Milton P. Charlton

Bio: Milton P. Charlton is an academic researcher from University of Toronto. The author has contributed to research in topics: Neurotransmission & Synaptic vesicle. The author has an hindex of 42, co-authored 90 publications receiving 8153 citations. Previous affiliations of Milton P. Charlton include Medical Research Council & Marine Biological Laboratory.

Calcium action in synaptic transmitter release.

Abstract: In this review we are concerned with the mechanisms by which the electrical potential across the membrane of presynaptic nerve terminals regulates the release of neurotransmitter substances into the synaptic cleft . Ca ions play a central role in this process: Release occurs when a voltage-depen­ dent Ca channel in the presynaptic membrane opens, thus permitting an influx of Ca ions and diffusion of Ca in cytoplasm, followed by binding of Ca at some cytoplasmic site that triggers the exocytotic release of quanta of neurotransmitter. These concepts, introduced mainly by the work of Katz and associates (Katz 1 969), comprise the "Ca hypothesis" of trans­ mitter release, a hypothesis now widely accepted. Although the general role of Ca as a presynaptic messenger is well supported, many important specifics of its action remain to be resolved. We review progress with these details in three parts, corresponding to

Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse

Abstract: A number of calcium buffers were examined for their ability to reduce evoked transmitter release when injected into the presynaptic terminal of the squid giant synapse. Injection of EGTA was virtually ineffective at reducing transmitter release, even at estimated intracellular concentrations up to 80 mM. Conversely, the buffer 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), which has an equilibrium affinity for calcium similar to that of EGTA at pH 7.2, produced a substantial reduction in transmitter release when injected presynaptically. This effect of BAPTA was reversible, presumably because the buffer diffused out of the terminal and into uninjected regions of the presynaptic axon. BAPTA derivatives with estimated intracellular calcium dissociation constants (Kd) ranging from 0.18 to 4.9 microM were effective at reducing transmitter release at similar estimated concentrations. A BAPTA derivative with an estimated intracellular Kd of 31 mM was less effective. BAPTA did not affect presynaptic action potentials or calcium spikes in ways that could explain its ability to reduce transmitter release. The relative effects of presynaptic injections of BAPTA and derivatives are consistent with the calcium-buffering capability of these compounds if the presynaptic calcium transient that triggers release is hundreds of microM or larger. The superior potency of BAPTA compared to EGTA apparently results from the faster calcium-binding kinetics of BAPTA and suggests that the calcium-binding molecule that triggers release binds calcium in considerably less than 200 microsec and is located very close to calcium channels.

Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons.

Abstract: To examine the role of Ca2+ in early neuronal death, we studied the impact of free intracellular calcium concentration ([Ca2+]i) on survivability in populations of cultured mouse spinal neurons We asked whether early neurotoxicity was triggered by Ca2+ influx, whether elevated [Ca2+]i was a predictive indicator of impending neuronal death, and whether factors other than [Ca2+]i increases influenced Ca2+ neurotoxicity We found that when neurons were lethally challenged with excitatory amino acids or high K+, they experienced a biphasic [Ca2+]i increase characterized by a primary [Ca2+]i transient that decayed within minutes, followed by a secondary, sustained, and irreversible [Ca2+]i rise that indicated imminent cell death We showed that in the case of glutamate-triggered neurotoxicity, processes triggering eventual cell death required Ca2+ influx, and that neurotoxicity was a function of the transmembrane Ca2+ gradient Fura-2 Ca2+ imaging revealed a "ceiling" on measurable changes in [Ca2+]i that contributed to the difficulty in relating [Ca2+]i to neurotoxicity We found, by evoking Ca2+ influx into neurons through different pathways, that the chief determinants of Ca2+ neurotoxicity were the Ca2+ source and the duration of the Ca2+ challenge When Ca2+ source and challenge duration were taken into account, a statistically significant relationship between measured [Ca2+]i and cell death was uncovered, although the likelihood of neuronal death depended much more on Ca2+ source than on the magnitude of the measured [Ca2+]i increase Thus, neurotoxicity evoked by glutamate far exceeded that evoked by membrane depolarization with high K+ when [Ca2+]i was made to increase equally in both groups The neurotoxicity of glutamate was triggered primarily by Ca2+ influx through NMDA receptor channels, and exceeded that triggered by non-NMDA receptors and Ca2+ channels when [Ca2+]i was made to rise equally through these separate pathways The greater neurotoxicity triggered by NMDA receptors was related to some attribute other than an ability to trigger greater [Ca2+]i increases as compared with other Ca2+ sources We hypothesize that this represents a physical colocalization of NMDA receptors with Ca(2+)-dependent rate-limiting processes that trigger early neuronal degeneration

Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging.

Abstract: The majority of functional neuroscience studies have focused on the brain's response to a task or stimulus. However, the brain is very active even in the absence of explicit input or output. In this Article we review recent studies examining spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal of functional magnetic resonance imaging as a potentially important and revealing manifestation of spontaneous neuronal activity. Although several challenges remain, these studies have provided insight into the intrinsic functional architecture of the brain, variability in behaviour and potential physiological correlates of neurological and psychiatric disease.

Short-Term Synaptic Plasticity

Abstract: ▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

Excitatory amino acids as a final common pathway for neurologic disorders.

Abstract: In many neurologic disorders, injury to neurons may be caused at least in part by overstimulation of receptors for excitatory amino acids, including glutamate and aspartate. These neurologic conditions range from acute insults such as stroke, hypoglycemia, trauma, and epilepsy (Table 1) to chronic neurodegenerative states such as Huntington's disease, the acquired immunodeficiency syndrome (AIDS) dementia complex, amyotrophic lateral sclerosis, and perhaps Alzheimer's disease (Table 2)1–3. Glutamate is the principal excitatory neurotransmitter in the brain, and its interactions with specific membrane receptors are responsible for many neurologic functions, including cognition, memory, movement, and sensation4. In addition, excitatory . . .

The synaptic vesicle cycle: a cascade of protein–protein interactions

Abstract: The synaptic vesicle cycle at the nerve terminal consists of vesicle exocytosis with neurotransmitter release, endocytosis of empty vesicles, and regeneration of fresh vesicles. Of all cellular transport pathways, the synaptic vesicle cycle is the fastest and the most tightly regulated. A convergence of results now allows formulation of molecular models for key steps of the cycle. These developments may form the basis for a mechanistic understanding of higher neural function.