Faculty Bibliography

Bath application of compound T-588, a neuroprotective agent, reduced paired-pulse and repetitive-pulse facilitation at mammalian and crustacean neuromuscular junctions. In addition, it reduced voltage-gated sodium and potassium currents in a use-dependent fashion, but had only a small effect on the presynaptic Ca(2+) conductance. By contrast, it blocked FM 1-43 vesicular uptake but not its release, in both species. Postsynaptically, T-588 reduced acetylcholine currents at the mammalian junction in a voltage-independent manner, but had no effect on the crayfish glutamate junction. All of these effects were rapidly reversible and were observed at concentrations close to the compound's acute protective level. We propose that this set of mechanisms, which reduces high-frequency synaptic transmission, is an important contributory factor in the neuroprotective action of T-588

A woman (LR), unconscious for 20 years, spontaneously produces infrequent, isolated words unrelated to any environmental context. Fluorodeoxy-glucose-positron emission tomography (FDG-PET) imaging coregistered with magnetic resonance imaging (MRI) revealed a mean brain metabolism equivalent to deep anesthesia. Nevertheless, PET imaging demonstrated islands of modestly higher metabolism that included Broca's and Wernicke's areas. Functional brain imaging with magnetoencephalographic (MEG) imaging, a technique providing a temporal resolution of better than 1 msec, identified preserved dynamic patterns of spontaneous and evoked brain activity in response to sensory stimulation. Specifically, we examined spontaneous gamma-band activity (near 40 Hz) and its reset or modification during early auditory processing, a measure that correlated with human perception of sensory stimuli (Joliot, Ribary, & Llinas, 1994). Evidence of abnormal and incomplete gamma-band responses appeared in the left hemisphere only in response to auditory or somatosensory stimulation. MEG single-dipole reconstructions localized to the auditory cortex in the left hemisphere and overlapped with metabolically active regions identified by FDG-PET. The observation demonstrates that isolated neuronal groups may express well-defined fragments of activity in a severely damaged, unconscious brain. The motor fixed-action pattern character of her expressed words supports the notion of brain modularity in word generation

Tyrosine phosphorylation has been shown to be an important modulator of synaptic transmission in both vertebrates and invertebrates. Such findings hint toward the existence of extracellular ligands capable of activating this widely represented signaling mechanism at or close to the synapse. Examples of such ligands are the peptide growth factors which, on binding, activate receptor tyrosine kinases. To gain insight into the physiological consequences of receptor tyrosine kinase activation in squid giant synapse, a series of growth factors was tested in this preparation. Electrophysiological, pharmacological, and biochemical analysis demonstrated that nerve growth factor (NGF) triggers an acute and specific reduction of the postsynaptic potential amplitude, without affecting the presynaptic spike generation or presynaptic calcium current. The NGF target is localized at a postsynaptic site and involves a new TrkA-like receptor. The squid receptor crossreacts with antibodies generated against mammalian TrkA, is tyrosine phosphorylated in response to NGF stimulation, and is blocked by specific pharmacological inhibitors. The modulation described emphasizes the important role of growth factors on invertebrate synaptic transmission

Whole cell voltage-clamp techniques were employed to characterize the sodium (Na) conductances in acutely dissociated, mature guinea-pig cerebellar Purkinje cells. Three phenomenological components were noted: two inactivating and a persistent component (I(P)(Na). All exhibited similar sensitivities to tetrodotoxin (TTX; IC50 approximately 3 nM). The inactivating Na current demonstrates two components with different rates of inactivation. The persistent component activates at a more negative membrane potential than the inactivating components and shows little inactivation during a 5-s pulse. The amplitude of the persistent Na conductance had a higher Q10 than the inactivating Na conductance (2.7 vs. 1.3). (I(P)(Na) rapidly activates (approximately 1 ms) and deactivates (< 0.2 ms) and like the fast component appears to be exclusively Na permeable. (I(P)(Na) is not a 'window' current because its range of activation exceeds the small overlap between the steady-state activation and inactivation characteristics of the inactivating current. Anomalous tail currents were observed during voltage pulses above -40 mV after a prepulse above -30 mV. The tails rose to a maximum inward current with a time constant of 1.5 ms and decayed to a persistent inward current with a time constant of 20 ms. The tails probably arose as a result of recovery from inactivation through the open state. The noise characteristics of (I(P)(Na) were anomalous in that the measured variance was lower at threshold voltages than would be predicted by a binomial model. The form of the variance could be partially accounted for by postulating that the maximum probability of activation of the persistent current was less than unity. The noise characteristics of (I(P)(Na) are such as to minimize noise near spike activation threshold and sharpen the threshold