Synaptic Transfer Research Articles

Slow Kinetics of Miniature IPSCs during Early Postnatal Development in Granule Cells of the Dentate Gyrus

Whole-cell patch-clamp recordings were used to investigate the properties of GABAA receptor-mediated postsynaptic currents during development in dentate gyrus granule cells from neonatal [postnatal day 0 (P0)] to adult rats in brain slices. The frequency of miniature IPSCs (mIPSCs) was low at birth and increased progressively with age. The mIPSCs of all ages could be satisfactorily fitted with the sum of a single exponential rise and single exponential decay. From P0 to P14, both the rise time and the decay time constants were significantly longer than in the adult. The mIPSC rise and decay kinetics did not change during the first 2 postnatal weeks, but during the third week the kinetics sped up and by P21 attained adult values. In contrast, the amplitude of the mIPSCs did not change during development. The synaptic GABAA receptors in immature and adult cells showed differential sensitivity to modulators. The subunit-specific benzodiazepine agonist zolpidem increased the decay time constant of the IPSCs of immature granule cells with a reduced potency compared with the adult. Furthermore, zinc decreased the amplitude and decay time constant of mIPSCs from developing granule cells, whereas it had no effect on mIPSCs in adult neurons. The results reveal for the first time that until the end of the second postnatal week the synaptic GABAA receptor-mediated currents in dentate granule cells display slower rise and decay kinetics but similar amplitudes compared with adult, resulting in a net decrease in synaptic charge transfer during development.

Subtle re-location of dendritic spine branches containing membrane with fast spiking mechanisms can alter synaptic efficacy

The potential physiological impact of morphological changes in the active dendritic spines, which are believed to be associated with altered synaptic efficacy, was investigated in a computer simulation study using the NEURON package [1]. A compartmental model of a simplified neuron was built, which included 30 complex spines (neck, head, and active zone) and accommodating AMPA-type synaptic inputs with alpha-function conductances. Hodgkin-Huxley type excitable membranes were inserted into the spine heads. It was shown that arranging spines in dense clusters, as opposed to a uniformly random spine distribution, has a negligible effect on the synaptic signal transfer (other model conditions, including synaptic input and spine density, remained unchanged). However, if a proportion (e.g., 3–20%) of the spines partly fuse with their neighbors forming branched spines, this could increase dramatically the cell response to the unchanged synaptic input. Results of this pilot study provide the basis for a more detailed investigation of the relationship between the spine arrangement and synaptic function, considering dual-component synaptic currents and mechanisms controlling ion fluxes in the dendritic compartments.

Calcium currents, transmitter release and facilitation of release at voltage-clamped crayfish nerve terminals.

1. The presynaptic terminals at crayfish (Procambarus spp.) opener neuromuscular junctions were voltage clamped. Calcium currents were measured during (ICa) and following (tail ICa) presynaptic depolarizations; EPSPs or IPSPs were simultaneously recorded from the (postsynaptic) muscle fibre directly beneath the presynaptic impalement. 2. For short (< or = 6 ms) presynaptic depolarizations, most of the transmitter release occurred during the tail ICa. EPSP or IPSP amplitudes at the end of the 6 ms pulse (end EPSP or end IPSP) increased monotonically with the integral of the ICa ([symbol: see text]ICa). The suppression potential for transmitter release was near the apparent reversal potential for ICa. 3. When the end EPSP or end IPSP amplitude was plotted against the peak ICa elicited during a presynaptic pulse (peak ICa), large and small depolarizations which evoked the same peak ICa evoked different amounts of transmitter release. The differences in transmitter release were eliminated when end EPSP amplitude was plotted against [symbol: see text] ICa, suggesting that transmitter release during a depolarization depends only upon calcium current and not upon a subsequent voltage-dependent step. 4. The synaptic transfer function of various measurements of EPSP or IPSP amplitude vs. [symbol: see text]ICa evoked during a presynaptic depolarization was a power function having an exponent of about 3. Similar measurements of EPSP amplitude vs. [symbol: see text]tail ICa evoked following a presynaptic depolarization had an exponent of about 2. 5. Facilitation of an EPSP or IPSP was not due to increases in calcium current at the test depolarization. 6. When the conditioning depolarization was increased and the test depolarization remained constant, EPSP amplitude at the test depolarization and facilitation increased . When the conditioning depolarization remained constant and the test depolarization was increased, EPSP amplitude at the test depolarization increased, while facilitation decreased. 7. Our data suggested that transmitter release at crayfish neuromuscular junctions is a non-linear function of calcium influx, and that facilitated release utilizes intracellular calcium differently from non-facilitated release. These data contradict simple models of facilitation which combine the residual calcium hypothesis with the calcium co-operativity hypothesis of non-facilitated release.

Decoding Synapses

The strength of many synapses is modified by various use and time-dependent processes, including facilitation and depression. A general description of synaptic transfer characteristics must account for the history-dependence of synaptic efficacy and should be able to predict the postsynaptic response to any temporal pattern of presynaptic activity. To generate such a description, we use an approach similar to the decoding method used to reconstruct a sensory input from a neuronal firing pattern. Specifically, a mathematical fit of the postsynaptic response to an isolated action potential is multiplied by an amplitude factor that depends on a time-dependent function summed over all previous presynaptic spikes. The amplitude factor is, in general, a nonlinear function of this sum. Approximate forms of the time-dependent function and the nonlinearity are extracted from the data, and then both functions are constructed more precisely by a learning algorithm. This approach, which should be applicable to a wide variety of synapses, is applied here to several crustacean neuromuscular junctions. After training on data from random spike sequences, the method predicts the postsynaptic response to an arbitrary train of presynaptic action potentials. Using a model synapse, we relate the functions used in the fit to underlying biophysical processes. Fitting different neuromuscular junctions allows us to compare their responses to sequences of action potentials and to contrast the time course and degree of facilitation or depression that they exhibit.

Branching of active dendritic spines as a mechanism for controlling synaptic efficacy

Recent experimental findings [Yuste R. and Denk W. (1995) Nature 375, 682–684] suggest that dendritic spines possess excitable membranes. Theoretically, it was shown earlier that the shape of active spines can significantly affect somatopetal synaptic signal transfer. Studies of long-term potentiation in the hippocampus have related the increased synaptic efficacy to a number of structural modifications of spines, including an increased number of branched spines [Trommald M. et al. (1990) In Neurotoxicity of Excitatory Amino Acids, pp. 163–174. Raven Press, New York] and a strengthened capability for spines to alter their spatial positions [Hosokawa T. et al. (1995) J. Neurosci. 15, 5560–5573]. In the present simulation study, the potential physiological impact of several types of spine changes was examined in a compartmental neuron model built using the neuromodelling software NEURON [Hines M. (1993) In Neural Systems: Analysis and Modeling, pp. 127–136. Kluwer Academic, Norwell, MA]. The model included 30 complex spines, with dual component synaptic currents and mechanisms of Ca 2+ uptake, diffusion, binding and extrusion within spine heads. The results show that local clustering properties of spine distributions along dendrites are unlikely to affect synaptic efficacy. However, partial fusion of active spines, which results in formation of spine branches, or subtle changes in spine branch positions, could alone significantly increase synaptic signal transfer. These data illustrate possible mechanisms whereby subtle morphological changes in dendritic spines (compatible with changes reported in the literature) may be linked to the cellular mechanisms of learning and memory.

Intracellular acidification reduced gap junction coupling between immature rat neocortical pyramidal neurones.

1. Developmental changes in electrophysiological properties of pyramidal neurones correlated with the developmental decline in gap junction-dependent dye coupling were investigated in coronal slices of rat prefrontal and sensorimotor cortex. Effects of intracellular acidification induced by application of weak organic acids on neuronal dye coupling, electrotonic parameters as well as synaptic potentials were examined using the patch clamp technique. Optical monitoring of intracellular pH revealed an acidic shift of 0.4-0.5 pH units following sodium propionate application. 2. Dye coupling between layer II-III neurones was prominent during the first two postnatal weeks. During this period, pre-incubation of slices with 30 mM of the sodium salts of weak organic acids reduced the number of cells coupled to the injected neurones by 64%. 3. Between postnatal days 1 and 18, the mean neuronal input resistance decreased significantly (by 81.0%). Both the membrane time constant (tau 0) and the first equalizing time constant (tau 1) also showed a significant developmental decline of 25.8 and 65.8%, respectively. Electrotonic length decreased by 34.9%. The electrophysiological properties of neurones displayed a pronounced intercellular variability which decreased with on-going development. 4. During the first two postnatal weeks, intracellular acidification led to a mean increase in neuronal input resistance of 55.9% and a mean decreae in electrotonic length of 22.2%. The membrane time constant was reduced by approximately 25% in the majority of neurones tested. Significant electrophysiological effects induced by intracellular acidification were not detected in uncoupled neurones from 18-day-old rats. 5. EPSP width at half-maximal amplitude showed a substantial reduction of approximately 50%, while rise times of the non-NMDA receptor-mediated EPSP components displayed no significant change during development. Both weak organic acids, as well as the gap junction blocker 1-octanol, reduced excitatory synaptic transmission independent of developmental age. 6. We conclude that gap junction permeability is regulated by intracellular pH in developing layer II-III pyramidal cells in the rat neocortex. The prominent correlation between pH-induced reduction in dye coupling and changes in electrophysiological cell properties suggests a significant influence of gap junctions on synaptic integration and information transfer in the immature neocortex.

Electro-geometrical coupling in non-uniform branching dendrites

The relationships between somatofugal electronic voltage spread, somatopetal charge transfer and non-uniform geometry of the neuronal dendrites were studied on the basis of the linear cable theory. It is demonstrated that for the dendritic arborization of arbitrary geometry, the path distribution of the relative effectiveness of somatopetal synaptic charge transfer defined as in Barrett and Crill (1974) is identical to that of the somatofugal steady electronic voltage normalized to the voltage at the soma. The features of both distributions are determined by breaks in the voltage gradient (the slope of monotonic voltage decay) at the sites of local non-uniformity of the dendritic geometry, such as abrupt change in diameter and asymmetric branching. If the membrane- and cytoplasm-specific electrical parameters are assumed as uniform and the branch diameter as piece-wise uniform, then at any site of step change the square reciprocal ratio of the pre- and poststep diameters determines the ratio of the pre- and poststep electronic gradients. At branching points this ratio is modulated by partition of the core current between the daughter branches in proportion to their input conductances depending on global geometries of the daughter subtrees originating there. Thus, simply computed steady somatofugal voltages provide a physiologically meaningful estimation of the relative influence of synaptic inputs in different parts of the dendritic arborization on the output of the neuron.

Gain control of synaptic transfer from second- to third-order neurons of cockroach ocelli.

Synaptic transmission from second- to third-order neurons of cockroach ocelli occurs in an exponentially rising part of the overall sigmoidal characteristic curve relating pre- and postsynaptic voltage. Because of the nonlinear nature of the synapse, linear responses of second-order neurons to changes in ligh intensity are half-wave rectified, i.e., the response to a decrement in light is amplified whereas that to an increment in light is compressed. Here I report that the gain of synaptic transmission from second- to third-order neurons changes by ambient light levels and by wind stimulation applied to the cerci. Transfer characteristics of the synapse were studied by simultaneous intracellular recordings of second- and third-order neurons. Potential changes were evoked in second-order neurons by a sinusoidally modulated light with various mean luminances. With a decrease in the mean luminance (a) the mean membrane potential of second-order neurons was depolarized, (b) the synapse between the second- and third-order neurons operated in a steeper range of the exponential characteristic curve, where the gain to transmit modulatory signals was higher, and (c) the gain of third-order neurons to detect a decrement in light increased. Second-order neurons were depolarized when a wind or tactile stimulus was applied to various parts of the body including the cerci. During a wind-evoked depolarization, the synapse operated in a steeper range of the characteristic curve, which resulted in an increased gain of third-order neurons to detect light decrements. I conclude that the nonlinear nature of the synapse between the second- and third-order neurons provides an opportunity for an adjustment of gain to transmit signals of intensity change. The possibility that a similar gain control occurs in other visual systems and underlies a more advanced visual function, i.e., detection of motion, is discussed.

Regulation of nicotinic acetylcholine receptors on human neuroblastoma cells during differentiation

Neuronal nicotinic acetylcholine receptors are expressed on a variety of cells in the nervous system where they play key roles in synaptic transmission and information transfer. Little is known, however, about the molecular mechanisms that control their expression, distribution, and function during nervous system development. We have investigated the control of expression during differentiation of one class of acetylcholine receptors that bind α-bungarotoxin of human neuroblastoma cells. We report that induction of differentiation of SH-SY5Y, SK-n-SH or IMR-32 cells by the phorbol ester 12- O-tetradecanoyl phorbol 13-myristate (10 nM, TPA) or by retinoic acid resulted in as much as a 70% decline in α-bungarotoxin receptors on the cells. The response to the phorbol ester was blocked by the protein kinase C inhibitors staurosporine and bisindolylmaleimide. The decrease in receptors induced by 10 μM retinoic acid was not affected by either agent. However, responses to lower (10 nM) concentrations of retinoic acid were blocked by staurosporine but not bisindolylmaleimide, suggesting a dual mechanism of action for retinoic acid in regulating acetylcholine receptors. It appears that acetylcholine receptors on neuroblastoma cells are regulated during differentiation by both protein kinase C-dependent and -independent mechanisms.

Afferent synaptic drive of rat medial nucleus tractus solitarius neurons: dynamic simulation of graded vesicular mobilization, release, and non-NMDA receptor kinetics.

1. We have developed a comprehensive mathematical model of an afferent synaptic connection to the soma of a medial nucleus tractus solitarius (mNTS) neuron. Model development is based on numerical fits to quantitative data recorded in our laboratory. This work is part of a continuing collaborative effort aimed at identifying and characterizing the mechanisms responsible for the non-linear integrative properties of this first synapse in the baroreceptor reflex. 2. The complete model consists of three major parts: 1) a Hodgkin-Huxley (HH)-type membrane model of the prejunctional sensory terminal bouton; 2) a multistage model describing vesicular storage, adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca(2+)-dependent mobilization, release and recycling; and 3) a HH-type membrane model of the postjunctional mNTS cell that includes descriptions for a desensitizing non-N-methyl-D-aspartate (NMDA) ionic current that is responsible for the fast excitatory postsynaptic potentials (EPSPs) observed in mNTS cells. The membrane models for both the terminal bouton and the mNTS neuron are coupled to separate lumped fluid compartment models describing intracellular Ca2+ ion concentration dynamics. 3. Our modeling strategy is twofold. The first is to validate model performance by reproducing a wide variety of experimental data both from our laboratory and from the literature. The second is to explore the functional aspects of the model in order to gain a greater appreciation for the balance between presynaptic mechanisms (e.g., terminal membrane properties and vesicular dynamics) and postsynaptic mechanisms (e.g., non-NMDA receptor kinetics and neuronal dynamics) that underlie the afferent synaptic drive of mNTS neurons. 4. The model accurately reproduces EPSP dynamics recorded with the use of a wide range of stimulus protocols. The model can also mirror the unique pattern of graded frequency- and use-dependent reduction in peak EPSP magnitude observed experimentally through 60 s of constant, suprathreshold synaptic activation. We demonstrate how vesicular mobilization, recycling, and receptor kinetics can function synergistically in establishing synaptic transfer. Furthermore, we show that by allowing the aggregate rate of vesicle mobilization to respond in a use-dependent manner, it is possible to compensate for the attenuating affects of desensitization at elevated rates of stimulation. 5. Our simulations indicate that the low-frequency characteristics of this synapse are dominated by vesicular dynamics, whereas the high-frequency properties arise from a combination of Ca(2+)-dependent vesicular mobilization and the kinetics of the non-NMDA receptor. Desensitization can influence the peak magnitude and decay time of the EPSP, thereby affecting synaptic throughput. However, we demonstrate that, as the time course of neurotransmitter in the synaptic cleft decreases, the influence of desensitization should be somewhat diminished. As a result, the effective bandwidth of the synapse increases and becomes limited by the gating characteristics of the non-NMDA channel. 6. The model also includes a neuromodulatory aspect in that the frequency response of the synapse can be modulated by an adenylate cyclase-mediated regulatory mechanism. Although our simulations indicate the behavior of a limited number of possible neuromodulatory agents, the results demonstrate the pivotal role such agents could play in modifying synaptic transfer characteristics presynaptically. 7. Both continuous and burst-mode tract stimulation evoke patterns of action potentials in spontaneously active mNTS neurons that are mimicked very well by our model. Our simulations demonstrate that, as the rate of stimulation increases beyond approximately 20-30 Hz, the inherent low-pass frequency-response characteristics of the synapse limit the overall dynamic range of the mNTS neuron, causing the postsynaptic cell to "entrain" at frequencies within its normal operating range.

Tonic transmitter release in a graded potential synapse

1. We studied graded synaptic transmission in the fly photoreceptor-interneuron synapse by using intracellular in situ recordings from pre- and postsynaptic cells. 2. A large presynaptic hyperpolarization after light adaptation, caused by the activation of the electrogenic Na+/K+ pump, drastically reduced the conspicuous postsynaptic dark noise. At the same time, the postsynaptic neurons depolarized, with an increase of input resistance of 5-10 M omega. 3. The spectral characteristics of the postsynaptic membrane noise in dark and during noise reduction, together with the other results, suggested that the transmitter release decreased dramatically approximately 12 mV below the resting potential of the presynaptic photoreceptors. 4. During the postsynaptic noise reduction, the saturated and subsaturated first-order visual interneuron responses were increased up to 9 mV with a time constant of recovery of approximately 10 s. This increase was shown to be caused by the negative shift of the reversal potential of the transmitter-gated (mainly Cl-) conductance, caused apparently by the reduced transmitter input. 5. The results strongly suggest that the photoreceptor transmitter release in fly is tonic, even in dark, and further support the modulation of the synaptic voltage transfer by postsynaptic Cl- extrusion.

The transfer of signals from photoreceptor cells to large second-order neurones in the ocellar visual system of the locust Locusta migratoria

The operation of the first synapse in the ocellar pathway of the locust Locusta migratoria has been studied by making simultaneous intracellular recordings from photoreceptors and large, second-order L-neurones. 1. The transfer curve for the synapse, obtained by plotting the amplitudes of the initial peak responses by the two cells to pulses of light against each other, shows that L-neurones are extremely sensitive to changes in photoreceptor potential and that the connection is tonically active in darkness. 2. Postsynaptic current in an L-neurone, produced when pulses of light are delivered from a dark background, saturates at a slightly brighter light intensity than does the postsynaptic potential. 3. The signal-to-noise ratio improves with increases in light intensity in both cells, but the reduction in noise as signals are transmitted from photoreceptors to L-neurones is less than would be expected from the number of photoreceptors that probably converge on each L-neurone. 4. In both cells, in the presence of different intensities of background illumination, the slope of the intensity&shy;response curve is maintained as the curve moves along the light intensity axis. Adaptation is relatively slow so that, at least for several minutes after an increase in background illumination, both cells maintain a sustained response and the responses to stimuli of increased illumination are reduced in amplitude. During sustained background illumination, the transfer curve for the synapse between a photoreceptor and an L-neurone shifts along both axes without a change in its maximum slope. 5. The slope of the synaptic transfer curve depends on the speed as well as the amplitude of changes in light. 6. In response to injection of depolarising pulses of current into a photoreceptor, an L-neurone generates brief, hyperpolarising responses. The amplitude of the responses depends on the strength and speed of the depolarising stimuli. After an initial response by an L-neurone, subsequent responses are reduced in amplitude for 200 ms. 7. The amplitude of L-neurone responses to electrical stimulation of a photoreceptor increases when the hyperpolarising constant current is injected into the photoreceptor.

Transfer of graded potentials at the photoreceptor-interneuron synapse.

To characterize the transfer of graded potentials and the properties of the associated noise in the photoreceptor-interneuron synapse of the blowfly (Calliphora vicina) compound eye, we recorded voltage responses of photoreceptors (R1-6) and large monopolar cells (LMC) evoked by: (a) steps of light presented in the dark; (b) contrast steps; and (c) pseudorandomly modulated contrast stimuli at backgrounds covering 6 log intensity units. Additionally, we made recordings from photoreceptor axon terminals. Increased light adaptation gradually changed the synaptic signal transfer from low-pass to band-pass filtering. This was accompanied by decreased synaptic delay and increased contrast gain, but the overall synaptic gain and the intrinsic noise (i.e., transmission noise) were reduced. Based on these results, we describe a descriptive synaptic model, in which the kinetics of the tonic transmitter (histamine) release from the photoreceptor axon terminals change with mean photoreceptor depolarization. During signal transmission, tonic transmitter release is augmented by voltage-dependent contrast-enhancing mechanisms in the photoreceptor axons that produce fast transients from the rising phases of the photoreceptor responses and add these enhanced voltages to the original photoreceptor responses. The model can predict the experimental findings and it agrees with the recently proposed theory of maximizing sensory information.

Modulation of synaptic transfer between retinal cones and horizontal cells by spatial contrast.

We studied the influence of steady annular light on the kinetics and sensitivity of horizontal cell (HC) responses to modulation of the intensity of small concentric spots in the turtle retina. As shown by previous investigators, when the intensity of the annulus was equal to the mean spot intensity, spot response kinetics were the same as those for the modulation of spatially uniform light. Turning off the annulus attenuated dramatically high-frequency flicker sensitivity and enhanced somewhat low-frequency sensitivity. This phenomenon reflects a modulation of synaptic transfer between cones and second-order neurons that is mediated by cones, and it will be referred to as cone-mediated surround enhancement (CMSE). Our main results are as follows: (a) The change in test-spot response sensitivity and kinetics upon dimming a steady surrounding annulus is a consequence of the change in spatial contrast rather than change in overall light level. (b) Introduction of moderate contrast between the mean spot intensity and steady surrounding light intensity causes a marked change in spot response kinetics. (c) The dependence of spot response kinetics on surrounding light can be described by a phenomenological model in which the steady state gain and the time constant of one or two single-stage, low-pass filters increase with decreasing annular light intensity (d) The effect of surrounding light on spot responses of a given HC is not determined by change in the steady component of the membrane potential of that cell. (e) Light outside the receptive field of an HC can affect that cell's spot response kinetics. (f) In an expanding annulus experiment, the distance over which steady annular light affects spot response kinetics varies among HCs and can be quite different even between two cells with closely matched receptive field sizes. (g) The degree of CMSE is correlated with HC receptive field size. This correlation suggests that part of the enhancement mechanism is located in the HC. Taken together, our results suggest the involvement of the inner retina in CMSE.

Desensitization in cholinergic synapse: mechanisms and physiologic role

The development of desensitization during the rhythmic activity of synapse as a result of the action of mediator nonquantal secretion is described, the data of a capacity to accelerate desensitization in a series of drugs and biologically active compounds are. presented. A concept of postsynaptic plasticity qr chemical senapse is proposed which provided the basis for short-term and long-term transfers of cholinoreccptors into different kinetic state under the influence of acetyccholine by itself resulting in the adaptation of synaptic apparatus to the new conditions and is the basis for purposeful correction of the synaptic transfer.

Nerve growth factor increases nicotinic ACh receptor gene expression and current density in wild-type and protein kinase A-deficient PC12 cells

Although neuronal nicotinic ACh receptors (nAChR) play a key role in synaptic transmission and information transfer in the nervous system, little is known about the molecular mechanisms that govern the expression of the multiple subunits that form the receptors and determine their functional properties. Using electrophysiological and molecular biological approaches, we have investigated the NGF-mediated regulation of nAChR expression in rat pheochromocytoma (PC12) cells and protein kinase A (PKA)-deficient PC12 cells. We report that NGF treatment increases steady state levels of mRNA encoding the alpha 3, alpha 5, alpha 7, beta 2, and beta 4 subunits, increases the occurrence of ACh-induced single-channel activity in excised patches, and increases ACh-induced macroscopic current density, all by mechanisms independent of PKA activity.

Modulation of transmission gain by protons at the photoreceptor output synapse.

Synaptic transmission of the light response from photoreceptors to second-order cells of the retina was studied with the whole-cell patch-clamp technique in tiger salamander (Ambystoma tigrinum) retinal slices. Synaptic strength is modulated by extracellular pH in a striking manner: Light-sensitive postsynaptic currents in horizontal and bipolar cells were found to be exponential functions of pH, exhibiting an e-fold increase per 0.23 pH unit over the pH range from 7 to 8. Calcium channel currents in isolated photoreceptors were measured and also exhibited proton sensitivity. External alkalinization from pH 7 to 8 shifted the voltage dependence of channel activation negative by 12 mV. A model of the synaptic transfer function suggested that presynaptic Ca channels could be the primary sites of proton action. Increased Ca influx and transmitter release brought about by alkalinization give rise to larger postsynaptic currents. These results suggest that activity-dependent interstitial pH changes known to occur in the retina, while not alleviating signal clipping at this synapse, may provide an adaptative mechanism controlling gain at the photoreceptor output synapse.

Effects of submicromolar concentrations of dopamine on photoreceptor to horizontal cell communication

Dopamine has been postulated to act as an intraretinal messenger for light adaptation by biasing retinal circuits to favor cone over rod inputs to second- and third-order neurons. As an experimental test, we studied the effects of dopamine and related ligands on rod to horizontal cell synaptic transfer. Rods and horizontal cells (HC) were recorded from simulataneosly. Red and green light-emitting diodes were modulated sinusoidally in counterphase at 1 Hz and their relative intensities adjusted to elicit a rod null. Dark-adapted HC's also showed a null, but exposure to 0.5–1.0 μM dopamine, which corresponds to the endogenous levels, elicited a large imbalance in the HC response while the rod null was maintained. Similar effects were achieved with either a D1 dopamine agonist, SKF 38393 (20 μM) or a D2 dopamine agonist, quinpirole HCl (1 μM). Correspondingly, the frequency range over which the HC responded to red flickering lights increased very substantially. Exposure to a D2, but not a D1 dopamine agonist increased rod flicker, but not as dramatically as in the HC. These data indicate that the synaptic gains of rod and cone transmission to a second order retinal neuron are modifiable by endogenous levels of dopamine. Secondly, the bandpass of rod flicker is altered by dopamine, acting through a D2 dopamine receptor.

A dendritic gain control mechanism in axonless neurons of the locust, Schistocerca americana.

1. To understand the possible function of active dendritic currents in local neurons, the non-linear electrical properties of locust axonless non-spiking interneurons were considered in parallel with the properties of graded transmitter release from their dendrites. 2. The dendritic membrane of the non-spiking interneurons was least responsive to an applied or synaptic current at potentials between -55 and -45 mV. This is because, at these potentials, the input resistance of the dendrites is reduced by the activation of voltage-dependent K+ conductances. Conversely, the membrane of the non-spiking interneurons was most responsive to an applied or synaptic current at potentials more negative than -55 mV (where the membrane behaves more or less passively), or more positive than -45 mV (where the activation of a Ca2+ current can boost depolarizing potentials). 3. The threshold for detectable release at the non-spiking synapse was around -65 mV. The dynamic gain of the synape (slope of the synaptic transfer curve) was maximum around -50 mV. Saturation was observed around -40 mV. Synaptic transfer is therefore most efficient at presynaptic potentials where the non-spiking dendritic membrane is least responsive to incoming signals. 4. The possible consequences of this matching of membrane and synaptic non-linearities was studied theoretically, with computer-assisted simulations, and experimentally, by recording simultaneously from the dendrites of synaptically connected non-spiking interneurons and motoneurons. This precise matching of non-linearities was found to have two important consequences: (i) it allowed the effective gain of polysynaptic pathways via non-spiking dendrites to depend little on the state of the interposed interneuron (linearization) and (ii) it optimized coding by preventing undesired over-amplification and synaptic saturation.

A model of graded synaptic transmission for use in dynamic network simulations

1. The heartbeat central pattern-generating network of the medicinal leech contains elemental neural oscillators, comprising reciprocally inhibitory pairs of segmental heart interneurons, that use graded as well as spike-mediated synaptic transmission. We are in the process of developing a general computer model of this pattern generator. Our modeling goal is to explore the interaction of membrane currents and synaptic transmission that promote oscillation in heart interneurons. As a first step toward this goal, we have developed a computer model of graded synaptic transmission between reciprocally inhibitory heart interneurons. Previously gathered voltage-clamp data of presynaptic Ca2+ currents and simultaneous postsynaptic currents and potentials (5 mM external [Ca2+]) were used as the bases of the model. 2. We assumed that presynaptic Ca2+ current was composed of distinct fast (ICaF) and slow (Icas) components because there are two distinct time courses of inactivation for this current. We fitted standard Hodgkin-Huxley equations (Eq. 1 and 2, APPENDIX) to these components using first-order activation and inactivation kinetics. 3. Graded synaptic transfer in the model is based on calculation of a dimensionless variable [P]. A portion of both IcaF and ICaS determined by a factor A contributes to [P], and a removal factor B decreases [P] (Eq. 4, APPENDIX). [P] can be roughly equated to the [Ca2+] in an unspecified volume that is effective in causing transmitter release. Transmitter release, and thus postsynaptic conductance, is related to [P]3 (Eq. 3, APPENDIX). 4. We adapted our model to voltage-clamp data gathered at physiological external [Ca2+] (2.0 mM) and tested it for shorter presynaptic voltage steps. Presynaptic Ca2+ currents and synaptic transfer were well simulated under all conditions. 5. The graded synaptic transfer model could be used in a network simulation to reproduce the oscillatory activity of a reciprocally inhibitory pair of heart interneurons. Because synaptic transmission in the model is an explicit function of presynaptic Ca2+ current, the model should prove useful to explore the interaction between membrane currents and synaptic transmission that promote and modulate oscillation in reciprocally inhibitory heart interneurons.