Cellular Analogues of Conditioning and Neural Plasticity: Satellite Symposium of the 28th International Congress of Physiological Sciences Szeged, Hungary, 1980
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Cellular Analogues of Conditioning and Neural Plasticity - O. Fehér
Fehér
NEUROPLASTICITY IN THE SUPERIOR CERVICAL GANGLION AS A CONSEQUENCE OF LONG-LASTING INHIBITION
J.R. Wolff¹, F. Joó², W. Dames¹ and O. Fehér³, ¹Max-Planck Institute for Biophysical Chemistry and Department of Anatomy, Developmental Neurobiology Unit, University of Göttingen, D-3400, FRG; ²Laboratory for Molecular Neurobiology, Institute of Biophysics, Biological Research Center, H-6701 Szeged, Hungary; ³Department of Comparative Physiology, József Attila University, H-6726 Szeged, Hungary
Publisher Summary
Synaptogenesis creates specific contacts between pre-synaptic and postsynaptic elements, which can be formed separately from each other. The neuroplastic (re-)distribution of synapses occurs under two conditions. First, in the mammalian central nervous system, partial denervation is followed by the terminal sprouting of specific nonlesioned axons, which re-innervate the surviving neurons. Second, during development, the distribution of synapses is regulated by some sort of functional interaction or competition between various afferent axon systems. Postsynaptic mechanisms may be important factors in regulating the interaction between pre- and postsynaptic elements during synaptogenesis. This chapter presents the experimental evidence indicating that the inhibition of neuronal activation might play an important role in producing the postsynaptic offerings, which are the prerequisites of excitatory synaptic contacts. The long-lasting application of gamma-aminobutyric acid (GABA) and NaBr suppresses the synaptic activation of ganglion cells and changes the structure of dendrites in the superior cervical ganglion (SCG). The neuroplasticity consists of (1) the formation and aggregation of numerous cytoplasmic vesicles, (2) a dramatic increase of the dendritic surface area, and (3) the formation and maintenance of free post-synaptic thickenings.
Introduction
Synaptogenesis creates specific contacts between presynaptic and postsynaptic elements which can be formed separately from each other (Hinds and Hinds 1976). The mechanisms inducing the formation of pre- or postsynaptic elements are largely unknown.
Neuroplastic (re-)distribution of synapses occurs under two conditions: (1) In the mammalian CNS partial denervation is followed by terminal sprouting of specific non-lesioned axons which re-innervate the surviving neurons. Even if enough axons are available, neuroplastic re-innervation often does not produce the original amount of synapses (Raisman et al. 1974). This indicates that the lack of postsynaptic sites might limit re-innervation. (2) During development the distribution of synapses is regulated by some sort of functional interaction or competition between various afferent axon systems (ref. see Hirsch and Leventhal 1979). This type of neuroplasticity is usually restricted to early postnatal periods. It was shown, however, that the irreversibility of the competitive neuroplasticity can be influenced by bicuculline (Duffy et al. 1976) and local application of norepinephrine (Kasamatsu and Pettigrew 1979). This suggests again that postsynaptic mechanisms may be important factors in regulating the interaction between pre- and postsynaptic elements during synaptogenesis.
Here, experimental evidence is presented, which indicates that inhibition of neuronal activation might play an important role in producing such postsynaptic offerings which are prerequisites of excitatory synaptic contacts.
Material and methods
γ-aminobutyric acid (GABA) and sodium bromide (NaBr) were dissolved in artificial cerebrospinal fluid (aCSF) at concentrations of 48 mM and 500 mM, respectively. The solutions were applied in two ways to the superior cervical ganglion (SCG) of adult female Sprague-Dawley rats:
(1) Small glass bulbs (φ 2 to 3 mm) connected to 50 μm glass pipettes filled with one of the solutions or with aCSF as controls were inserted into the SCG and glued to the long colli muscle. By this device GABA, NaBr or aCSF was released into the ganglion of freely moving animals for 1 to 30 days.
(2) Under anaesthesia with urethane-chloralose the SCG was exposed and the ganglion sheath was opened leaving intact the vascular and nerve connections. Thus, the solutions mentioned above were externally applied to the exposed ganglion for up to 7 hours.
During the electrophysiological experiments the pre-ganglionic cervical nerve was stimulated by a bipolar electrode. (0.4 ms pulse width, 2 cps with supramaximal intensity). Action potentials were recorded from the ganglionic surface by a silver ball.
In some cases, GABA was administered via glass bulbs for varying periods, 2 to 30 days. In a second operation the ganglionic capsule was split and the hypoglossal nerve cut and implanted in addition to the glass bulb.
All ganglia were fixed by cardiac perfusion with 2.5% glutaraldehyde in cacodylate buffer (0.1 M, pH 7.3) and embedded in Epon 812. The autoradiagrams were prepared by dipping semithin Epon sections in K2 emulsion; (Ilford). For further methodological details see Wolff et al. (1979), Dames et al. (1979) and Joó et al. (1979).
Results
Regardless of which technique was used to apply aCSF, no significant change was found in synaptic transmission of pre-ganglionic axons or in the structure of ganglionic neurons. In contrast, GABA and NaBr both suppressed synaptic activation and structure of ganglion cells. The effect of both substances was so similar that we will give a common description.
Effects of synaptic transmission
External application of GABA or NaBr caused a strong depression of the N1-component of ganglionic action potentials elicited by pre-ganglionic stimulation (Fig. 1). The size of the depression increased with time after the beginning of applying the substance to the ganglion. The P1-potential finally reached 50 to 20% of the normal value. The depression could be abolished by washing with aCSF and could be repeated by another application of either substance.
Fig. 1 The diagram shows the effects on ganglionic action potentials of externally applied 100 mM solution of GABA (≅) and NaBr (*), respectively. Ordinate: amplitude of the N1 component of the action potential as per cent of control values (upper trace of inset). Every point represents the average of 50 potentials. Bar on top: time of application. The maximum effect was reached after 2 to 3 hours (see lower trace of inset).
Localization of GABA within the SCG.
After in vivo application of ³H-GABA, autoradiograms showed that most of the GABA retained in the SCG was accumulated within satellite glial cells. The highest concentration of GABA was found in glial cells surrounding the tip of the glass pipette. No GABA accumulating neurons were observed in the SCG.
Effects on synaptic contacts
Neither short term (0.5 h to 2 days) nor long term (2 to 35 days) application of GABA or NaBr changed significantly the structure of synapses between pre-ganglionic axons and principle ganglion cells. Sometimes cyto-lysosomes of unknown origin appeared in postsynaptic structures, i.e. mainly in dendrites. However, the lysosomes did not show any regular relation to synapses or to free postsynaptic thickenings.
Effects on dendrites
GABA and NaBr induced the formation of numerous spinelike protrusions on the dendrites of ganglion cells (Fig. 2). As a consequence, the dendrites increased their surface-to-volume ratio by about 50 per cent.
Fig. 2: Spine-like protrusions were observed on the dendrites of ganglion cells after GABA (A) or NaBr applications (B). F-POST’s are indicated by arrows, mv=microvesicles, r=ribosomes, M=mitochondrion.
The surface area of dendrites increased mainly by exocytosis of vesicles with a varying size (φ = 40 to 200 nm). Similar vesicles accumulated locally in the cytoplasm of dendrites. The vast majority of these vesicles did not show any osmiophilic contents, but a few dense cored vesicles were always present in or near the aggregates. The location of vesicle clusters varied considerably. Mostly, they developed in the stems of dendrites displacing cytoplasm containing ribosomes and rough endoplasmic reticulum. Sometimes vesicles aggregated near the plasma membrane or even in the vicinity of submembraneous densities which are described below as free postsynaptic thickenings. Although these structural complexes may resemble active zones of presynaptic elements, we did not observe any typical dendro-dendritic synapses in the SCG.
A very striking structural change was the development of numerous zones which showed filamentous material aggregated and adherent to the cytoplasmic aspect of dendritic membranes (Fig. 2). These structures resembled closely postsynaptic membrane thickenings of Gray’s type I synapses. Since they were not in contact with presynaptic elements, we called them free postsynaptic thickenings (F-POST, Wolff et al. 1979). F-POSTs mostly faced glial processes; occasionally they were in direct contact with the basal lamina or with dendrites; relatively often two F-POSTs were apposed to each other forming symmetrical desmosome-like contacts. Confirming observations of Raisman et al. (1974), we found a few F-POSTs and desmosome-like contacts also in control ganglia, but their number increased enormously after treatment either with GABA or with NaBr, i.e. by much more than one order of magnitude.
F-POSTs developed after less than 2 hours of GABA or NaBr treatment and persisted as long as these substances were applied (about 30 days). However, after short application most F-POSTs were not fully developed. As indicated by an increasing amount and density of the filamentous material, F-POSTs undergo a maturation which lasts for two to several days.
Composition and possibility to innervate F-POST
Very little is yet known about the composition of F-POSTs. According to autoradiograms prepared after binding of H-α-Bungarotoxin, the topography of the binding sites for this toxin in the SCG changes after GABA application. The binding sites seem to form clusters which show a similar distribution as F-POSTs and the spine-like protrusions of dendrites. In normal ganglia the toxin binds much more homogeneously.
During longlasting application of GABA, the hypoglossal nerve was implanted into the SCG in addition to the intact preganglionic nerve. In a few experiments the hypoglossal nerve regenerated and persisted at least for two months in the ganglion (Fig. 3). However, the number of experiments is still too small and the formation and location of the new synapses has yet to be analysed.
Fig. 3 Superior cervical ganglion (SCG) taken out from a rat two months after a hypoglossal nerve has been implanted in the presence of a glass bulb containing GABA. The arrow points to the site where the perineural sheath has fused with the ganglionic capsule.
Comments
In many parts of the central and peripheral nervous system free postsynaptic thickenings (F-POSTs) appear after denervation. This temporo-spatial coincidence with terminal degeneration suggested that F-POSTs represent vacated and persisting postsynaptic densities (Sotelo 1968, Pinching 1969). Quantitative comparisons revealed, however, that the persistence of postsynaptic densities is a rather uncommon event during terminal degeneration (Raisman and Field 1973, Raisman et al. 1974, Gruner et al. 1974). Hence, apart from degeneration of the presynaptic element, there might be a second condition which is necessary to make vacant postsynaptic thickenings appear.
Additionally, it was demonstrated that F-POSTs can develop in the absence of appropriate presynaptic elements (Sotello 1973). This indicates that vacation cannot be the only way to produce F-POSTs, but that they can be newly formed (Hinds and Hinds 1976).
The present results demonstrate that the formation of F-POSTs can be induced by GABA (Wolff et al. 1978, 1979). In the SCG, GABA is not a synaptic transmitter. Consequently the formation of F-POSTs is mediated by extrasynaptic receptors for GABA. These increase the Cl− conductance of neuronal membranes and diminish postsynaptic action potentials by shunting the inward current (Adams and Brown 1975). Since the effects of GABA and NaBr are similar both probably depend on their common effects on chloride channels (Riker and Montoya 1978).
Thus, F-POSTs do not only appear after denervation, but also in the presence of excitatory synapses as long as the activation of neurons is prevented by tonic inhibition. The stimulus for producing or preserving F-POSTs might, therefore, be the deprivation of a neuron from being activated by excitatory input, irrespective of whether this is caused by physical or functional denervation or inhibition. Further experiments are needed to check whether postsynaptic densities can really persist during terminal degeneration or whether F-POSTs are always newly formed whenever the equilibrium between excitatory and inhibition is changed. F-POSTs would then appear when postsynaptic offerings
cannot be transformed into synapses because of a lack of presynaptic elements.
At present, our knowledge about the molecular composition and the possibility to innervate F-POSTs in the SCG is still insufficient. Preliminary observations suggest, however, two unexpected aspects of this neuroplasticity: (1) F-POSTs seem to contain many binding sites for α-Bungarotoxin and can possibly be innervated by the cholinergic hypoglossal nerve. This means that the newly formed synapses should accumulate a type of acetyl choline receptor which is normally restricted to extrajunctional sites (Carbonetto et al. 1978). Hence, the synapses made by the preganglionic nerve and by the hypoglossal nerve should be pharmacologically different. This hypothesis is currently tested: (2) Although the physiological role of GABA in the SCG is not well understood (Bowery et al. 1979), GABA might represent some sort of inhibitory modulator. The presented results suggest that GABA - at least under pathological conditions - might help to stabilize the excitatory synapses in the SCG.
Summary
Longlasting application of GABA and NaBr suppresses the synaptic activation of ganglion cells and changes the structure of dendrites in the SCG. This neuroplasticity consists of (1) formation and aggregation of numerous cytoplasmic vesicles, (2) a dramatic increase of the dendritic surface area, (3) formation and maintenance of free postsynaptic thickenings. The latter seem to accumulate α-Bungarotoxin binding sites and might be innervated by the hypoglossal nerve if implanted in the presence of the preganglionic input.
Acknowledgement
This study was supported by DFG-grants: SFB 33 E3, E5 and UNG 436, Wo 279/2.
References
Adams, P.R., Brown, D.A. Actions of γ-aminobutyric acid on sympathetic ganglion cells. J. Physiol. 1975; 250:85–120.
Bowery, N.G., Brown, D.A., Marsh, S. γ-Aminobutyric acid efflux from sympathetic glial cells: effect of ‘depolarizing’ agents. J. Physiol. 1979; 293:75–101.
Carbonetto, S.T., Fambrough, D. M. and Muller, K. J., (1978). Nonequivalence of α-bungarotoxin receptors and acetylcholine receptors in duck sympathetic neurons. Proc. Natl. Acad. Sci. USA, 75, 1016–1020
Dames, W., Joó, F., Wolff, J.R. A method for localized and longlasting microapplication of drugs into nervous tissue of freely moving animals. Exp. Brain Res. 1979; 36:259–264.
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Gruner, J.E., Hirsch, J.C., Sotelo, C. Ultrastructural features of the isolated suprasylvian gyrus in the cat. J. Comp. Neurol. 1974; 154:1–28.
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Hirsch, H.V.B., Leventhal, A.G. Functional modification of the developing visual system. Hdb. of Sensory Physiol. 1979; 19:279–335.
Joó, F., Dames, W., Wolff, J.R. Effect of prolonged sodium bromide administration on the fine structure of dendrites in the superior cervical ganglion of adult rat. Progr. Brain Res. 1979; 51:109–115.
Kasamatsu, T., Pettigrew, J.D. Preservation of binocularity after monocular deprivation in the striate cortex of kittens treated with 6-hydroxydopamine. J. Comp. Neurol. 1979; 185:139–162.
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INHIBITION AS THE BASIS FOR NEURONAL PLASTICITY
A.S. Batuev, A.A. Alexandrov and N.A. Scheynikov, Department of Higher Nervous Acivity, Leningrad State University, 199164 Leningrad, USSR
Publisher Summary
Inhibition process, which is a basic property of the central nervous system, is thought responsible for activity coordination. Recent evidence that inhibitory post-synaptic processes are induced by specific inhibitory transmitters released from certain presynaptic endings is of importance. Good results have been obtained for the spinal cord, cerebellum, and hippocampus, while the study of inhibitory mechanisms of cerebral cortex is still in an embryonic state. The knowledge of the sensory motor cortex—a better investigated structure—is hypothetical, because inhibitory elements are difficult to identify functionally and structurally. Inhibition plays an important role in the brain integrative action; inhibitory neurons connect some units in the functional center and form labile neuronal assemblies of different complexity. Results indicate that picrotoxin reducing inhibition and glutamate augmenting inhibitory processes through excitation of inhibitory neurons modify neuronal receptive fields. Picrotoxin affects a small portion of the membrane. Wide-spreading complex inhibitory systems might be related to the neuron capacity to respond to certain stimuli and to control the switching on-off of neurons in different functional systems.
Inhibition processes, a basic property of CNS is thought responsible for activity coordination. Of particular importance is recent evidence that inhibitory post-synaptic processes are induced by specific inhibitory transmitters released from certain presynaptic endings.
There seem to be good results obtained for the spinal cord, cerebellum and hippocampus, while the study of inhibitory mechanisms of cerebral cortex is still in an embryonic state. Our knowledge of the sensory motor cortex.a better investigated structure, is also hypothetical, since inhibitory elements are difficult to identify both functionally and structurally. Inhibition plays an important role in the brain integrative action; inhibitory neurons connect some units in the functional center and form labile neuronal assemblies of different complexity (Batuev et al.,1979).
Methods.
The experiments were performed on cats lightly anesthetized with 40 mg/kg Nembutal intraperitoneally. The animals were then immobilized with Flaxedyl or Dyplacine and given artificial respiration. Five-barrel micropipettes with 4–6 μm tip diameter were used for unit activity recording and electro phoretic administration of drugs. Barrels filled with 1.5–2M K-citrate were used for extracellular recording and passing a balance current. Other barrels contained 0.5 M Na-glutamate solution (pH 8–9); a solution of 0.5 M gamma-amino-butyric acid (GABA, pH 4–5); 0.9% Na-citrate solution saturated with picrotoxin. To prevent leakage of drugs from the micropipette tips, the retaining currents of 10 nA were passed through the