Seminars in Neuroscience最新文献

Fast synaptic transmission mediated by P_2XATP receptors is a recent discovery in the central nervous system and new information on the distribution of P_2Xbinding sites and mRNA for P_2Xreceptor subunits in the brain suggests that transmission mediated by ATP may be widespread. P_2XATP receptors have many functional similarities to other receptors mediating fast excitatory synaptic transmission and some significant differences. ATP release is calcium-dependent and vesicular in nature. Individual synaptic currents are small in size (around 10 pA at −70 mV), have a fast rise-time and decay with a time-course (decay tau = 18 ms at −70 mV) intermediate between that of AMPA receptor-mediated synaptic currents and NMDA receptor-mediated synaptic currents. It is likely that P_2XATP receptor channels are permeable to calcium suggesting by analogy with glutamatergic transmission that purinergic transmission will participate in the regulation of calcium-dependent processes in neurones.

Neural release of ATP can be elicited through or modulated through presynaptic receptors, as is known for classical transmitter substances. Activation of presynaptic nicotinic and serotonin receptors induces ATP release from postganglionic sympathetic axons. Inhibition of depolarization-evoked ATP release from these axons is mediated by, e.g. α₂- and β₂-adrenoceptors, adenosine A₁-receptors and receptors for prostaglandin E₂, neuropeptide Y and atrial natriuretic peptide. Enhancement of release is mediated by receptors for angiotensin and endothelin-3. Whether presynaptic P₂-purinoceptors affect neural ATP release is unknown. A₁-Receptors also mediate an inhibition of ATP release from cholinergic axons. Activation of some (e.g. neuropeptide Y) receptors causes an identical change in cotransmitter release. In other cases there is evidence for a differential modulation. A₁-Receptors, for example, affect ATP release more markedly than noradrenaline release. The mechanisms causing differential modulation of cotransmitter release remain to be identified.

ATP-gated ion channels (P2X receptors) are ubiquitously present in autonomic and sensory neurons as well as in smooth muscle; they mediate fast excitatory synaptic transmission at sympathetic neuromuscular junctions, at some neuro-neuronal synapses and may be involved in the generation and transmission of primary afferent information. Five subtypes of native P2X receptors can be distinguished by their kinetics and their agonist and antagonist profile. Six distinct P2X receptors have been cloned; all are present in sensory neurons and most are present in autonomic neurons; homomeric or heteromeric forms of these cloned receptors reproduce the five phenotypes observed in native cells.

In the last two years, gene targeting approaches have been applied to generate mutant mouse strains bearing heritable alterations of neurotransmitter receptor genes. The analysis of mouse strains with planned mutations of receptor genes is proving to be a valuable approach to examine the contributions of particular receptor subtypes to neural development, physiology, behavior and drug actions. In the near future, a large number of receptor mutant strains will become available for the analysis of receptor function. This review will focus on recent studies of such strains, and the potential benefits and limitations of gene targeting approaches to receptor function will be discussed.

The genes encoding each of the known neurotrophins and their receptors have been targeted in mice. As predicted by earlier studies, each mutation results in loss of specific classes of peripheral neurons. Apoptosis during the period of naturally occurring cell death appears to be responsible for many of these losses. In some cases, deficits may reflect earlier abnormalities in precursor proliferation, commitment or differentiation. Specific examples of abnormal target innervation and neuronal differentiation have been observed in these mutants, which are beginning to be used to address other postulated functions of neurotrophins, such as modulation of synaptic efficacy and plasticity.

Single gene manipulation allows one to create mutant mammalian organisms that may be useful for genetic dissection of mechanisms underlying brain function and behavior. Alterations in a mutant organism may be directly related to the mutation or due to compensatory mechanisms. Analysis of these responses may reveal molecular organization of the brain. However, the results of several recent molecular neurobiology studies are difficult to interpret since they are flawed by the problems resulting from genetic linkage of and variability in background genes. The behavioral analysis of mutant mice may also be uninterpretable if one ignores species-specific characteristics of the experimental animals.

Our understanding of patterning along the dorsoventral (DV) axis has been advanced by embryological studies which have allowed the identification of dorsal and ventral organizing centers, and of molecular signals that can actin vitroto specify cell fate. However, in order to establish anin-vivorole for a signal it is necessary to show that the molecule is present in the right place and time, that exogenous addition or ectopic expression of the signal mimics its proposed effect and that deletion of its activity results in an absence of the presumed biological response. Such evidence can be provided by gene deletion (knock-out) or ectopic expression (transgenic) studies. In this review, experimental embryological studies that have increased our understanding of DV patterning will be discussed, and studies in which gene manipulation has provided evidence about the in-vivo role of a molecule will be highlighted.

The motor neuron diseases (MND) are an etiologically heterogeneous group of disorders characterized by weakness and muscle atrophy. These clinical signs are attributable to the involvement of lower motor neurons; the presence of spasticity and hyperreflexia indicates involvement of upper motor neurons. Depending on the characteristics of the disease process, vulnerable cells develop inclusions, alterations in the cytoskeleton, etc., before undergoing cell death. Over the past several years, significant progress has been made in understanding the genetics of some of these disorders, including familial amyotrophic lateral sclerosis (FALS), spinal muscular atrophy (SMA), and spinal bulbar muscular atrophy (SBMA). For example, some of the autosomal dominant cases of FALS are linked to mutations in the superoxide dismutase 1 (SOD1) gene. Several groups have introduced these SOD1 mutations into transgenic mice, and these animals develop features of the human disease. Other investigators have used transgenic strategies to overexpress wild-type (wt) or mutant neurofilament (NF) genes, and some of these mice show abnormalities of the neuronal cytoskeleton that resemble those occurring in sporadic amyotrophic lateral sclerosis (ALS). Finally, in efforts to define trophic influences on these cells, investigators have used gene-targeting strategies to ablate genes coding for these factors or their receptors and to assess the consequences of the null state on behavior and cell phenotype. This review outlines some of the progress that has been made in modeling disorders of motor neurons, either by introducing mutant SOD1 transgenes or by overexpressing wt or mutant NF genes, and the recent advances made using gene-targeting strategies to define trophic dependencies of motor neurons.