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Previous studies of short-term plasticity in central nervous systems synapses have largely focused on average synaptic properties. In this study, we use recordings from putative single synaptic release sites in hippocampal slices to show that significant heterogeneity exists in facilitation and depletion among synapses. In particular, the amount of paired-pulse facilitation is inversely related to the initial release probability of the synapse. We also examined depletion at individual synapses using high frequency stimulation, and estimated the size of the readily releasable vesicle pool, which averaged 5.0 +/- 3.0 quanta (n = 13 synapses). In addition, these experiments demonstrate that the release probability at a synapse is directly correlated with the size of its readily releasable vesicle pool.

During an investigation of the mechanisms through which the local environment controls the fate specification of adult neural stem cells, we discovered that adult astrocytes from hippocampus are capable of regulating neurogenesis by instructing the stem cells to adopt a neuronal fate. This role in fate specification was unexpected because, during development, neurons are generated before most of the astrocytes. Our findings, together with recent reports that astrocytes regulate synapse formation and synaptic transmission, reinforce the emerging view that astrocytes have an active regulatory role--rather than merely supportive roles traditionally assigned to them--in the mature central nervous system.

A readily releasable pool of quanta, tentatively identified with docked synaptic vesicles, has been defined by analysis of the neurotransmitter release caused by application of hypertonic solutions. The goal of this work is to determine the relationship of this functionally defined readily releasable pool to the one drawn upon by action potential-evoked release. We find that hypertonic solutions do not act through changes in intracellular calcium. Since the release produced by action potentials and hypertonic solutions varies in parallel as the pool size is changed, we conclude that the same pool is shared by both mechanisms. This conclusion, taken together with other observations in the literature, means that the synaptic release probability depends on the size of the readily releasable pool.

In all synapses, Ca2+ triggers neurotransmitter release to initiate signal transmission. Ca2+ presumably acts by activating synaptic Ca2+ sensors, but the nature of these sensors--which are the gatekeepers to neurotransmission--remains unclear. One of the candidate Ca2+ sensors in release is the synaptic Ca2+-binding protein synaptotagmin I. Here we have studied a point mutation in synaptotagmin I that causes a twofold decrease in overall Ca2+ affinity without inducing structural or conformational changes. When introduced by homologous recombination into the endogenous synaptotagmin I gene in mice, this point mutation decreases the Ca2+ sensitivity of neurotransmitter release twofold, but does not alter spontaneous release or the size of the readily releasable pool of neurotransmitters. Therefore, Ca2+ binding to synaptotagmin I participates in triggering neurotransmitter release at the synapse.

From three-dimensional reconstructions of CA1 excitatory synapses in the rodent hippocampus and in culture, we have estimated statistical distributions of active zone and postsynaptic density (PSD) sizes (average area ϳ0.04 m 2 ), the number of active zones per bouton (usually one), the number of docked vesicles per active zone (ϳ10), and the total number of vesicles per bouton (ϳ200), and we have determined relationships between these quantities, all of which vary from synapse to synapse but are highly correlated. These measurements have been related to synaptic physiology. In particular, we propose that the distribution of active zone areas can account for the distribution of synaptic release probabilities and that each active zone constitutes a release site as identified in the standard quantal theory attributable to Katz (1969).Key words: synaptic vesicle; active zone; release; statistical distribution; hippocampus; release probabilitySince the pioneering work of Katz and his collaborators on synaptic f unction (summarized in Katz, 1969) and that of the early electron microscopists on synaptic structure (Palay and Palade, 1955;L use, 1956;Wyckoff and Young, 1956), a consistent goal of neurobiologists has been to identif y the structural basis for the entities identified in Katz's theory of synaptic transmission (Katz, 1969). The synaptic vesicle is generally accepted as corresponding to Katz's quantum, although still without definitive evidence. The number of release sites [N s in Katz's (1969) scheme] associated with an axon has been identified with the total number of releasable vesicles, with the number of boutons, and with the number of active zones (Zucker, 1973;Jack et al., 1981;Korn et al., 1981;Neale et al., 1983;Redman and Walmsley, 1983;Walmsley et al., 1985;Pun et al., 1986;Propst and Ko, 1987;Redman, 1990;Walmsley, 1991;Pierce and Mendell, 1993;Pierce and Lewin, 1994). A possible anatomical counterpart of Katz's release probability p has been subject to less speculation, but several authors have noted that p might be related to synaptic size (see Pierce and Lewin, 1994).With the development of optical techniques to study synaptic transmission and the extension of these techniques to hippocampal neurons in culture (Ryan et al., 1993;Ryan and Smith, 1995;Ryan et al., 1996), many synaptic properties can now be investigated in culture at the level of single central synapses. Although individual hippocampal synapses differ greatly from one another with respect to any one of these properties, a variety of the properties are highly correlated with the release probability of the synapse (Ryan et al., 1996;Murthy et al., 1997). To relate results from physiological investigations of synapse populations to synaptic structure, one must know the statistical distribution of morphological characteristics. Current statistical information about hippocampal synapses comes from studies by Harris and Stevens (1989), Harris et al. (1992), Sorra and Harris (1993), and Harris and Sultan (1995), but this work has focus...

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As a first step in a program to use genetically altered mice in the study of memory mechanisms, mutant mice were produced that do not express the alpha-calcium-calmodulin-dependent kinase II (alpha-CaMKII). The alpha-CaMKII is highly enriched in postsynaptic densities of hippocampus and neocortex and may be involved in the regulation of long-term potentiation (LTP). Such mutant mice exhibited mostly normal behaviors and presented no obvious neuroanatomical defects. Whole cell recordings reveal that postsynaptic mechanisms, including N-methyl-D-aspartate (NMDA) receptor function, are intact. Despite normal postsynaptic mechanisms, these mice are deficient in their ability to produce LTP and are therefore a suitable model for studying the relation between LTP and learning processes.