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Slovak Academy of Sciences, Institute of Animal Biochemistry and Genetics, 900 28 Ivanka pri Dunaji, Czech and Slovak Federal Republic The assumption is introduced that there are two types of adaptive responses in central neurons in response to signi cantly changed circuit activity. Morphological synaptic modi cations and synapse turnover are thought to be involved in both of these responses, in such a way that in the rst case they are to restore the circuit activity level as it was in the past, and in the second case they are to switch to a new pattern. The events eliciting synaptogenesis are proposed to be di erent in these instances. The role of compensatory extrasynaptic receptors insertion and preferential insertion of synaptic receptors induced by enhanced presynaptic activity are discussed. The hypothesis as to how these two adaptive responses come into action during depression and antidepressant treatment is then proposed.
The hypothesis I intend to introduce concerns the possible mechanisms which are involved in the action of antidepressants. It makes some suggestions for further testing of the classical amine hypothesis of depression (1{3) which claims that depressions are asociated with an absolute or relative de ciency of noradrenaline (NA) and/or 5-hydroxytryptamine (5-HT) at functionally important receptor sites in the brain. First I shall list the main clusters of ndings from which the hypothesis has emerged.
E ects of antidepressant treatment 1. Potentiation of amine metabolism by monoamine oxidase inhibitors (MAOI), inhibition of amine reuptake by tricyclic antidepressants (TCA) and some of so-called novel antidepressants, as well as -2 adrenoreceptor antagonism of mianserin are known biochemical actions of antidepressant (AD) drugs (4, 5).
These e ects can increase the e ectiveness of released amines in synaptic transmission.
2. Drugs used to treat depressions frequently have to be administered for several weeks before clinical 3. Long-term administration of TCA, MAOI, novel antidepressants, and electroconvulsive treatment induce a reduction in the number of - adrenoreceptors ( -AR) as well as 5-HT receptors in the rat brain (7, 8).
In contrast to the down-regulation of these two receptor types, an increase in -adrenoreceptor ( -AR) number is observed after chronic administration of AD therapy (7, 8). The down-regulation of amine receptors is considered to be a controversal nding in regard to the amine hypothesis of depression because enhanced synaptic transmission at the aminergic synapses should be the expected result of AD treatment.
4. Soubrie et al. (9) observed a delay in behavioral response to AD drugs following selective 6-hydroxydo- pamine (6-OHDA) damage to the hippocampal noradrenergic innervation in rats.
Adaptive changes on neurons in response to partial dea erentation 1. 6-OHDA{induced lesions of the noradrenergic neurons in rats (10) and chicks (11) which decrease markedly NA concentrations in neocortex or atria respectively, caused a signi cant increase in the -AR number in the regions treated. On the contrary, after surgical and 6-OHDA denervation there was a decrease in the number of -AR in the chick expansor secundarium smooth muscle (12). It follows, that damage to noradrenergic innervation causes, at least in these cases, an e ect on the number of -AR and -AR, opposite 2. In general, partial denervation of adult vertebrate central neurons causes intact nerve bers to sprout new endings and form new synapses that replace those lost as a consequence of the lesion (13, 14). When a neuron receives more than one type of a erent, there is a hierarchy in the relative capacity of the various a erents to grow in response to synapse loss (depending on the overlapping of their terminal elds, cell type, receptor and/or neurotransmitter "similarity", and other as yet unidenti ed factors). It is to be noticed that the lesion-induced reactive synaptogenesis occurs over a time span of several weeks until the pre-lesion synaptic density is restored (13, 15). In the majority of cases 7{9 days are required before any initiation of sprouting is noticed (13).
Synaptic plasticity in the learning and memory formation processes There is growing evidence for the involvement of synaptic morphological changes in appropriate regions of vertebrate central nervous system (CNS) in the process of learning and memory formation.
1. After training procedures used in these studies, the degree of dendritic branching (16), synapse density (17), spine density and spine size (18, 19) was found to be signi cantly higher on neurons in the central pathway relevant to the learned task.
2. Correspondingly, sensory and/or social early and later developmental experience yields an increase in the synapse and spine density per unit tissue area, as well as synaptic ultrastructural changes (enlargment of spines and terminals), and increase of the amount of dendrites per neuron (14, 20{22). On the contrary, sensory and/or social deprivation results in the opposite changes, e.g. atrophy of postsynaptic surface and 3. The observations of synaptic morphological modi cations accompanying the synaptic e cacy enhance- ment corresponding to the long-term potentiation (LTP) (23{25) also re ect the possible e ect of presynaptic 4. All these ndings lead to the growth theory of learning (26) according to which the more used modi able interneuron synaptic connections undergo hypertrophy and/or branching along with increase in their number, while the less used or disused ones undergo atrophy and loss. So, an increase in activity of a particular neuronal circuit leads to new synapse formation as well as synaptic morphological modi cations corresponding to the enhanced synaptic e ciency, and vice versa.
E ects of psychotropic drugs on synaptic plasticity 1. After daily administration of haloperidol for two weeks there was an increase in the number of synapses containing perforated postsynaptic densities in the rat caudate nucleus (27). The morphological changes were reversible after two weeks of drug cessation. The origin of the bers with these modi ed synapses has not been revealed. The authors suggest that the observed synapse increase might be related to the early and/or late extrapyramidal motor disorders induced by neuroleptic treatment.
2. Three weeks of daily haloperidol administration resulted in an increase in the number of synapses on dendritic shafts in parallel with a decrease in the number of spine-neck synapses in the rat medial prefrontal cortex (28). The mean area of presynaptic terminals as well as the mean length of postsynaptic densities decreased in the axo-dendritic synapses. The authors interpret the latter kind of changes as decreased synaptic e cacy caused by the dopamine receptor blockade by haloperidol. After three weeks of daily administration of amphetamine, in the same region, there was an increase in the number of axo-dendritic synapses and decrease in the number of axo-spinous synapses (29). Besides these changes which are similar to the haloperidol-induced e ect, there were opposite changes in the synaptic parameters in all synapse types: the mean area of synaptic terminals and the mean length of postsynaptic densities as well as the area of spines increased. This might re ect enhanced synaptic e cacy. However, the origins of modi ed synapses have not been identi ed in these studies, either. A supposition of the involvement of other neurotransmitter systems besides the dopaminergic one in the observed morphological modi cations was proposed.
Extrasynaptic receptors and synaptogenesis 1. At present the process of synaptogenesis during maturation and in adulthood in the vertebrate nervous system is viewed as a sequence of certain speci c pre- and postsynaptic events which trigger and are dependent upon each other in a highly speci c manner (30). However, the degree of possible interdependence of these events as well as their order and mechanisms have not been resolved de nitively. I now draw attention to the widely accepted idea concerning the signal or information exchange between pre- and postsynaptic elements during synaptogenesis via trophic factors (31, 32). It could well be (33) that these trophic factors are transported inside and released outside by means of endocytosis and exocytosis respectively, of vesicles which bear "new" and "old" membrane components in the process of membrane renewal (34). As has been proposed (31), in the case of reactive synaptogenesis or axonal sprouting induction, the nerve growth-like factor secretion 2. There are two types of nicotinic acetylcholine receptors (AChR) on the postsynaptic membrane of skeletal muscle cells (35). The density of AChR at the neuromuscular junction di ers from the density of AChR on the extrajunctional surface { the order 10 vs. 10 per square micrometre. Denervation studies in adult animals and other studies investigating the e ect of depressed presynaptic activity on the neuromuscular { These manipulations yield an increase in the number of extrajunctional AChR.
{ As the number of extrajunctional AChR increases, remaining axons sprout when this increase is prevented, { During muscle cell reinnervation the initial multiple innervation loss is accompanied by the loss of corre- sponding nerve terminals. The postsynaptic receptor elimination begins before terminal elimination.
Perhaps, by insertion of additional receptors into the plasma membrane via fusion of transport vesicles, the di usible factors which control sprouting are released.
3. It appears that the existence of extrajunctional postsynaptic neurotransmitter receptors is not restricted only to muscles. The presence of extrasynaptic adenosine receptors (37) and extrasynaptic GABA receptors (38) has been found on the CA1 cell dendritic membrane in the rat hippocampus.
In response to modulation of the amount of neurotransmitter in the nervous system there are two types of postsynaptic cell responses. Down-regulation and hyposensitivity of postsynaptic receptors occur in response to an increased amount of neurotransmitter while up-regulation leading to hypersensitivity of receptors occurs in response to a decreased neurotransmitter amount (39). Taking into account the presence of extrasynaptic neurotransmitter receptors on central neurons, it may well be that the contribution of changes in density of extrasynaptic receptors is more signi cant than the contribution of synaptic receptor density changes. From the point of synaptic transmission the role of extrasynaptic receptors is negligible. However, if the increase in their number initiated the sprouting and formation of new synapses, then the reason for an increase in the number of extrasynaptic receptors in response to a decreased amount of neurotransmitter is to induce additional synapse formation in order to enhance synaptic transmission e ciency, and to compensate the decreased synaptic activity in the circuit. In the case of down-regulation, the postsynaptic cells tend to prevent the formation of new additional synapses by decreasing the number of the extrasynaptic receptors.
In addition to this type of neuron adaptive behavior, it is worth considering the other type of adaptive neuron response: the potentiation of more used pathway synapses, and the depression of less used pathway synapses (as has been observed in the studies of LTP, cellular correlates of learning and studies of environment complexity e ects on the neurons in the CNS). It is reasonable to suppose that in the more used circuits neurotransmitters are being released in greater amounts then in the less used ones. In this adaptive response type, the potentiation of synaptic e ciency is related to additional synapse growth and the enlargement of "old" ones. Therefore, there should be an increase in the number of synaptic receptors, also. In accord with this, the loss of synapses and their size in the depression of synaptic e cacy in the less used circuits should be accompanied by the loss of synaptic receptors as well.
So, two types of adaptive responses in neurons might exist: the rst one is compensatory and tends to restore the circuit activity level as it was in the past the second one consists of plastic changes which provide for switching circuit activity to a new pattern.
One may ask, if in case of reactive synaptogenesis which is to compensate for a neurotransmitter de ciency, the synapse growth eliciting event is the extrasynaptic receptor insertion, then what elicits synapse growth in case of enhanced presynaptic activity? The answer can be only hypothetical. Fedor et al. (40) and Horwitz (41) estimated the intensity of the intracellular electric eld in dendritic spines and branches during excitatory synapse activation. Exploring these values they supposed that the electrophoretic attraction of charged particles bearing new membrane material including receptors might take place in spines and other dendritic branches. This attraction is proportional to the postsynaptic potential amplitude and duration and therefore to the level of presynaptic activity. The trophic growth factor inside vesicles bearing new membrane components is released outside during vesicle fusion and insertion of preferentially synaptic receptors. This might be the case because electrophoretic movement directs vesicles to the synaptic places preferentially. The growth of postsynaptic membrane is provided for at the same time.
Taking into account this possibility of two neuronal adaptive responses we can proceed to the formulation of a hypothesis as to how they come into action during the process of depression pathogenesis and AD treatment.
Let us say, in depressions (whatever is their etiology) the production of 5-HT and NA is decreased in some relevant (at this time not known) brain area(s). As a result the atrophy of synaptic connections between the aminergic neurons and their target neurons occurs. This is accompanied by a decrease in the number of synaptic receptors. At the same time, target neurons try to compensate for this de cit and synthesize greater amounts of postsynaptic receptors which are inserted into the whole (postsynaptic) plasma membrane. The number of extrasynaptic receptors increases in order to initiate new synapse growth which is to compensate for the weakened synaptic transmission e ciency. Because of long duration of the intense amine de cit, this compensation fails, postsynaptic cells become exhausted, and an overall decreased density of postsynaptic receptors may be observed (42). Now, the agents blocking amine reuptake (or stimulating their production, or their release) come into action. A greater amount of amine is available in synapses this corresponds to enhanced presynaptic stimulation, and so a erent axons sprout and form additional synapses. New postsynaptic sites are created. The number of synaptic receptors increases. Compensation on the part of postsynaptic cells is not neccessary now, and the extrasynaptic receptors are degraded, their overall number decreasing. So, during AD treatment an adequate balance between the synaptic and extrasynaptic receptors is achieved and is accompanied by the enhancement of synaptic transmission e ciency.
This hypothesis o ers a possible explanation as to why the number of -AR decreases and -AR increases after AD treatment. However, I do not claim -AR and -AR are present exclusively in the extrasynaptic and synaptic places respectively the relative representation of these two receptor types in these two receptor populations is important. Another fact in agreement with the proposal concerning the involvement of synapse growth processes in antidepressant action is that the time course of reactive synaptogenesis in the CNS is similar to the observed time course of receptor changes after AD treatment as well as of the apparent behavioral I am aware that the situation is far more complex, especially concerning the interplay between various types of pre- and postsynaptic amine receptors as well as the action of antidepressants on these various receptor types, and the consequences of these interactions. However, I propose that the growth processes cannot be excluded from the investigation of antidepressant action and search for depression etiopathogenesis. Although, I did not state it explicitly, the involvement of other neurotransmitter systems and their interplay must also be neccessary to take into account in this matter. However, to speculate about it, more detailed knowledge of the involved brain neuronal circuits hardwiring is required. The proposed synaptic turnover taking place during depression pathogenesis and treatment o ers a basis for investigation of other neurotransmitter systems To conclude, here is a suggestion concerning the design of an experimental study of the hypothesis proposed.
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