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Biomedical subjects

Charles F Stevens

Publications and source records attributed to Charles F Stevens.

At least 19 recordsLinked to original sources
PubMed2005

Synaptotagmin mutants Y311N and K326/327A alter the calcium dependence of neurotransmission.

Synaptotagmin I, a calcium-binding synaptic vesicle protein, is thought to act as the calcium sensor for fast neurotransmission, but what synaptotagmin I does, upon binding calcium, to trigger exocytosis is still unknown. To begin to examine the role of synaptotagmin I's interactions with calcium-dependent binding partners, three mutant versions of synaptotagmin I reported to affect calcium-dependent self-oligomerization (Y311N, K327A, and K326/327A) were expressed in cultured mouse hippocampal neurons lacking endogenous synaptotagmin I, and effects on neurotransmission were evaluated by comparison with transmission rescued by wild-type synaptotagmin I. All three mutants reduced transmitter release. To separate effects on calcium binding from effects on calcium-dependent oligomerization, we measured the calcium dependence of exocytosis for two of the mutants. Both showed apparent calcium affinity much lower than wild-type, a reduction sufficient to account for the neurotransmission defects. We conclude that self-oligomerization is unlikely to play any significant role in triggering synaptic vesicle exocytosis.

Amino Acid Substitution↗
PubMed2004

Preserving properties of object shape by computations in primary visual cortex.

Although our visual system is extremely good at extracting objects from the visual scene, this process involves complicated computations that are thought to require image processing by many successive cortical areas. Thus, intermediate stages in object extraction should not eliminate essential properties of the objects that are still required by later stages. A particularly important characteristic of an object is its shape, and shape has the property that it is unchanged by translations, rotations, and magnifications of the image. I show that the requirement for this property of shape to be preserved in the image, as represented by the firing of neurons in the primary visual cortex (V1), is equivalent to a particular type of computation, known as a wavelet transform, determining the firing rate of V1 neurons in response to an image on the retina. Experimental data support the conclusion that the neural representation of images in V1 is described by a wavelet transform and, therefore, that the properties of shape are preserved.

Fourier Analysis↗
PubMed2004

Topographic specificity of functional connections from hippocampal CA3 to CA1.

The hippocampus is a cortical region thought to play an important role in learning and memory. Most of our knowledge about the detailed organization of hippocampal circuitry responsible for these functions is derived from anatomical studies. These studies present an incomplete picture, however, because the functional character and importance of connections are often not revealed by anatomy. Here, we used a physiological method (photostimulation with caged glutamate) to probe the fine pattern of functional connectivity between the CA3 and CA1 subfields in the mouse hippocampal slice preparation. We recorded intracellularly from CA1 and CA3 pyramidal neurons while scanning with photostimulation across the entire CA3 subfield with high spatial resolution. Our results show that, at a given septotemporal level, nearby CA1 neurons receive synaptic inputs from neighboring CA3 neurons. Thus, the CA3 to CA1 mapping preserves neighbor relations.

Animals↗
PubMed2004

Presynaptic function.

Changing the strength of synapses is key to the adaptive modifications of what neuronal circuits compute. Unsurprisingly, many different mechanisms have evolved to alter synaptic strength. Some of these mechanisms depend on the history of synaptic use, others reflect the activity of modulatory neurons that are controlled through neural computations, and still others involve more global measures of neural activity. The molecular machinery synapses use to convey information from one neuron to the next not only plays an essential part in brain function but also is at the basis of processes that are vital to all cells. Because membrane fusion events at synapses are so precisely controlled, synapses offer an especially favorable system in which to study these basic processes. Here, I review some of the recent progress that has been made in understanding both how synaptic strength is regulated and how fundamental cell biological mechanisms are used to accomplish neuronal intercommunication.

Animals↗
PubMed2003

Neurotransmitter release at central synapses.

Our understanding of synaptic transmission has grown dramatically during the 15 years since the first issue of Neuron was published, a growth rate expected from the rapid progress in modern biology. As in all of biology, new techniques have led to major advances in the cell and molecular biology of synapses, and the subject has evolved in ways (like the production of genetically engineered mice) that could not even be imagined 15 years ago. My plan for this review is to summarize what we knew about neurotransmitter release when Neuron first appeared and what we recognized we did not know, and then to describe how our views have changed in the intervening decade and a half. Some things we knew about synapses--"knew" in the sense that the field had reached a consensus--are no longer accepted, but for the most part, impressive advances have led to a new consensus on many issues. What I find fascinating is that in certain ways nothing has changed--many of the old arguments persist or recur in a different guise--but in other ways the field would be unrecognizable to a neurobiologist time-transported from 1988 to 2003.

Animals↗
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↗