters in the Developing and Adult Nervous System
169-197
10.1615/CritRevNeurobiol.v13.i2.30
Karen D.
Sims
Departments of Neuroscience and Pediatrics, Children's Hospital of Philadelphia, Children's Seashore House, University of Pennsylvania, Philadelphia, PA 19104
Michael B.
Robinson
Departments of Pharmacology and Pediatrics, Children's Hospital of Philadelphia, Children's Seashore House, University of Pennsylvania, Philadelphia, PA 19104
development
excitotoxicity
glutamate uptake
neurodegenerative diseases
astrocytes
sodium-dependent
Glutamate and aspartate are the primary excitatory neurotransmitters in the mammalian central nervous system and have also been implicated as mediators of excitotoxic neuronal injury and death. The precise control of extracellular glutamate and aspartate is crucial to the maintenance of normal synaptic transmission and the prevention of excitotoxicity following acute insults to the brain, such as stroke or head trauma, or during the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis. The removal of excitatory amino acids (EAAs) from the extracellular space is primarily mediated by a family of sodium-dependent glutamate transporters. These transporters use the sodium electrochemical gradients of the cell to actively concentrate EAAs in both neurons and glia. Five members of this transporter family have been cloned recently and include both 'glial'-specific and 'neuron'-specific subtypes. Although these subtypes share many common functional properties, there are considerable differences in developmental expression, chronic and acute regulation by cellular signaling pathways, and contribution to disease processes among the subtypes. In this review recent studies of glutamate transporter expression, regulation, function, and pathological relevance are summarized, and some of the discrepancies and unexpected results common to any rapidly progressing field are discussed.
Changes in Apparent Rates of Receptor Binding in the Intact Brain in Relation to the Heterogeneity of Reaction Environments
199-225
10.1615/CritRevNeurobiol.v13.i2.40
Osamu
Inoue
School of Allied Health Sciences, Osaka University Faculty of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan
Kaoru
Kobayashi
School of Allied Health Sciences, Osaka University Faculty of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan
Antony
Gee
PET Center, Aarhus University Hospital, Norrebrogade 44,8000 Aarhus C., Denmark
PET
receptors
brain
association
dissociation
heterogeneity
Neuroreceptor imaging by PET or SPECT has been widely applied in the field of neurobiology, from basic to clinical investigations, and has the potential to reveal the neurochemical basis of various neurological and psychiatric diseases as well as to provide new knowledge in the field of neuropharmacology. In contrast to the static nature of in vitro systems, neurotransmission systems in the intact brain constitute part of a dynamic and communicating environment. Thus, it is important to develop new functional imaging methods that reflect neural communications and the dynamism of signal transmission in the living brain. In vivo receptor binding can be altered not only by competitive inhibition by endogenous neurotransmitters but by trans-synaptic effects, and investigation of neural interactions by detection of changes in receptor binding therefore presents a potential method for studying this phenomenon. Recently, several PET studies on in vivo neural interactions using the D2 receptor ligand [11C]-raclopride concluded that the phenomenon was mediated by changes in synaptic endogenous dopamine concentrations that compete with [11C]-raclopride binding for neuroreceptor occupancy. However, a growing body of evidence indicates that these changes in in vivo receptor binding cannot be fully explained by competitive inhibition by endogenous ligand, and alternative mechanisms for the interneuronal modulation of receptor binding are addressed. This review highlights some of the discrepancies observed between in vitro and in vivo receptor binding studies with respect to a number of phenomena, including the heterogeneity of the reaction field surrounding receptors. Quantitative receptor binding studies are usually analyzed by using 'static' binding parameters, such as the Bmax and KD, which are normally determined by in vitro assays. In addition to these parameters, the apparent association and dissociation rate constants (kon, koff) play equally significant roles in receptor binding in the intact brain is expected. The cncepts of "diffusion boundary" and "reaction volume" are introduced, and discussions on some of the discrepancies between in vivo and in vitro receptor binding phenomena are presented.