Synaptic Average Size

A growing number of reports from the current literature documents that synaptic size is a very sensitive ultrastructural parameter undergoing significant changes as a consequence of different environmental stimulations. Reasonably, it can be assumed that the size of the synaptic contact area may influence the amount of transmitter released and also the extent of trafficking of the many substances involved in information processing, thus strengthening the transmission of the nervous impulse among neurons. As a consequence, enlargement or reduction in synaptic size supposedly may lead to changes in function. On the other hand, the possibility to modulate the extension of the junctional zones may be considered a means to carry out a significant structural intervention on the plastic condition of the synapses. The awareness of the biological significance of changes in synaptic size has prompted the development of several methods to estimate this parameter by applying conventional morphometric formulas since the early investigations performed around the late 1970s to early 1980s (Dyson and Jones, 1976; Bertoni-Freddari and Giuli, 1980; Hillman and Chen, 1984) up to the present application of the disector (Mayhew, 1996; Bertoni-Freddari et al., 2002). Synaptic size has been frequently estimated by measuring the profile length of the postsynaptic apposition (L) in tissue samples prepared according to both the conventional osmium tetroxide method and to the E-PTA preferential technique. Some authors have considered L as the cord of circular disk (assumed to be the shape of the synaptic contact) and have calculated mathematically the radius and the area (S) of the synaptic disks. In E-PTA processed samples the postsynaptic membrane appears always sharply contrasted, which facilitates the identification and measurement of L by semiautomatic computerized procedures. In the brain of old laboratory animals and human beings it has been found that the size of the synapses is increased. Although not all the data obtained from different laboratories in old subjects are statistically significant vs. the adult values, the synaptic contact zones appear to enlarge with advancing age, and this alteration, in addition to being a feature occurring in different zones of the CNS, has also been documented in the CNS of patients suffering from AD (Bertoni-Freddari et al., 1990; DeKosky and Scheff, 1990). The percent distribution of S showed that the complement of larger synapses increases in physiological aging and AD (see Figure 40.5). This occurs both in zones reported to be very vulnerable to aging and age-related pathologies (e.g., the hippocampus) and in zones documented to be less sensitive to time-related damage (e.g., the cerebellar cortex), thus supporting that this modification in the composition of the synaptic population is a ubiquitous feature of the aging CNS.

In looking for a tenable interpretation of the age-and pathology-related increased complement of enlarged synapses, some current concepts on the mechanism(s) and steps supposed to be involved in synaptic structural remodeling must be taken into account. Along with their dynamic condition, it has been clearly demonstrated that the synaptic junctional areas undergo continuous rearrangements of their ultrastructural features, and, accordingly, some papers report studies proposing mechanisms and suggesting sequential steps occurring during the functional modulation of synapses (Carlin and Siekevitz, 1983; Wolff et al., 1995; Bertoni-Freddari et al., 1996). Although some differences exist in the interpretation of the single steps by different authors, at present, a concept that can be reasonably sustained is that, as a consequence of repeated stimulations, the synaptic size (0.2-0.3 ^m) may increase two- to threefold and up to more than 1 ^m. These megasynapses can perforate and split into smaller junctional areas that may again increase in size, perforate, and split (see Figure 40.6).

Figure 40.5 Percent distribution of the synaptic average size (area: S) in the cerebellum and hippocampus of adult, old, and demented (AD) patients. An increased complement (%) of synapses of larger size is present in the hippocampal dentate gyrus of old and demented patients. The same change can be envisaged also in the cerebellum, although at a lesser degree.

Figure 40.5 Percent distribution of the synaptic average size (area: S) in the cerebellum and hippocampus of adult, old, and demented (AD) patients. An increased complement (%) of synapses of larger size is present in the hippocampal dentate gyrus of old and demented patients. The same change can be envisaged also in the cerebellum, although at a lesser degree.

Figure 40.6 Proposed steps of synaptic remodeling. Each diagram reports the cross-section of a synapse. A: simple synapse reported to measure 0.2-03. ^m. B: on stimulation, synapse length may increase two- or threefold and even more. C: if synaptic size attains a still undefined limit, perforations may appear. D: the holes in the enlarged synapse cause a break into smaller synaptic clods that, in turn, may give rise to daughter junctions or undergo regression with disconnection of the interested area. (Reproduced with permission from Gerontology 42, 170-180, 1996).

Figure 40.6 Proposed steps of synaptic remodeling. Each diagram reports the cross-section of a synapse. A: simple synapse reported to measure 0.2-03. ^m. B: on stimulation, synapse length may increase two- or threefold and even more. C: if synaptic size attains a still undefined limit, perforations may appear. D: the holes in the enlarged synapse cause a break into smaller synaptic clods that, in turn, may give rise to daughter junctions or undergo regression with disconnection of the interested area. (Reproduced with permission from Gerontology 42, 170-180, 1996).

The reasons why larger contact zones should divide are not known; however, since they have been found to be associated with a decrease in synaptic number, it has been proposed that synaptic enlargement is carried out as a compensating reaction to balance the lost contacts. Thus, interpreting the results reported in aging, it can be supposed that the preceding proposed cycle of events occurring in synaptic remodeling is halted at the early step of synaptic enlargement, thus resulting in only a partial compensation for the reduced number of junctions. Whatever mechanism(s) are activated in synaptic remodeling, the consistent presence of larger contacts in the aging CNS may be considered, at the same time, a sign of impairment and of the CNS plastic reaction to unfavorable conditions as supported by studies conducted on malnourished laboratory animals (Chen and Hillman, 1980).

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