Publisher Summary This chapter provides an overview of the principal features of perikaryal responses to axon injury. The neuron is an unusual cell. Its axon terminals may be situated at what in cellular terms is an enormous distance from the cell body (perikaryon); the volume of the latter may be but a small fraction of the total cellular volume. Yet the neuronal processes are maintained and their substance is constantly renewed from the perikaryon. The separation of an axon from its cell body results (in vertebrates) in the degeneration of the separated portion and is followed by a series of morphological changes in the perikarya. The most conspicuous of these is the disintegration, redistribution, and apparent disappearance from the cell body of cytoplasmic basophil material. Changes in axotomized neurons are generally assessed by comparison with the corresponding contralateral neurons of the experimental animal.

The Axon Reaction: A Review of the Principal Features of Perikaryal Responses to Axon Injury

Transient receptor potential (TRP) proteins are cation-selective channels that function in processes as diverse as sensation and vasoregulation. Mammalian TRP channels that are gated by heat and capsaicin (>43 °C; TRPV1 (ref. 1)), noxious heat (>52 °C; TRPV2 (ref. 2)), and cooling (< 22 °C; TRPM8 (refs 3, 4)) have been cloned; however, little is known about the molecular determinants of temperature sensing in the range between ∼22 °C and 40 °C. Here we have identified a member of the vanilloid channel family, human TRPV3 (hTRPV3) that is expressed in skin, tongue, dorsal root ganglion, trigeminal ganglion, spinal cord and brain. Increasing temperature from 22 °C to 40 °C in mammalian cells transfected with hTRPV3 elevated intracellular calcium by activating a nonselective cationic conductance. As in published recordings from sensory neurons, the current was steeply dependent on temperature, sensitized with repeated heating, and displayed a marked hysteresis on heating and cooling5,6,7,8,9,10. On the basis of these properties, we propose that hTRPV3 is thermosensitive in the physiological range of temperatures between TRPM8 and TRPV1.

TRPV3 is a calcium-permeable temperature-sensitive cation channel

The prevalence of severe dementia in the United States is about 1.3 million cases, of which at least 50 to 60% are of the Alzheimer type. Severe dementia of the Alzheimer type is found rarely in a clearly dominant pattern, although often one or more relatives are affected. Down's syndrome in adults is often associated with Alzheimer changes. The diagnosis is a clinicopathological one; there is a considerable error rate in the clinical diagnosis early in the course of the disease, especially in regard to dementia in depression. The differential diagnosis involves a great many disorders, including multi-infarct dementia, tumors, subdural hematomas, and others. Physiological aspects of Alzheimer's disease include a diffusely slow electroencephalogram, reduced cerebral blood flow, and particular patterns noted on positron emission tomographic scanning. The latter technique has also demonstrated that oxygen extraction is normal in Alzheimer's disease, thus excluding ischemia from possible pathogenetic factors. Morphological changes, that is, the presence of plaques and tangles, are widely distributed in neocortex, paleocortex, and many deep gray areas down through the pontine tegmentum, but largely exclude the basal ganglia, thalamus, and substantia nigra. Numerous plaques without neocortical tangles are found in many demented persons older than 75 years. A severe loss of large neocortical neurons is characteristic of the disease. The chemical nature of the paired helical filaments that make up the neurofibrillary tangle has not yet been ascertained. Neurons are markedly deficient in the basal forebrain nuclei, and this deficiency may account for the severe diminution of choline acetyltransferase and acetylcholine in the neocortex and paleocortex. Muscarinic cholinergic receptors are present in normal amounts. Norepinephrine is reduced in some cases, and somatostatin in most. Substance P is low in severe cases. The etiology of the disorder is unknown and the role of aluminum is disputed. Management of patients with Alzheimer's disease is difficult, and neuroleptics are to be used with great caution because of their side effects. Substrate therapy has not been effective; physostigmine improves memory but is not suitable for general use. Trophic factors, gangliosides, and aluminum chelation are being investigated for use in pharmacological intervention.

Senile dementia of the Alzheimer type.

Neurodegeneration in Excitotoxicity, Global Cerebral Ischemia, and Target Deprivation: A Perspective on the Contributions of Apoptosis and Necrosis

A nuclear framework structure termed the nuclear matrix has been isolated and characterized. This matrix forms the major residual structure of isolated nuclei and consists largely of protein with smaller amounts of RNA, DNA, carbohydrate, and phospholipid. The nuclear matrix can be further resolved by combined treatment with DNase and RNase. The remaining nuclear protein structure, after extraction of 90 percent of the nuclear protein, 99.9 percent of the DNA, and 98 percent of the RNA and phospholipid, is termed the nuclear protein matrix. Electron microscopy of this final nuclear protein matrix reveals an interior framework structure composed of residual nucleolar structures associated with a granular and fibrous internal matrix structure. The internal matrix framework is derived from the interchromatinic structures of the nucleus, and is connected to a surrounding residual nuclear envelope layer containing residual nuclear pore complex structures. Sodium dodecyl sulfate-acrylamide gel electrophoresis of the nuclear matrix proteins demonstrates three major polypeptide fractions, P-1, P-2, and P-3, with average molecular weights of approximately 69,000, 66,000 and 62,000, as well as several minor polypeptides which migrate at approximately 50,000 and at higher molecular weights (>100,000). Polypeptides with molecular weights identical to those of P-1, P-2 and P-3 are also components of isolated nuclear envelopes and nucleoli, whereas isolated chromatin contains no detectable matrix polypeptides. This suggests that the major matrix polypeptides are localized in specific structural regions of the nucleus, i.e., nuclear envelope, nucleoli, and interchromatinic structures. The presence of cytochrome oxidase activity in the isolated nuclear matrix indicates that at least some integral proteins of the nuclear membrane are associated with the matrix.

Nuclear matrix: Isolation and characterization of a framework structure from rat liver nuclei

Study of the developing chick retina with the electron microscope revealed that dyad ribbon synapses begin to form in the inner plexiform layer before synaptic ribbons begin to appear in photoreceptor terminals of the outer plexiform layer. This centrifugal (inner to outer) sequence of synaptogenesis in the predominantly cone retina of the chick differs from the centripetal sequence that has been reported for the predominantly rod retinas of the mouse and rat. This difference does not favor the hypothesis, suggested by others, that the photo-receptor may influence the maturation of inner retinal elements. The different patterns of synaptogenesis are discussed briefly with reference to anatomical differences between the retinas of different species.

Arthur LaVelle

Papers

On the synaptogenic sequence in the chick retina

Neuronal swelling and chromatolysis as influenced by the state of cell development

The nucleolar apparatus and neuronal reactivity to injury during development.

Nucleolar and Nissl substance development in nerve cells.

1 – Neuronal Reaction to Injury during Development