Critical reviews in neurobiology最新文献

Neuronal nitric oxide synthase (nNOS) has been implicated in a wide variety of physiological and pathological processes. These include neurotransmission, neurotoxicity, skeletal muscle contraction, sexual function, body fluid homeostasis and atherosclerosis, among others. Consistent with the involvement of nNOS in such varied aspects of cellular biology, nNOS mRNA and protein are expressed in numerous tissues. Both its gene structure and expressional regulation are exceedingly complex. Characterization of the genomic organization of the human nNOS has revealed that the transcription unit of 29 exons spans a region greater than 240 kb at 12q24.2. The gene produces multiple mRNA transcripts via a variety of intriguing mechanisms: alternate promoter usage, alternative splicing, cassette insertions/deletions, and varied sites for 3'-UTR cleavage and polyadenylation. Allelic diversity in mRNA structure also exists. Some, but not all, of these various transcripts affect the encoded amino acid sequence and translate into nNOS protein isoforms with altered structural and functional properties. Interestingly, much of this diversity is restricted to the untranslated regions of the mRNA transcript and may affect its translation or stability. Taken together, these properties present nNOS as one of the most complex human genes described to date. Given the importance of nNOS in human health and disease, understanding this intricate genetic regulation has been a major focus in nNOS research. This review addresses the structure of the nNOS gene, its mRNA diversity, and overall genetic regulation with an emphasis on their biological implications.

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.

The issue of how neurons communicate with each other through patterns of action potentials, that is, of what is the neural code, is one of the major problems in modern science. Because complex stimuli can be easily and rapidly presented to the visual system, and because vision is both behaviorally important to and occupies a large amount of neural tissue in humans, a great deal of the research on the neuronal code has been done in the primate visual system. One of the more challenging aspects of this research concerns how the time-varying nature of neuronal responses might be used by the nervous system. This review addresses some of the major lines of investigation as to how the temporal variation of a neural response might function in transferring information in the primate visual system.

Lipoproteins are macromolecular complexes composed of lipids and proteins. The role of these complexes is to provide cells of the organism with lipids to be used as a source of energy, building blocks for biomembrane synthesis, and lipophilic molecules (e.g., steroid hormones and vitamin E) for other physiological purposes, such as cell signaling and antioxidative mechanisms. Lipoproteins also promote the cellular efflux of cholesterol for its disposal into bile. Thus, lipoproteins play an important role in the maintenance of lipid homeostasis throughout the organism. Accordingly, lipoprotein particles have been found circulating in blood, lymph, and interstitial fluid. Despite the existence of the blood-brain barrier, lipoprotein particles have been shown to be also present in the cerebrospinal fluid (CSF). Although a portion of their protein components may filter through the barrier from the vascular compartment, experimental evidence indicates that these particles originate from the nervous tissue. The other protein components include apolipoproteins E, J, and D, and these have been shown to be synthesized by cells within the central nervous system (CNS). Furthermore, it was shown that lipoprotein particles can be isolated from the conditioned medium of astrocytic cultures. The differences in size, structure, and composition of in vitro assembled particles compared with those isolated from the CSF suggest that the particles are modified following their secretion in vivo. This is supported by observations that lipoprotein-modifying enzymes and transfer proteins are also present within CNS tissue and CSF. The fate of CSF lipoproteins is unclear but is probably related to the turnover and clearance of lipids from the CNS or, alternatively, the particles may be recaptured and recycled back into the CNS tissue. The presence of several cell surface receptors for apoE-containing lipoproteins on ependymal cells, as well as on neurons and glial cells, supports this notion and suggests that the isolated brain possesses its own system to maintain local lipid homeostasis. This is further exemplified by the salvage and recycling of lipids shown to occur following a lesion in order to allow surviving neurons to sprout and reestablish lost synapses. Not much is currently known about lipoprotein metabolism in neurodegenerative diseases, but lipid alterations have been repeatedly reported in Alzheimer brains in which neuronal loss and deafferentation are major features. Although the mechanism underlying the link between the epsilon4 allele of the apolipoprotein E gene and Alzheimer's disease is presently unclear, it may well be postulated that it is related to disturbances in brain lipoprotein metabolism.

Lysophospholipids (LPs) such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) 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 (lpA1/vzg-1) 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.

Noradrenergic and/or serotonergic deficits, as well as other abnormalities, may contribute to predisposition to some epilepsies and depressions. Evidence for this hypothesis stems from several sources. Epidemiological investigations are intriguing but incomplete. Pharmacological studies show that noradrenergic and/or serotonergic transmission are both anticonvulsant and antidepressant. Therapeutically pertinent investigations show that antidepressant drugs have anticonvulsant properties, whereas antiepileptic drugs are effective in the management of affective disorders. Additional investigations demonstrate that seizures, whether spontaneously occurring or therapeutically induced, protect against depression. Through studies of innate pathophysiology, noradrenergic and serotonergic deficits have been identified in individuals with depression and in animal models of epilepsy, as well as in some humans with epilepsy. Vagal nerve stimulation, a treatment already known to be effective in the epilepsies, is presently under investigation for effectiveness in affective disorder. New evidence suggests that vagal nerve stimulation exerts at least some of its therapeutic effects through its capacity to increase noradrenergic and serotonergic transmission. Finally, emerging evidence supports the concept that some genetic mammalian models of the human epilepsies exhibit analogous manifestations of depression.

Estrogen exerts a variety of electrophysiological, neurotrophic, and metabolic effects on neurons in the adult central nervous system. Recent epidemiological studies have suggested that estrogen, as hormone replacement therapy in postmenopausal women, may be protective against Alzheimer's disease; the biological basis for a potential neuroprotective effect of estrogen in humans is an area of intense current research. This review summarizes electrophysiological and cellular effects of estrogen on neuronal function, with particular emphasis on hypothalamic and hippocampal neurons. Classic electrophysiological studies are compared with more recent cellular and molecular analyses in an effort to illuminate significant relationships between data gathered over the last 30 years and from varied sources. Hypotheses are made for the mechanisms of estrogen action in the brain as well as the functional consequences of estrogen's effects for both normal brain function and pathological states.

In the nervous system, prostanoids are well recognized as mediators in a variety of processes, including fever generation, modulation of the stress response, sleep/wake cycle, control of cerebral blood flow, and hyperalgesia. Two isoforms of cyclooxygenase (COX), the enzyme that catalyzes the conversion of arachidonic acid to prostanoids, are now recognized: a constitutively expressed COX-1 and a highly regulated COX-2. New molecular and pharmacologic tools have provided a better understanding of the roles of COX-generated prostanoids in the nervous system. Other studies reveal that COX may represent an important target for new therapeutic approaches to neurologic disorders. This review summarizes our current understanding of cyclooxygenase expression and prostanoid actions in the nervous system, with special reference to COX-2 and studies demonstrating its expression in different cell types responding to a variety of stimuli. A brief review of the molecular biology, pharmacology, and primary actions of COX-2 outside of the nervous system provides a context for understanding potential neurobiological roles for COX-2 and prostanoid production. Information about the role of COX in human neurological disorders, including cerebrovascular disease, Alzheimer' s disease, and hyperalgesia, is covered in the last section.

Two subtypes of cannabinoid receptors have been identified to date, the CB1 receptor, essentially located in the CNS, but also in peripheral tissues, and the CB2 receptor, found only at the periphery. The identification of delta9-tetrahydrocannabinol (delta9-THC) as the major active component of marijuana (Cannabis sativa), the recent emergence of potent synthetic ligands and the identification of anandamide and sn-2 arachidonylglycerol as putative endogenous ligands for cannabinoid receptors in the brain, have contributed to advancing cannabinoid pharmacology and approaching the neurobiological mechanisms involved in physiological and behavioral effects of cannabinoids. Most of the agonists exhibit nonselective affinity for CB1/CB2 receptors, and delta9-THC and anandamide probably act as partial agonists. Some recently synthesized molecules are highly selective for CB2 receptors, whereas selective agonists for the CB1 receptors are not yet available. A small number of antagonists exist that display a high selectivity for either CB1 or CB2 receptors. Cannabinomimetics produce complex pharmacological and behavioral effects that probably involve numerous neuronal substrates. Interactions with dopamine, acetylcholine, opiate, and GABAergic systems have been demonstrated in several brain structures. In animals, cannabinoid agonists such as delta9-THC, WIN 55,212-2, and CP 55,940 produce a characteristic combination of four symptoms, hypothermia, analgesia, hypoactivity, and catalepsy. They are reversed by the selective CB1 receptor antagonist, SR 141716, providing good evidence for the involvement of CB1-related mechanisms. Anandamide exhibits several differences, compared with other agonists. In particular, hypothermia, analgesia, and catalepsy induced by this endogenous ligand are not reversed by SR 141716. Cannabinoid-related processes seem also involved in cognition, memory, anxiety, control of appetite, emesis, inflammatory, and immune responses. Agonists may induce biphasic effects, for example, hyperactivity at low doses and severe motor deficits at larger doses. Intriguingly, although cannabis is widely used as recreational drug in humans, only a few studies revealed an appetitive potential of cannabimimetics in animals, and evidence for aversive effects of delta9-THC, WIN 55,212-2, and CP 55,940 is more readily obtained in a variety of tests. The selective blockade of CB1 receptors by SR 141716 impaired the perception of the appetitive value of positive reinforcers (food, cocaine, morphine) and reduced the motivation for sucrose, beer and alcohol consumption, indicating that positive incentive and/or motivational processes could be under a permissive control of CB1-related mechanisms. There is little evidence that cannabinoid systems are activated under basal conditions. However, by using SR 141716 as a tool, a tonic involvement of a CB1-mediated cannabinoid link has been demonstrated, notably in animals suffering from chronic pain, fa