Annual Review of Neuroscience - Volume 19, 1996

RNA editing is a term describing a variety of novel mechanisms for the modification of nucleotide sequences of RNA transcripts in different organisms. These editing events include (a) the U-insertion and -deletion type of editing found in the mitochondrion of kinetoplastid protozoa, (b) the C-insertion editing found in the mitochondrion of Physarum, (c) the C-to-U substitution editing of the mammalian apoB mRNA, (d)a similar C-to-U substitution editing of mRNAs in higher plant mitochondria and chloroplasts and in tRNAs of marsupials and rats, (e) a diverse nucleotide substitution editing of tRNAs in Acanthomoeba mitochondria, and (f) the A-to-I type of editing found in the mammalian glutamate receptor subunits. These diverse phenomena involve several different enzymatic mechanisms. In several cases, duplex RNAs with internal or external guide sequences help determine the site specificity of editing. The A-to-I editing observed in RNAs encoding non-NMDA glutamate receptor subunits may be due to the actions of a double-stranded RNA-specific adenosine deaminase that is widespread in higher organisms. Although the function of many RNA editing events is unclear, the biological importance of RNA editing in other systems may prove as significant as the nucleotide modifications regulating the cation selectivity and electrophysiological profiles elaborated by non-NMDA glutamate receptors in the mammalian brain.

The apolipoprotein E locus (APOE) is associated with variations in the age of onset and risk of Alzheimer's disease. The APOE4 allele increases the probability of disease at an earlier age. In contrasL the APOE3 and APOE2 alleles decrease the probability of disease and increase the age of onset. Therefore the metabolism of apolipoprotein E is relevant to Alzheimer's disease. Isoform-specific interactions of apolipoprotein E with other molecules may determine the rate of disease expression through molecular pathways that appear unique to the disease. In addition, some isoform-specific interactions of apolipoprotein E have been demonstrated with the defining pathological lesions of Alzheimer's disease, the neurofibrillary tangle and neuritic plaque. Several hypotheses of disease pathogenesis are now based on the relevance of apolipoprotein E.

Trinucleotide repeat expansion is increasingly recognized as a cause of neurogenetic diseases. To date, seven diseases have been identified as expanded repeat disorders: the fragile X syndrome of mental retardation (both FRAXA and FRAXE loci), myotonic dystrophy, X-linked spinal and bulbar muscular atrophy, Huntington’s disease, spinocerebellar ataxia type 1, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease. All are neurologic disorders, affecting one or more regions of the neuraxis. Moreover, five of the seven (the last five above) are progressive neurodegenerative disorders whose strikingly similar mutations suggest a common mechanism of neuronal degeneration. In this article we discuss specific characteristics of each trinucleotide repeat disease, review their shared clinical and genetic features, and address possible molecular mechanisms underlying the neuropathology in each disease. Particular attention is paid to the neurodegenerative diseases, all of which are caused by CAG repeats encoding polyglutamine tracts in the disease gene protein.

Cells in area TE of the inferotemporal cortex of the monkey brain selectively respond to various moderately complex object features, and those that cluster in a columnar region that runs perpendicular to the cortical surface respond to similar features. Although cells within a column respond to similar features, their selectivity is not necessarily identical. The data of optical imaging in TE have suggested that the borders between neighboring columns are not discrete; a continuous mapping of complex feature space within a larger region contains several partially overlapped columns. This continuous mapping may be used for various computations, such as production of the image of the object at different viewing angles, illumination conditions. and articulation poses.

Myotonias and periodic paralyses constitute a diverse group of inherited disorders of muscle in which the primary defect is an alteration in the electrical excitability of the muscle fiber. The ion channel defects underlying these excitability derangements have recently been elucidated at the molecular and functional levels. This review focuses on sodium channel mutations that disrupt inactivation and thereby cause both the enhanced excitability of myotonia (muscle stiffness due to repetitive discharges) and the inexcitability resulting from depolarization during attacks of paralysis.

The neurotrophins are a small group of dimeric proteins that profoundly affect the development of the nervous system of vertebrates. Recent studies have established clear correlations between the survival requirements for different neurotrophins of functionally distinct subsets of sensory neurons. The biological role of the neurotrophins is not limited to the prevention of programmed cell death of specific groups of neurons during development. Neurotrophin-3 in particular seems to act on neurons well before the period of target innervation and of normally occuning cell death. In animals lacking functional neurotrophin or receptor genes, neuronal numbers do not seem to be massively reduced in the CNS, unlike in the PNS. Finally, rapid actions of neurotrophins on synaptic efficacy, as well as the regulation of their mRNAs by electrical activity, suggest that neurotrophins might play important roles in regulating neuronal connectivity in the developing and in the adult central nervous system.

Long-term depression (LTD) is a lasting decrease in synaptic effectiveness that follows some types of electrical stimulation in the hippocampus. Two broad types of LTD may be distinguished. Heterosynaptic LTD can occur at synapses that are inactive, normally during high-frequency stimulation of a converging synaptic input. Homosynaptic LTD can occur at synapses that are activated, normally at low frequencies. Here we discuss the mechanisms of LTD and their possible relevance to hippocampal function.

Because the actions of neurotrophic factors appear distinct from those of traditional growth factors and cytokines, it was long assumed that the neurotrophic factors utilized receptors and signaling systems fundamentally different from those used by growth factors operating elsewhere in the body. Recent advances in the understanding of the structure of the receptors for neurotrophic factors have unexpectedly revealed that they are in fact similar to the receptors used by the traditional growth factors and cytokines. The expression of the receptors for the neurotrophic factors is exclusively or predominantly in the nervous system; activation of these receptors in the context of the neuron allows these factors to display distinctive actions. While the precise roles of the neurotrophic factors and their therapeutic potential in various disease states still remain to be elucidated, this review describes studies on their receptor systems, their notable biological activities in the nervous system, and recent insights provided by targeted gene disruptions.