Search

The efficacy of synaptic transmission between two neurons changes as a function of the history of previous activations of the synaptic connection. This history dependence can be characterized by examining the dependence of transmission on the frequency of stimulation. In this framework synaptic plasticity can also be examined in terms of changes in the frequency dependence of transmission and not merely in terms of synaptic strength which constitutes only a linear scaling mechanism. Recent work shows that the frequency dependence of transmission determines the content of information transmitted between neurons and that synaptic modifications can change the content of information transmitted. Multipatch-clamp recordings revealed that the frequency dependence of transmission is potentially unique for each synaptic connection made by a single axon and that the class of pre-postsynaptic neuron determines the class of frequency dependence (activity independent), while the unique activity relationship between any two neurons could determine the precise values of the parameters within a specific class (activity dependent). The content of information transmitted between neurons is also formalized to provide synaptic transfer functions which can be used to determine the role of the synaptic connection within a network of neurons. It is proposed that deriving synaptic transfer functions is crucial in order to understand the link between synaptic transmission and information processing within networks of neurons and to understand the link between synaptic plasticity and learning and memory., (Copyright 1998 Academic Press.)

Action potentials evoke calcium transients in dendrites of neocortical pyramidal neurons with time constants of < 100 ms at physiological temperature. This time period may not be sufficient for inflowing calcium ions to equilibrate with all present Ca2+-binding molecules. We therefore explored nonequilibrium dynamics of Ca2+ binding to numerous Ca2+ reaction partners within a dendritelike compartment using numerical simulations. After a brief Ca2+ influx, the reaction partner with the fastest Ca2+ binding kinetics initially binds more Ca2+ than predicted from chemical equilibrium, while companion reaction partners bind less. This difference is consolidated and may result in bypassing of slow reaction partners if a Ca2+ clearance mechanism is active. On the other hand, slower reaction partners effectively bind Ca2+ during repetitive calcium current pulses or during slower Ca2+ influx. Nonequilibrium Ca2+ distribution can further be enhanced through strategic placement of the reaction partners within the compartment. Using the Ca2+ buffer EGTA as a competitor of fluo-3, we demonstrate competitive Ca2+ binding within dendrites experimentally. Nonequilibrium calcium dynamics is proposed as a potential mechanism for differential and conditional activation of intradendritic targets.

Transmission across neocortical synapses depends on the frequency of presynaptic activity (Thomson & Deuchars, 1994). Interpyramidal synapses in layer V exhibit fast depression of synaptic transmission, while other types of synapses exhibit facilitation of transmission. To study the role of dynamic synapses in network computation, we propose a unified phenomenological model that allows computation of the postsynaptic current generated by both types of synapses when driven by an arbitrary pattern of action potential (AP) activity in a presynaptic population. Using this formalism, we analyze different regimes of synaptic transmission and demonstrate that dynamic synapses transmit different aspects of the presynaptic activity depending on the average presynaptic frequency. The model also allows for derivation of mean-field equations, which govern the activity of large, interconnected networks. We show that the dynamics of synaptic transmission results in complex sets of regular and irregular regimes of network activity.

The nature of information stemming from a single neuron and conveyed simultaneously to several hundred target neurons is not known. Triple and quadruple neuron recordings revealed that each synaptic connection established by neocortical pyramidal neurons is potentially unique. Specifically, synaptic connections onto the same morphological class differed in the numbers and dendritic locations of synaptic contacts, their absolute synaptic strengths, as well as their rates of synaptic depression and recovery from depression. The same axon of a pyramidal neuron innervating another pyramidal neuron and an interneuron mediated frequency-dependent depression and facilitation, respectively, during high frequency discharges of presynaptic action potentials, suggesting that the different natures of the target neurons underlie qualitative differences in synaptic properties. Facilitating-type synaptic connections established by three pyramidal neurons of the same class onto a single interneuron, were all qualitatively similar with a combination of facilitation and depression mechanisms. The time courses of facilitation and depression, however, differed for these convergent connections, suggesting that different pre-postsynaptic interactions underlie quantitative differences in synaptic properties. Mathematical analysis of the transfer functions of frequency-dependent synapses revealed supra-linear, linear, and sub-linear signaling regimes in which mixtures of presynaptic rates, integrals of rates, and derivatives of rates are transferred to targets depending on the precise values of the synaptic parameters and the history of presynaptic action potential activity. Heterogeneity of synaptic transfer functions therefore allows multiple synaptic representations of the same presynaptic action potential train and suggests that these synaptic representations are regulated in a complex manner. It is therefore proposed that differential signaling is a key mechanism in neocortical information processing, which can be regulated by selective synaptic modifications.

Computational neuroscience has contributed significantly to our understanding of higher brain function by combining experimental neurobiology, psychophysics, modeling, and mathematical analysis. This article reviews recent advances in a key area: neural coding and information processing. It is shown that synapses are capable of supporting computations based on highly structured temporal codes. Such codes could provide a substrate for unambiguous representations of complex stimuli and be used to solve difficult cognitive tasks, such as the binding problem. Unsupervised learning rules could generate the circuitry required for precise temporal codes. Together, these results indicate that neural systems perform a rich repertoire of computations based on action potential timing.

Although signaling between neurons is central to the functioning of the brain, we still do not understand how the code used in signaling depends on the properties of synaptic transmission. Theoretical analysis combined with patch clamp recordings from pairs of neocortical pyramidal neurons revealed that the rate of synaptic depression, which depends on the probability of neurotransmitter release, dictates the extent to which firing rate and temporal coherence of action potentials within a presynaptic population are signaled to the postsynaptic neuron. The postsynaptic response primarily reflects rates of firing when depression is slow and temporal coherence when depression is fast. A wide range of rates of synaptic depression between different pairs of pyramidal neurons was found, suggesting that the relative contribution of rate and temporal signals varies along a continuum. We conclude that by setting the rate of synaptic depression, release probability is an important factor in determining the neural code.

Activity-driven modifications in synaptic connections between neurons in the neocortex may occur during development and learning. In dual whole-cell voltage recordings from pyramidal neurons, the coincidence of postsynaptic action potentials (APs) and unitary excitatory postsynaptic potentials (EPSPs) was found to induce changes in EPSPs. Their average amplitudes were differentially up- or down-regulated, depending on the precise timing of postsynaptic APs relative to EPSPs. These observations suggest that APs propagating back into dendrites serve to modify single active synaptic connections, depending on the pattern of electrical activity in the pre- and postsynaptic neurons.

Experience-dependent potentiation and depression of synaptic strength has been proposed to subserve learning and memory by changing the gain of signals conveyed between neurons. Here we examine synaptic plasticity between individual neocortical layer-5 pyramidal neurons. We show that an increase in the synaptic response, induced by pairing action-potential activity in pre- and postsynaptic neurons, was only observed when synaptic input occurred at low frequencies. This frequency-dependent increase in synaptic responses arises because of a redistribution of the available synaptic efficacy and not because of an increase in the efficacy. Redistribution of synaptic efficacy could represent a mechanism to change the content, rather than the gain, of signals conveyed between neurons.

Synaptic contacts formed by the axon of a neuron on its own dendrites are known as autapses. Autaptic contacts occur frequently in cultured neurons and have been considered to be aberrant structures. We examined the regular occurrence, dendritic distribution, and fine structure of autapses established on layer 5 pyramidal neurons in the developing rat neocortex. Whole-cell recordings were made from single neurons and synaptically coupled pairs of pyramidal cells, which were filled with biocytin, morphologically reconstructed, and quantitatively analyzed. Autapses were found in most neurons (in 80% of all cells analyzed; n = 41). On average, 2.3 +/- 0.9 autapses per neuron were found, located primarily on basal dendrites (64%; 50-70 microns from the soma), to a lesser extent on apical oblique dendrites (31%; 130-200 microns from the soma), and rarely on the main apical dendrite (5% 480-540 microns from the soma). About three times more synaptic than autaptic contacts (ratio 2.4:1) were formed by a single adjacent synaptically coupled neuron of the same type. The dendritic locations of these synapses were remarkably similar to those of autapses. Electron microscopic examination of serial ultrathin sections confirmed the formation of autapses and synapses, respectively, and showed that both types of contacts were located either on dendritic spines or shafts. The similarities between autapses and synapses suggest that autaptic and synaptic circuits are governed by some common principles of synapse formation.

The therapeutic action of lithium in affective disorders is still unclear. One effect of lithium is to deplete membrane inositol and consequently to exhaust the phosphoinositide (PI) pathway. Under chronic lithium treatment, rats showed persistent performance deficits in an active avoidance task and in a visually cued maze. The same treatment, however, resulted in only a transient deficit in the performance of rats in a spatial memory task. Lithium treatment caused a similarly transient deficit in the ability of acetylcholine to potentiate responses to N-methyl-D-aspartate (NMDA) in neurons of the hippocampal slice. The authors propose that the development of compensatory mechanisms may account for the lack of severe memory impairments during lithium treatment. It is suggested that the effects of lithium on the PI pathway are not sufficient to explain the behavioral consequences of chronic lithium treatment.

We examined the effect of elevating intracellular calcium ([Ca2+]i) on responses to iontophoretically applied N-methyl-D-aspartate (NMDA), and quisqualate in CA1 neurons of the hippocampal slice. Topical application of calcimycin (A23187), a calcium ionophore, potentiated responses to NMDA but not to quisqualate. This potentiation was prevented by loading cells with the calcium chelator, BAPTA, suggesting that the action of calcimycin on NMDA receptors was mediated by an elevation of [Ca2+]i in the recorded cell. The potentiation was also recorded in voltage-clamped and in cesium-loaded cells, suggesting that it was not mediated by non-specific changes in voltage or input resistance of the cell that may have resulted from the rise in [Ca2+]i. We propose that intracellular calcium plays a crucial role in regulating the activity of the NMDA subtype of L-glutamate receptor.

Acting at postsynaptic alpha 1- and beta 1-receptors, norepinephrine (NE) exerts a complex action in rat hippocampus. It is currently believed that beta 1-receptor activation enhances excitability of recorded neurons, whereas alpha 1 activation suppresses reactivity to afferent stimulation. These reported effects of alpha-agonists are not consistent with alpha 1 effects found elsewhere in the brain. We have conducted experiments in the anesthetized rat and found that an amphetamine-induced increase in the dentate gyrus population spike can be blocked by a beta-antagonist but also by an alpha 1-antagonist. We have conducted experiments in the brain slide preparation and found that an alpha-agonist, phenylephrine (PHE), selectively enhances responses to N-methyl-D-aspartate (NMDA) but not to quisqualate. We propose that the product of activation of both alpha- and beta-receptor types will enhance reactivity of hippocampal cells to afferent stimulation.

The effect of acetylcholine (ACh) on intracellular responses to ionophoretic application of N-methyl-D-aspartate (NMDA) was examined in rat hippocampal slice. Recordings were obtained from CA1 neurons under current- and voltage-clamp conditions. Drugs were applied topically by ionophoretic and microdrop techniques. ACh produced an atropine-sensitive potentiation of responses to NMDA. The effect of ACh on NMDA receptor-mediated responses was independent of changes in voltage or potassium conductances caused by ACh. ACh also potentiated responses to L-glutamate but not to kainate or quisqualate. This effect was blocked by DL-2-amino-5-phosphonovalerate (2-APV), an NMDA receptor antagonist. We conclude that ACh, acting on muscarinic receptors, potentiates selectively, the NMDA subclass of L-glutamate receptor.

We examined the electrophysiological properties of cholinergic and non-cholinergic neurons in the medial septum-diagonal band complex (MSDB) of the rat in the in vitro slice preparation. Cells were identified electrophysiologically, filled with Lucifer yellow, fixed and processed for immunohistochemistry with fluorescent labeled anti-choline acetyltransferase (ChAT) antibody. Cholinergic and non-cholinergic neurons differed in action potential parameters, spike afterpotentials and in current-voltage relationships. In addition, cholinergic neurons expressed a potent transient outward rectification in response to a depolarizing current pulse.

The hippocampus is among the regions in the brain richest in M1 cholinergic receptors. Topical application of acetylcholine (ACh) onto hippocampal slices produces a characteristic complex response consisting of a depolarization, an increase in input resistance especially upon depolarization and a blockade of a slow afterhyperpolarization (AHP). The first two of these responses can be recorded also in non-cholinergic septal neurons in an area which contains about 8% of the M1 muscarinic receptors found in the hippocampus. The responses of hippocampal but not septal neurons to ACh involve an increase in the spontaneous synaptic activity and a decrease in evoked responses to afferent stimulation. The dissociated hippocampal culture was used to study these presynaptic effects. The neurons in culture possess muscarinic receptors which develop gradually over a period of several weeks after plating. ACh rarely depolarizes hippocampal neurons in culture. Instead, it causes an increase in spontaneous discharge of small postsynaptic currents (PSC's) and a marked decrease of large, evoked PSC's. In some cultured hippocampal cells ACh reduced ICa without affecting any of several outward K currents studied. It is suggested that ACh reduces evoked activity by reducing Ca currents at presynaptic terminals.