Transmission at excitatory synapses in the mammalian brain is thought to depend on the release of transmitter quanta through exocytosis of presynaptic vesicles (Katz, 1969). The number of vesicles released by a single presynaptic action potential is important for understanding the impact of a single synapse, and the variability in transmission from one impulse to the next. In addition, the number of vesicles released may be an important factor for synaptic regulation and plasticity, such as facilitation, post-tetanic potentiation and long-term potentiation (LTP). Three recent studies suggest that an increase in the number of transmitter quanta underlies hippocampal LTP (Malinow and Tsien, 1990; Bekkers and Stevens 1990; Malinow, 1991), whereas other reports suggest a postsynaptic mechanism (Kauer et al., 1988; Muller et al., 1988; Foster and McNaughton, 1989). We have used the whole-cell recording technique to compare putative quantal and single fibre responses at excitatory synapses in rat hippocampal slices, and find (i) a surprisingly large variability in single fibre excitatory postsynaptic currents (sfEPSCs); (ii) an equally large variability of putative quantal (pq) EPSCs elicited by hyperosmolar media or ruthenium red; (iii) the observed amplitude ranges for the sfEPSCs and the pqEPSCs overlap almost completely; and (iv) in neither case can the variability be attributed to a scatter in electrotonic distance from the soma of the engaged synapses. Thus, the data are compatible with the hypothesis that a presynaptic action potential usually releases only a single quantum. Other possibilities are also discussed.
Along unmyelinated central axons, synapses occur at focal swellings called axonal varicosities (boutons). The mechanisms regulating how frequently synapses and varicosities occur along axons remain poorly understood. Here, to investigate varicosity distribution patterns and the extent to which they may be conserved across different axons, we analyzed varicosity numbers and positions along fluorescently labeled axon branches in hippocampal area CA1 (CA3-to-CA1 ''Schaffer collateral'' axons) and five other synaptic regions of rat hippocampus and cerebellum. Varicosity spacing varied by region; e.g., 3.7 ؎ 0.6 m (mean ؎ SD) for CA3-to-CA1 axons and 5.2 ؎ 1.0 m for cerebellar parallel fibers. Surprisingly, when 56 axons from these different regions were pooled into a single heterogeneous group, a general relationship emerged: the spacing variability (SD) was a constant fraction of the mean spacing, suggesting that varicosities along different axons are distributed in a fundamentally similar, scaled manner. Varicosity spacing was neither regular nor random but followed a pattern consistent with random synaptic distributions and the occurrence of multiple-synapse boutons. A quantitative model reproduced the salient features of the data and distinguished between two proposed mechanisms relating axonal morphogenesis and synaptogenesis.A rborizing varicose axons in the central nervous system are complex circuit elements: a single hippocampal CA3 cell axon makes Ϸ50,000 synapses over Ϸ0.2 m, all within the hippocampus (1, 2). Understanding connectivity in specific circuits requires detailed quantitative information about axonal synaptic distributions. At the ultrastructural level, synaptic boutons have been characterized as Ϸ1-m long (3-5) varicosities that usually occur en passant along the axon, separated from other varicosities by short axonal shaft segments. For CA3-to-CA1 and other axons, the average synapse͞varicosity ratio is 1.1-1.7 (4-11), reflecting the occurrence of multiple-synapse boutons (MSBs). MSBs may serve as intermediate or final stages of morphological plasticity associated with long-term synaptic plasticity (12-17).The organization of varicosities and their synapses over longer axonal distances merits quantification for several reasons. First, varicosity spacing is a key aspect of the complex geometry of axon-dendrite interactions. Second, synaptic and varicosity distribution patterns likely reflect fundamental connectivity rules. The report by Hellwig et al. (18) of a purely random pattern along neocortical axons carries numerous implications but has not yet been extended to other axon types. Third, varicosity spacing patterns may hold clues about mechanisms of synaptogenesis and development, an unexplored possibility relevant for synaptic plasticity models invoking varicosity neogenesis (15,16,19). Here, we used the strategy of quantifying varicosity spacing and its variability at the single axonal branch level for diverse types of central varicose axons, focusing on hippocampal CA3-to-CA1 axons an...
Whether all action potentials propagate faithfully throughout axon arbors in the mammalian CNS has long been debated, and remains an important issue because many synapses occur far from the soma along extremely thin, unmyelinated, varicosity-laden branches of axon arbors. We detected unitary action potentials along individual axon branches of adult hippocampal CA3 pyramidal cells using extracellular electrodes, and analysed their conduction across long distances (mean, 2.1 mm) at 22 and 37 degrees C. Axons nearly always transmitted low-frequency impulses. At higher frequencies, most axons also transmitted impulses with striking fidelity. However, at paired-pulse frequencies in the hundreds of kilohertz range, axons exhibited variability: refractory periods ranged from 2.5 to 10 ms at 37 degrees C and from 5 to 40 ms at 22 degrees C. Although the basis for the refractory period variability could not be determined, these limits overlap with CA3 spike frequencies observed in vivo, raising the possibility that some axonal branches act as filters for the higher-order spikes in bursts, in contrast to the observed first-spike reliability. These results extend the observations of propagation reliability to a much longer distance and higher frequency domain than previously reported, and suggest a high safety factor for action potential propagation along thin, varicose axons.
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