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GAP-43 as a plasticity protein in neuronal form and repair.

Neurons exhibit a remarkable plasticity of form, both during neural development and during the subsequent remodelling of synaptic connectivity. Here we review work on GAP-43 and G0, and focus upon the thesis that their interaction may endow neurons with such plasticity. We also present new data on the role of G proteins in neurite growth, and on the interaction of GAP-43 and actin. GAP-43 is a protein induced during periods of axonal extension and highly enriched on the inner surface of the growth cone membrane. Its membrane localization is primarily due to a short amino terminal sequence which is subject to palmitoylation. Binding to actin filaments may also assist in restricting the protein to specific cellular domains. Consistent with its role as a "plasticity protein," there is evidence that GAP-43 can directly alter cell shape and neurite extension, and several theses have been advanced for how it might do so. Two other prominent components of the growth cone membrane are the alpha and beta subunits of G0. GAP-43 regulates their guanine nucleotide exchange, which is an unusual role for an intracellular protein. We speculate that GAP-43 may adjust the "set point" of responsiveness for G0 stimulation by receptors, thereby altering the neuronal propensity to growth, without actually causing growth. To begin to address how G protein activity affects axon growth, we have developed a means to introduce guanine nucleotide analogs into sympathetic neurons. Stimulation of G proteins with GTP-gamma-S retards axon growth, whereas GDP-beta-S enhances it. This is compatible with G protein registration of inhibitory signals.

Actins↗

Experience-dependent structural plasticity in cortex heterotopic to focal sensorimotor cortical damage.

Structural plasticity following focal neocortical damage in adult rats has recently been found to be sensitive to postinjury rehabilitative training. Experience on a complex motor skills task, the acrobatic task, after unilateral lesions of the forelimb representation region of the sensorimotor cortex (FLsmc) enhanced synaptic structural changes in the cortex contralateral and homotopic to the lesions. Using tissue from this previous study, the present study examined whether a heterotopic region of the sensorimotor cortex of either hemisphere, the hindlimb representation area (HLsmc), would undergo structural changes following unilateral FLsmc lesions and whether these changes would also be sensitive to postinjury training on the acrobatic task. Stereological methods for light and electron microscopy were used to assess structural changes in lesion or sham-operated rats following 28 days of postoperative acrobatic training or simple repetitive exercise (motor controls). In the HLsmc contralateral to the lesions of rats receiving acrobatic training, there was a subtle, but significant, increase in cortical volume and in layer II/III neuropil and dendritic volume per neuron in comparison to shams. In rats receiving simple exercise after the lesions, these changes were not significantly different from shams. Acrobatic training also prevented a loss of cortical volume in the HLsmc adjacent to the lesion in comparison to shams. These data suggest that behavioral training following cortical injury facilitates structural plasticity in behaviorally relevant areas of the neocortex other than the homotopic cortex contralateral to the lesion. This structural plasticity might be relevant to the development of behavioral compensation after cortical injury.

Animals↗

Synaptic plasticity in the caudate nucleus of patients with Parkinson's disease.

The loss of dopaminergic neurons from the substantia nigra in Parkinson's disease (PD) may provoke a reorganization of cellular interactions in the nigrostriatal pathway. Indeed, a plasticity of putative corticostriatal synapses has been evidenced in the striatum of rats with a 6-hydroxy-dopamine-induced lesion of the substantia nigra. However, to our knowledge, synaptic plasticity in the striatum has not previously been investigated in human PD. In this study, we have analysed, at electron microscope level, the morphological characteristics of the synapses formed by afferents in asymmetric contact with dendritic spines of neurons in the caudate nucleus of three patients with PD and three matched controls. The length of the postsynaptic densities and the number of perforated synapses were both significantly increased (24 and 88%, respectively) in the PD patients; the size of these afferents and the surface area occupied by their mitochondria also showed an increase (24 and 50%, respectively), although not statistically significant. The size and density of dendritic spines and the size of postsynaptic density perforations were unchanged. These data indicate the presence of plasticity of the putative corticostriatal synapses in PD and suggest a hyperactivity of cortical afferents to GABAergic neurons.

Aged↗

Properties and mechanisms of long-term synaptic plasticity in the mammalian brain: relationships to learning and memory.

Long-term potentiation (LTP) in the hippocampus and long-term depression (LTD) in the cerebellum are two forms of long-lasting synaptic plasticity that currently serve as our primary experimental models of learning and memory formation in mammals. In recent years, there have been considerable advances in our understanding of the cellular and molecular mechanisms of these and other forms of synaptic plasticity. This article presents an overview of these developments, considers the relationship of long-term synaptic plasticity mechanisms to learning and memory in view of these developments, and suggests future directions for research in this rapidly growing area of neuroscience.

Animals↗

Synaptic plasticity and learning and memory: 15 years of progress.

Much has been learned over the past 15 years about the mechanisms of synaptic plasticity and their relationships to learning and memory processes. Some of the questions raised 15 years ago have been answered while others still remain elusive. This brief review attempts to evaluate the progress accomplished in this field and discusses four specific issues: (i) the relationships between mechanisms of synaptic plasticity and memory types, (ii) the relationships between stabilization of synaptic modifications and memory consolidation, (iii) the links between gene regulation and regulation of synaptic efficacy, and (iv) the relationships between synaptic dynamics and synaptic plasticity. Although it is relatively easy to identify areas in which progress has been made, it is also clear that many areas remain highly controversial and will keep neuroscientists busy for years to come.

Animals↗

Neurobiology and treatment of anxiety: signal transduction and neural plasticity.

The stress-dependence and chronic nature of anxiety disorders along with the anxiolytic effectiveness of antidepressant drugs suggests that neuronal plasticity may play a role in the pathophysiology of anxiety. Intracellular signaling pathways are known in many systems to be critical links in the cascades from surface signals to the molecular alterations that result in functional plasticity. Chronic antidepressant treatments can regulate intracellular signaling pathways and can induce molecular, cellular, and structural changes over time. These changes may be important to the anxiolytic effectiveness of these drugs. In addition, the signaling proteins implicated in the actions of chronic antidepressant action, such as cAMP response element binding protein (CREB), have also been implicated in conditioned fear and in anxiety. The cellular mechanisms underlying conditioned fear indicate roles for additional signaling pathways; however, less is known about such mechanisms in anxiety. The challenge to identify intracellular signaling pathways and related molecular and structural changes that are critical to the etiology and treatment of anxiety will further establish the importance of mechanisms of neuronal plasticity in functional outcome and improve treatment strategies.

Animals↗

The role of muscarinic acetylcholine receptors in ocular dominance plasticity.

During a critical period of postnatal development neuronal connections in the visual cortex are susceptible to experience-dependent modifications. In normally reared kittens the majority of neurons respond to visual stimulation of either eye. A few days of monocular deprivation, however, are sufficient to render most cortical neurons unresponsive to visual stimuli presented to the deprived eye. Among other factors the cholinergic projection to striate cortex has been identified as having a permissive role in this use-dependent modification of synaptic transmission. In order to analyze further the influence of acetylcholine in cortical plasticity, we tested whether the blockade of muscarinic or nicotinic receptors interfered with ocular dominance plasticity. At four weeks of age kittens had one eyelid sutured closed and osmotic minipumps implanted, which delivered scopolamine (1 nmol/h) or hexamethonium (1 or 10 nmol/h) into the striate cortex of one hemisphere and vehicle solution (saline) into the other. After one week, ocular dominance distributions were determined in area 17 with single unit recording. In the control hemispheres, most neurons became unresponsive to the deprived eye, while in the scopolamine-treated hemispheres most neurons remained binocular. In contrast to the effects of scopolamine, the intracortical infusion of hexamethonium had no effect on ocular dominance plasticity. These results demonstrate that blockade of muscarinic, but not nicotinic receptors renders kitten striate cortex resistant to the effects of monocular deprivation.

Animals↗

[Use of endoscopy in plastic surgery].

Now that endoscopic techniques have been established in visceral and trauma surgery under the concept of minimal invasive surgery, plastic surgery has also begun to accept these techniques since minimal invasive surgery is very important in this field. In contrast to abdominal and thoracic surgery, plastic surgery cannot be done in preformed cavities. Therefore, it was necessary to develop new techniques and instruments. We present the most important operations in the field of plastic surgery that can so far be carried out endoscopically. The development phase is only at the beginning, and new indications are being added daily since the technical equipment can also only be gradually adapted to the needs that arise.

Animals↗

Synaptic plasticity induced in single neurones of the primary somatosensory cortex in vivo.

Experiments carried out in urethane-anaesthetized rats in which single neurones were recorded extracellularly from primary somatosensory (SI) cortex employed a procedure in which one of two vibrissal inputs was temporally paired with iontophoretic applications of glutamate. Following the pairing procedure. 31% of 49 neurones studied displayed some form of synaptic plasticity, in that responses to one or both vibrissal stimuli were altered. Homosynaptic potentiation occurred in 4 neurones, and these were recorded in layers II/III only. Homosynaptic depression occurred in 6 neurones and were mainly recorded in layer IV. Heterosynaptic depression was observed in 3 neurones. Non-selective depression was observed in 2 neurones. The duration of the induced plastic changes typically exceeded 15 min, and often lasted as long as stable recordings continued. The results from experiments in which repeated glutamate applications were given alone (without synaptic input) confirmed that the non-selective changes were due to repeated glutamate applications and not the temporal pairing with synaptic responses per se. Dual recordings confirmed that plasticity was restricted to the neurone at which pairings were made, and (at the other neurone) that synaptic responses remained stable over the course of study. In some neurones homosynaptic potentiation and depression were shown to occur to the early response component (< 10 ms), suggesting that direct thalamocortical synapses are modifiable.

Animals↗

On the role of vestibulo-ocular reflex plasticity in recovery after unilateral peripheral vestibular lesions.

Although adaptive plasticity is a well-known feature of the vestibulo-ocular reflex (VOR), deficits in VOR performance after unilateral labyrinthectomy are poorly compensated in a large percentage of cats. To assess whether VOR plastic capabilities are affected by labyrinthectomy, forced oscillation in front of a patterned surround was imposed in unilaterally labyrinthectomized cats. This experimental paradigm has been shown to be very effective in inducing adaptive VOR gain changes in intact animals. We demonstrate that plasticity of VOR gain is still present both in acute and chronic stages following vestibular lesions. By contrast, forced oscillation did not significantly alter the lesion-induced asymmetry of responses. We conclude that VOR gain control mechanisms are not used to their fullest possible extent in a large percentage of animals suffering unilateral vestibular damage.

Acoustic Stimulation↗

Cortical activity blockade prevents ocular dominance plasticity in the kitten visual cortex.

Recordings from single units in kitten primary visual cortex show that a reversible blockade of the discharge activities of cortical neurons and geniculocortical afferent terminals by intracortical infusion of the sodium channel blocker tetrodotoxin (TTX) completely prevented the ocular dominance shift that would normally be seen after monocular deprivation. The blockade of cortical plasticity, like the blockade of discharge activity, was reversible, and plasticity was restored following recovery from the effects of TTX. These results extend previous work suggesting involvement of electrical activity at the level of the cortex in the phenomenon of cortical plasticity by demonstrating an absolute requirement for discharge activities in the primary visual cortex.

Action Potentials↗

An old friendship revisited: plastic surgery and transplantation.

Plastic surgery has a rich history in the development of the field of transplantation. Many prominent plastic surgeons, while undertaking experimental as well as clinical efforts, pioneered and assisted in the establishment of journals and societies devoted exclusively to the field of transplantation. Much of this work was initiated during World War II, a time when transplantation was viewed with suspicion by both scientists and clinicians. While work in this area has undergone a quiescence among members of our specialty, advances in microsurgery and immunology have rekindled interest among plastic surgeons.

History, 20th Century↗

Immunohistochemical demonstration of DNA-incorporated 5-bromodeoxyuridine in frozen and plastic embedded sections.

The application of an immunohistochemical method in the detection of replicating cells, that have incorporated 5-bromodeoxyuridine (BrdUrd), was studied on frozen and plastic embedded sections of different rat tissues. Hydrolysis conditions employed in the Feulgen procedure are essential in making the incorporated BrdUrd accessible to the monoclonal anti-BrdUrd antibodies. To demonstrate the incorporated BrdUrd in plastic embedded sections a subsequent etching with xylene and digestion with protease is necessary. Data obtained with this method are completely comparable with those found by the tritiated thymidine method. In comparison with the thymidine method, the BrdUrd method is much less time consuming and does not require precautions in working with radioactivity. The BrdUrd-method enables a more precise localization as is especially shown in the plastic embedded sections.

Animals↗

Adaptive plasticity in the spinal stretch reflex: an accessible substrate of memory?

The study of the substrates of memory in higher vertebrates is one of the major problems of neurobiology. A simple and technically accessible experimental model is needed. Recent studies have demonstrated long-term adaptive plasticity, a form of memory, in the spinal stretch reflex (SSR). The SSR is due largely to a two-neuron monosynaptic arc, the simplest, best-defined, and most accessible pathway in the primate central nervous system (CNS). Monkeys can slowly change SSR amplitude without a change in initial muscle length or alpha motoneuron tone, when reward is made contingent on amplitude. Change occurs over weeks and months and persists for long periods. It is relatively specific to the agonist muscle and affects movement. The salient features of SSR adaptive plasticity, combined with clinical and laboratory evidence indicating spinal cord capacity for intrinsic change, suggest that SSR change eventually involves persistent segmental alteration. If this is the case, SSR plasticity should be a powerful model for studying the neuronal and synaptic substrates of memory in a primate.

Adaptation, Physiological↗

Understanding microwave-stimulated Romanowsky--Giemsa staining of plastic embedded bone marrow.

Bone marrow smears were made and fixed in methanol or formaldehyde. Marrow sections of various thicknesses were also prepared from formaldehyde fixed marrows embedded in paraffin or plastic (glycol methacrylate). The different smears and sections were then stained by a Romanowsky--Giemsa procedure. Some specimens were stained using a standard microwave-stimulated method previously used diagnostically. The effects of technical variations were studied, including degree of microwave irradiation and the staining time. Comparisons of the resulting staining outcomes showed that microwave stimulated Romanowsky--Giemsa staining of plastic sections is a rate controlled process. Unusual aspects of the staining pattern of plastic sections (namely the purple basophilic cytoplasms and nucleoli, and blue chromatin) are due to microwave stimulation and formaldehyde fixation respectively.

Animals↗

A rapid immunogold-silver staining for detection of bromodeoxyuridine in large numbers of plastic sections, using microwave irradiation.

A rapid and convenient method for the large scale, immunogold-silver staining (IGSS) of bromodeoxyuridine (BrdU) incorporated by S phase cells, by means of a monoclonal antibody (anti-BrdU) is described. Nineteen slides at a time can be incubated with the antibodies and the protein A-gold (PAG) in staining jars. The antibody and protein A-gold solutions could be used at least five times to incubate new batches of slides. The incubation times with these solutions were shortened by means of microwave irradiation. In this way 200 slides carrying at least 800 sections could be easily processed under the same conditions in one day, using 1.25 ml neat antibody solutions of anti-BrdU and rabbit anti-mouse. For light microscopy both plastic embedding systems: methylmethacrylate (MMA) and glycolmethacrylate (GMA) can be stained with this technique. The MMA sections, of which the plastic has to be removed before the IGSS, has the advantage of a stronger labelling intensity. The GMA plastic, which contains a cross-linking agent cannot be removed and consequently for GMA sections it is necessary to incubate the sections with a proteolytic enzyme (trypsin) before the IGSS, to reexpose the antigenic binding sides. However, the GMA sections can be allowed to air dry during the IGSS without negative effects on the morphology. This makes it possible to perform the antibody and the PAG-incubating steps on one day and to finish the IGSS the next day. In this way twice as many GMA slides can be incubated with the same antibody and PAG solutions than with MMA slides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Plasticity of cone horizontal cell functioning in cyprinid fish retina: effects of background illumination of moderate intensity.

In electrophysiological experiments involving intracellular recording from horizontal cells in the isolated retina of the roach, light adaptation of the retina has been shown to result in potentiation both of (1) the depolarizing component of biphasic chromaticity type S-potentials, and (2) the temporal frequency transfer functions of photopic luminosity type horizontal cells. Under identical light adaptation conditions, the number of spinules on horizontal cell dendrites positioned laterally at cone pedicle ribbon synapses, increase by some threefold. The latter effect occurs equally in pedicles of red- and green-sensitive cones. Thus, horizontal cells are 'plastic' in both structural and electrophysiological respects. Furthermore, since the two electrophysiological parameters studied depend on negative feedback from horizontal cells onto cones, the results suggest that it is the inhibitory synapses that are plastic and that spinules may be sites of the negative feedback interaction. Physiological and behavioural aspects of light-dependent horizontal cell plasticity are also discussed.

Animals↗

Problems of aesthetic plastic surgery training within the National Health Service.

In 1949 a National Plastic Surgery Training Program was set up in Great Britain. At that time there was a relative shortage of trained specialists in such a new field, and a vast accumulation of wartime injuries and a backlog of untreated civilian cases. This situation has changed during the past 30 years so that emphasis in training has also had to adapt to include the subspecialties of hand surgery, microsurgery, craniofacial surgery, and aesthetic plastic surgery. The problems of training in aesthetic surgery and the formation of a new British Association of Aesthetic Plastic Surgeons are described.

Esthetics↗