Paul R. Adams

Substance P inhibits the M‐current in bullfrog sympathetic neurones

Substance P (SP, 2.5–10 μm) was applied by rapid bath perfusion to bullfrog lumbar sympathetic neurones in vitro, voltage‐clamped through a single micro‐electrode. In unclamped cells, SP produced a depolarization accompanied by an increase in apparent input resistance. Under voltage‐clamp a voltage‐dependent inward current was induced by SP, during which the time‐dependent relaxations induced by square voltage commands were inhibited. It is concluded that SP inhibits the M‐current (IM), a species of voltage‐dependent K+‐current, and that IM‐inhibition was the primary cause of the inward current and membrane depolarization in the cells tested.

Voltage-dependent conductances of vertebrate neurones

Abstract Until quite recently the electrical behaviour of vertebrate nerve cells revealed by microelectrode recordings has been largely explained in terms of quantitative data and concepts obtained with molluscan neurones. Attempts are now being made in several laboratories to characterize the voltage-dependent currents of vertebrate neurones themselves. Some of the terminology developed for molluscan excitable membranes is still useful in a vertebrate context. However, it is now clear that analogy is no substitute for direct knowledge. Various mixtures of a palette of membrane conductances made up the electrical personality of each vertebrate neurone type. Some of this new work is reviewed below.

Ca-activated potassium current in vertebrate sympathetic neurones

Ca-activated K-currents (IC) in sympathetic neurones have been triggered by intracellular Ca-injection or by activating ICa. IC is strongly voltage-dependent, with a peak slope of 11 mV/e-fold depolarization above -50 mV. Relaxation, fluctuation and single channel analysis suggests this to result from voltage-dependent opening and closing rates. Time-constants for channel opening and closing are about 15 msec near zero mV. Single channel conductance is about 100 pS. Currents can be blocked by TEA. IC is activated very rapidly (less than or equal to 5 msec) and sometimes transiently by a depolarizing voltage-step. It is suggested that IC contributes to both spike repolarization and spike after-hyperpolarization. Spontaneous miniature ICs have also been recorded, probably activated by the release of packets of intracellular Ca.

Effects of phorbol dibutyrate on M currents and M current inhibition in bullfrog sympathetic neurons.

Summary1.Effects of bath-applied phorbol dibutyrate (PDBu) on M currents (IM) and on the inhibition ofIM by muscarine and luteinizing hormone-releasing hormone (LHRH) were recorded in voltage-clamped bullfrog lumbar sympathetic ganglion cells.2.PDBu (0.1–30µM) produced a slowly developing, irreversible and partial (⩽60%) inhibition ofIM. This effect was not replicated by 4-α-phorbol or by vehicle.3.After treatment with PDBu, residualIM showed a reduced sensitivity to inhibition by muscarine or LHRH but not by Ba2+. The reduced response to muscarine appeared to result from a 10-fold shift in the concentration dependence for inhibition.4.PDBu did not clearly reproduce the ability of muscarine to inhibit the slow, Ca-activated K currentIAHP or to increase the leak conductance at hyperpolarized potentials. The latter effect of muscarine was enhanced, rather than inhibited, by PDBu.5.IM andIAHP were not inhibited by 1 mM dibutyryl cyclic AMP or by 20µM forskolin.6.It is concluded that activation of protein kinase C, but not protein kinase A, partly replicates the effect of muscarine on frog sympathetic neurons.

Spontaneous miniature outward currents in cultured bullfrog neurons

Spontaneous miniature hyperpolarizations were observed in cultured bullfrog neurons. Depolarization increased the frequency and amplitude of the events. Under voltage-clamp, these events were manifested as spontaneous miniature outward currents of SMOCs which were usually less than 2 nA, had a rapid rising phase and a slower voltage-dependent exponential decay. Analysis of inter-event intervals suggested that SMOCs occurred randomly, while analysis of their amplitudes yielded exponential amplitude distributions. Mean SMOC amplitudes and SMOC frequency increased with depolarization, even with 100 microM CdCl2 present. Time constants of SMOC decay resembled time constants obtained from voltage-jump experiments on Ca2+-loaded cells, and together with the sensitivity of SMOCs to tetraethyl ammonium (TEA), suggested that SMOCs are due to activation of fast Ca2+-gated potassium channels. We propose that a SMOC occurs when 10-5000 of these channels are activated by punctate intracellular Ca2+ release.

Hebbian errors in learning: An analysis using the Oja model

BACKGROUND Recent work on long term potentiation in brain slices shows that Hebbs rule is not completely synapse-specific, probably due to intersynapse diffusion of calcium or other factors. We previously suggested that such errors in Hebbian learning might be analogous to mutations in evolution. METHODS AND FINDINGS We examine this proposal quantitatively, extending the classical Oja unsupervised model of learning by a single linear neuron to include Hebbian inspecificity. We introduce an error matrix E, which expresses possible crosstalk between updating at different connections. When there is no inspecificity, this gives the classical result of convergence to the first principal component of the input distribution (PC1). We show the modified algorithm converges to the leading eigenvector of the matrix EC, where C is the input covariance matrix. In the most biologically plausible case when there are no intrinsically privileged connections, E has diagonal elements Q and off-diagonal elements (1-Q)/(n-1), where Q, the quality, is expected to decrease with the number of inputs n and with a synaptic parameter b that reflects synapse density, calcium diffusion, etc. We study the dependence of the learning accuracy on b, n and the amount of input activity or correlation (analytically and computationally). We find that accuracy increases (learning becomes gradually less useful) with increases in b, particularly for intermediate (i.e., biologically realistic) correlation strength, although some useful learning always occurs up to the trivial limit Q=1/n. CONCLUSIONS AND SIGNIFICANCE We discuss the relation of our results to Hebbian unsupervised learning in the brain. When the mechanism lacks specificity, the network fails to learn the expected, and typically most useful, result, especially when the input correlation is weak. Hebbian crosstalk would reflect the very high density of synapses along dendrites, and inevitably degrades learning.

Synaptic Darwinism and neocortical function

Abstract We propose that certain brain systems, such as those of neocortex, exploit a fusion of ideas from neural networks and evolutionary computation, and that several previously puzzling features of thalamocortical circuitry and physiology can be understood as consequences of this fusion. The starting point is a consideration of anatomical errors in the recently described digital strengthening of synaptic connections, which are analogous to mutations. A mathematical model of this process shows the equivalence of the intrinsic error rate and a “correlation ratio” which reflects the spatial variation in the degree of synchrony of neural firing. The correlation ratio plays a similar role to fitness ratios in genetic algorithms. It is argued that a major trend in brain evolution has been decreases in the intrinsic error rate, allowing increases in circuit complexity, but that biophysical limits to this trend have forced the neocortex to adopt a virtual error-reduction strategy. This requires online measurement of correlation ratios and control of the plasticity of the connections formed by individual neurons.

Implications of synaptic digitisation and error for neocortical function

Abstract Recent work in hippocampus suggests that correlation-based synaptic strengthening occurs both imprecisely and digitally. We explore this in a model in which synapses are created according to a fitness function and are occasionally incorrectly placed. Synapses spread beyond the high fitness (wm) area to lower fitness (wp) areas to an extent that depends on the error rate and the fitness ratio wm/wp. This limits the accuracy of connections and thus the size of neural networks. We suggest that in neocortex layer 6 cells measure wm/wp and control the plasticity of thalamic relay cells via their burst/tonic transition. If errors do occur despite this mechanism, they can act as seeds for new learning. This in turn requires offline rewiring of layer 6 connections by processes that resemble REM and slow-wave sleep.

Calcium-Activated Potassium Channels in Bullfrog Sympathetic Ganglion Cells

The existence of a calcium activated potassium current (Ic) in the somata of vertebrate sympathetic ganglion cells was postulated to account for the calcium-sensitive spike after-hyperpolarizations present in these cells [19,22,26]. We have studied Ic in bullfrog ganglion cells more directly by using various voltage-clamp techniques, partly in order to understand better the role this current plays in spike repolarization, spike afterhyperpolarization, and spontaneous hyperpolarizations, and partly to define the difference between Ic and the M-current Im [4]. Both Ic and Im are voltage-sensitive potassium currents sensitive to transmitters, the former being activated by internal calcium and the latter inactivated by external acetylcholine. Despite these superficial similarities, it turns out that the two currents have virtually nothing in common.

Transmitter-evoked channels in mammalian central neurons

Two recent reports in Nature illustrate the power and precision of the new patchclamp techniques for characterizing ion channels activated by transmitter molecules 1,2. The transmitters involved, GABA, glycine and glutamate, are thought to be among the most important of those used in the mammalian CNS. The inhibitory transmitters GABA and glycine were already known to act by increasing membrane chloride permeability 3, and some of the properties of the channels they open had been inferred using noise analysis 4,5. However, the new studies in Bert Sakmanns laboratory raise the possibility that both of these transmitters activate the same type of channel, albeit in different and complicated ways. The channels acted upon by the excitatory transmitter glutamate had previously only been clearly described in invertebrate muscle preparations 6,7, and there has been little agreement even as to the nature of the ion permeability changes induced by glutamate in mammalian central neurons 80. Philippe Ascher and his collaborators have now shown that much of the confusion may be due to a physiological blocking action of magnesium ions.