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Biomedical subjects

Charles F Stevens

Publications and source records attributed to Charles F Stevens.

9 recordsLinked to original sources
PubMed2003

The synaptotagmin C2A domain is part of the calcium sensor controlling fast synaptic transmission.

Synaptotagmin is a synaptic vesicle protein that has been proposed to be the calcium sensor responsible for fast neurotransmitter release at synapses. Synaptotagmin's two C2 domains, C2A and C2B, each provide a calcium binding pocket lined with negative charges contributed by five conserved aspartates. We find that even when all of C2A's conserved aspartates are neutralized by replacement with asparagines, neurotransmitter release still occurs at hippocampal synapses in culture. Because exocytosis continues to be dependent on extracellular calcium concentration, the C2A domain cannot represent the entire calcium sensor. C2A does appear to be part of the calcium sensor, however, because substitution of D232 alters the calcium dependence of release, perhaps by reducing the number of calcium ions that must bind to trigger exocytosis. We conclude that neutralization of the negative charge at D232 by coordination of a calcium ion is necessary--but not sufficient--for fast neurotransmission at mammalian CNS synapses.

Alcohol Oxidoreductases↗
PubMed2003

Connectivity optimization and the positioning of cortical areas.

By examining many alternative arrangements of cortical areas, we have found that the arrangement actually present in the brain minimizes the volume of the axons required for interconnecting the areas. Our observations support the notion that the organization of cortical areas has evolved to optimize interareal connections.

Axons↗
PubMed2003

Three modes of synaptic vesicular recycling revealed by single-vesicle imaging.

Synapses recycle their spent vesicles in order to keep up with on-going neurotransmitter release. To investigate vesicle recycling in the small synapses of hippocampal neurons, we have used an optical recording method that permits us to resolve single-vesicle events. Here we show that an exocytic event can terminate with three modes of vesicle retrieval: a fast (400-860 ms) 'kiss-and-run' mode that has a selective fusion pore; a slow (8-21 s) 'compensatory' mode; and a 'stranded' mode of recycling, in which a vesicle is left on the cell surface until a nerve impulse triggers its retrieval. We have also observed that, in response to a nerve impulse, synapses with low release probability primarily use the kiss-and-run mode, whereas high release probability terminals predominantly use the compensatory mode of vesicle retrieval.

Acids↗
PubMed2003

Independent sources of quantal variability at single glutamatergic synapses.

Variability in the size of single postsynaptic responses is a feature of most central neurons, although the source of this variability is not completely understood. The dominant source of variability could be either intersynaptic or intrasynaptic. To quantitatively examine this question, a biophysically realistic model of an idealized central axospinous synapse was used to assess mechanisms underlying synaptic variability measurements. Three independent sources of variability were considered: stochasticity of postsynaptic receptors ("channel noise"), variations of glutamate concentration in the synaptic cleft (Deltaq), and differences in the potency of vesicles released from different locations on the active zone [release-location dependence (RLD)]. As expected, channel noise was small (8% of the total variance) and Deltaq was the dominant source of variability (58% of total variance). Surprisingly, RLD accounted for a significant amount of variability (36%). Our simulations show that potency of release sites decreased with a length constant of approximately 100 nm, and that receptors were not activated by release events >300 nm away, which is consistent with the observation that single active zones are rarely >300 nm. RLD also predicts that the manner in which receptors are added or removed from synapses can dramatically affect the nature of the synaptic response, with increasing receptor density being more efficient than merely increasing synaptic area. Saturation levels and synaptic geometry were also important in determining the size and shape of the distribution of amplitudes recorded at different synapses.

Biophysics↗
PubMed2002

Predicting functional properties of visual cortex from an evolutionary scaling law.

The number of neurons in the primary visual cortex (V1) is, across primate species, related to the number of neurons in the visual thalamus (the lateral geniculate nucleus [LGN]) by a power law with an exponent of 3/2. This evolutionary scaling law is explained by a simple relation according to which the fineness of resolution in cortex is related to the number of neurons in the area of cortex used to process the information from a single point of light (the point-spread area). The same theory provides a link between two functional properties of the visual cortex, the areal cortical magnification factor (ACMF) and the receptive field (RF) area.

Animals↗
PubMed2002

Astroglia induce neurogenesis from adult neural stem cells.

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.

Aging↗
PubMed2002

Wiring optimization in cortical circuits.

Wiring a brain presents a formidable problem because neural circuits require an enormous number of fast and durable connections. We propose that evolution was likely to have optimized neural circuits to minimize conduction delays in axons, passive cable attenuation in dendrites, and the length of "wire" used to construct circuits, and to have maximized the density of synapses. Here we ask the question: "What fraction of the volume should be taken up by axons and dendrites (i.e., wire) when these variables are at their optimal values?" The biophysical properties of axons and dendrites dictate that wire should occupy 3/5 of the volume in an optimally wired gray matter. We have measured the fraction of the volume occupied by each cellular component and find that the volume of wire is close to the predicted optimal value.

Animals↗
PubMed2002

Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons.

Neural stem cells are present both in the developing nervous system and in the adult nervous system of all mammals, including humans. Little is known, however, about the extent to which stem cells in adults can give rise to new neurons. We used immunocytochemistry, electron microscopy, fluorescence microscopy (FM imaging) and electrophysiology to demonstrate that progeny of adult rat neural stem cells, when co-cultured with primary neurons and astrocytes from neonatal hippocampus, develop into electrically active neurons and integrate into neuronal networks with functional synaptic transmission. We also found that functional neurogenesis from adult stem cells is possible in co-culture with astrocytes from neonatal and adult hippocampus. These studies show that neural stem cells derived from adult tissues, like those derived from embryonic tissues, retain the potential to differentiate into functional neurons with essential properties of mature CNS neurons.

Action Potentials↗