Manual Cellular and Molecular Basis of Synaptic Transmission

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Figure 6. The stretch to the patella tendon stretches the extensor muscle. More specifically, it stretches a group of specific receptors known as muscle spindle receptors or simply stretch receptors. The sensory neurons also make synaptic connections with another type of neuron in the spinal cord called an interneuron. Interneurons are so named because they are interposed between one type of neuron and another. The particular interneuron shown is an inhibitory interneuron.

As a result of its activation through the process of synaptic transmission, action potentials are elicited in the interneuron. An action potential in the inhibitory neuron leads to the release of a chemical transmitter substance that inhibits the flexor motor neuron, thereby preventing an improper movement from occurring.

This particular reflex is known as the monosynaptic stretch reflex because this reflex is mediated by a single excitatory synaptic relay in the central nervous system. The figure at right illustrates how it is possible to experimentally examine some of the components of synaptic transmission in the reflex pathway that mediates the stretch reflex.

Normally, the sensory neuron is activated by a stretch to the stretch receptor, but this process can be bypassed by injecting a depolarizing current into the sensory neuron. That stimulus initiates an action potential in the sensory neuron which leads to a change in the potential of the motor neuron. This potential is known as an excitatory postsynaptic potential EPSP ; excitatory because it tends to depolarize the cell, thereby tending to increase the probability of firing an action potential in the motor neuron and postsynaptic because it is a potential recorded on the postsynaptic side of the synapse.

The ionic mechanisms for the EPSP in the spinal motor neuron are essentially identical to the ionic mechanisms for the EPSP at the neuromuscular junction. Specifically, the transmitter substance diffuses across the synaptic cleft and binds to specific ionotropic receptors on the postsynaptic membrane, leading to a simultaneous increase in the sodium and potassium permeability See Figure 4.

Synaptic Transmission

The mechanisms for release are also identical to those at the neuromuscular junction. There are two fundamental differences between the process of synaptic transmission at the sensorimotor synapse in the spinal cord and the process of synaptic transmission at the neuromuscular junction. First , transmitter substance released by the sensory neuron is not ACh but rather the amino acid glutamate. Indeed, there are many different transmitters in the central nervous system - up to 50 or more and the list grows every year. Fortunately, these 50 or more transmitter substances can be conveniently grouped into four basic categories: acetylcholine , monoamines , peptides , and the amino acids.

Second , in contrast to the mV amplitude of the synaptic potential at the neuromuscular junction, the amplitude of the synaptic potential in a spinal motor neuron, as a result of an action potential in a 1A afferent fiber, is only about 1 mV. If the amplitude of the postsynaptic potential is only 1 mV, how can an action potential in the motor neuron be triggered and the reflex function? Note that a 1-mV EPSP is unlikely to be sufficient to drive the membrane potential of the motor neuron to threshold to fire a spike.

If there is no spike, there will be no contraction of the muscle. The answer is that the stretch of the muscle fires multiple action potentials in many different stretch receptors.

In fact, the greater the stretch, the greater is the probability of activating more stretch receptors. This process is referred to as recruitment. Therefore, multiple 1A afferents will converge onto the spinal motor neuron and participate in its activation. This is not the whole answer, however. Recall that the greater the intensity of the stimulus, the greater is the number of action potentials elicited in a sensory receptor.

The greater the stretch, the greater the number of action potentials elicited in a single sensory neuron and the greater number of EPSPs produced in the motor neuron from that train of action potentials in the sensory cell. The processes by which the multiple EPSPs from presynaptic neurons summate over space and time are called temporal and spatial summation. Temporal summation. Now consider the consequences of firing two action potentials in quick succession See figure above.


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Two EPPs are elicited, the second of which summates on the falling edge of the first. As a result of two action potentials, a summated potential about 2 mV in amplitude occurs. Studies of retinal horizontal cells have shown that catecholamines, dopamine in particular, reduce the receptive field size and tracer coupling [ 19 — 22 ]. These effects were shown to result from activation of a D1 dopamine receptor that elevated intracellular cAMP via adenylyl cyclase activity [ 23 — 25 ], and depended on activation of protein kinase A [ 26 ].

The reduced electrical coupling in fish horizontal cells resulted from a reduction in the open probability of the gap junction channels without a change in unitary conductance [ 27 ]. The horizontal cells in fish contain several connexins: Cx It is not clear which, if any, of these contribute to the plasticity that has been observed in horizontal cells from the fish species studied physiologically. The vast majority of electrical synapses in the mammalian central nervous system utilize Cx36 homologous to Cx35 in non-mammalian vertebrates.

The biophysical basis of changes in macroscopic coupling has not been elucidated but changes in channel open probability, based upon changes in mean open time, have been suggested as the mechanism of plasticity [ 35 ]. A number of studies have revealed that Cx36 phosphorylation state changes with conditions that change coupling and is an accurate, and essentially linear, predictor of coupling as assessed by tracer transfer [ 36 — 39 ]. The signaling pathways that control these changes have been studied in detail in photoreceptor and AII amacrine cells in recent years, revealing a common theme of regulation by well-defined opposing signaling pathways.

A role for dopamine D2-like receptors in controlling rod to cone photoreceptor coupling has been known for some time [ 44 , 45 ]. In rodents, this is actually a D4 receptor [ 39 , 46 ], which inhibits adenylyl cyclase via Gi and reduces cAMP level. In both mouse and zebrafish, the action of the dopamine D4 receptor is opposed by the action of a Gs-coupled adenosine A2a receptor [ 39 , 47 ]. Secreted dopamine and extracellular adenosine levels vary in retina in opposite phase and are both regulated by circadian rhythms [ 48 ]: dopamine is high in the daytime or subjective day while adenosine is high in nighttime or subjective night.

Li et al. The Gi-coupled A1 receptor has higher affinity for adenosine than does the A2a and is activated in the daytime by the lower extracellular adenosine level that remains. This A1 receptor activation reinforces the inhibitory action of the dopamine D4 receptor on adenylyl cyclase, strongly suppressing Cx36 phosphorylation and photoreceptor coupling in the daytime [ 47 ].

Since all three receptors act on the same target, adenylyl cyclase, the regulation of Cx36 phosphorylation and photoreceptor coupling is a steep biphasic function that keeps coupling minimal during the daytime Fig.

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Signaling pathways that control coupling in two types of retinal neuron. Coupling through Cx36 gap junctions is regulated by Cx36 phosphorylation through an order of magnitude dynamic range. Phosphorylation enhances coupling and pathways that promote Cx36 phosphorylation are colored green in this diagram while those that reduce phosphorylation are colored red. Elements colored blue are hypothesized to play a role but have not been specifically demonstrated.


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  5. This process depends on spillover glutamate derived from bipolar cells and is enhanced by activation of synaptic AMPA-type glutamate receptors that depolarize the cell. Reduction of Cx36 phosphorylation is driven by an independent pathway in which activation of D1 dopamine receptors increases adenylyl cyclase activity, activating protein kinase A, which in turn activates protein phosphatase 2A. Protein phosphatase 1 suppresses this pathway. Both pathways are activated by light, but with different thresholds, leading to an inverted U-shaped light adaptation curve.

    AC activity is in turn controlled by an intricate set of G-protein coupled receptors regulated by circadian time and light adaptation. Darkness during the night phase increases extracellular adenosine such that activation of A2a adenosine receptors dominates signaling and activates AC.

    Light adaptation or subjective daytime result in reduced extracellular adenosine and increased dopamine secretion such that activation of dopamine D4 receptors dominates signaling to suppress AC activity. A1 adenosine receptors supplement this effect. The opposing signaling pathways routed through a common effector impart a steep monophasic character to the light adaptation and circadian control of coupling in this neural network. This plasticity is driven by light, with a biphasic pattern showing very low coupling in prolonged dark-adapted conditions, high coupling with low-intensity illumination, and low coupling again with bright illumination [ 50 , 51 ].

    The bright light-driven reduction in coupling is mediated by dopamine, with dopamine D1 receptors increasing adenylyl cyclase activity and enhancing protein kinase A activity [ 49 , 52 ]. AII amacrine cells use Cx36 [ 53 ], and the suppression of coupling by protein kinase A activity is inconsistent with the positive effect that protein kinase A activity has on photoreceptor coupling mediated by Cx36 [ 38 , 39 ]. This contradiction was resolved by Kothmann et al. The NMDA receptors on AII amacrine cells are non-synaptic and are closely associated with Cx36 [ 40 ], so their activation depends on spillover glutamate.

    This most likely comes from rod bipolar cells, which are presynaptic to the AII amacrine cell, but may also come from cone On bipolar cells that are nearby. Because the signaling pathways in AII amacrine cells that phosphorylate and dephosphorylate Cx36 are independent Fig. The activity-dependent potentiation of AII amacrine cell electrical synapses resembles that originally described in the mixed synapse of auditory VIIIth nerve club endings onto Mauthner cells in the goldfish [ 54 , 55 ].

    A similar form of plasticity dependent upon non-synaptic NMDA receptors has also been described recently in rat inferior olive neurons [ 56 ]. A variety of other signaling pathways have been found to modulate electrical synapses. In interneurons of the thalamic reticular nucleus TRN , excitatory input depresses electrical synapses through activation of metabotropic glutamate receptors mGluRs [ 57 ].

    Dept. of Cellular Neurobiology, Univ. of Tokyo | Research

    This signaling has been explored in detail recently. The dominant effect appears to be through activation of Group I mGluRs, which produce long-term depression by activation of a Gs signaling pathway, stimulating adenylyl cyclase and activating PKA. This shares the same pathway, routing ultimately through PKA activity. Since TRN neurons employ Cx36 [ 59 ], through which electrical coupling is increased by phosphorylation [ 35 , 37 — 39 ], this signaling mechanism must include a PKA-activated phosphatase to reduce Cx36 phosphorylation upon PKA activation in a manner similar to that in retinal AII amacrine cells.

    Histamine H1 and H2 receptors have been found to modulate coupling among various populations of neurons in the supraoptic nucleus [ 60 , 61 ]. H2 receptors signal through adenylyl cyclase, but H1 receptors instead activate NO synthase, signaling through nitric oxide, guanylyl cyclase, and protein kinase G. A potentially similar nitric oxide-driven signaling pathway also selectively regulates the heterologous electrical synapses between retinal AII amacrine cells and cone On bipolar cells [ 52 ].

    Thus it is apparent that a wide variety of signaling pathways have been employed to regulate electrical synaptic strength via connexin phosphorylation and dephosphorylation in different neurons throughout the central nervous system. Changes in the expression level of connexins provide a mechanism to alter coupling over time scales of hours to weeks. Such changes are most prominent in development.

    Electrical coupling in most areas of the vertebrate CNS tends to increase to high levels in early phases of development, and then reduce again [ 62 — 64 ]. One study found that activation of group II mGLuRs was responsible for the developmental increase of coupling, acting both through transcriptional and post-transcriptional mechanisms [ 65 ]. A surprisingly similar increase in neuronal coupling is also seen following various types of injury [ 66 ].

    Ischemic injuries result in an increase in neuronal coupling and the level of Cx36 protein, without an apparent increase in transcript level [ 67 , 68 ]. Traumatic injuries [ 69 , 70 ] and seizures [ 71 , 72 ] also result in increases of neuronal coupling, although these insults lead to increases in Cx36 transcript level. In these contexts, alteration in the expression level of connexins that form electrical synapses are important factors in long term changes in neuronal coupling. Electrical coupling of mature neurons is critically dependent on maintenance of a steady state population of gap junction proteins.

    A recent study showed that electrical coupling in goldfish Mauthner cell mixed synapses was reduced within a few minutes if perturbed by peptides that disrupted stabilizing interactions of Cx35 with scaffolding proteins or blocked SNARE-mediated trafficking of new Cx35 [ 73 ]. Another study found circadian regulation of Cx36 transcript and protein levels in photoreceptors [ 74 ].

    These studies reveal that electrical synapses are dynamic structures whose channels are turned over actively, suggesting that regulated trafficking of connexons may contribute to the modification of gap junctional conductance. As previously mentioned electrical coupling depends on both the resistance of the gap junction and the membrane resistance of the postsynaptic cell. In fact, while changes of the gap junction resistance due to modifications of the single channel conductance or the number of intercellular channels might produce significant changes in the coupling coefficient, modifications of the postsynaptic membrane can also underlie significant and highly dynamic changes in the strength of electrical coupling representing an additional point of regulation.

    The fact that the junctional resistance Rj and the membrane resistance of the postsynaptic cell R2 constitute a voltage divider Fig. In contrast, if R2 is big compared to Rj a correspondingly big fraction of the input voltage V1 will appear across the membrane of the postsynaptic cell V2. A large voltage drop across R2 corresponds to a large coupling coefficient meaning that cells are strongly coupled.

    This dependency of coupling coefficient on the input resistance of the postsynaptic cell determines the directionality of transmission when electrical coupling occurs between cells of dissimilar input resistances. In fact, electrical transmission will be more efficient from the lower input resistance to the higher input resistance cell in comparison to the opposite direction. Therefore, despite of the presence of non-rectifying contacts, symmetrical communication will occur only when connected cells present similar input resistances.

    Hence, the directionality of electrical transmission imposed by asymmetry of passive properties of connected cells might be a key determinant of the flow of information within neural circuits. Interestingly, modifications of the membrane resistance Rm of coupled cells due to nearby chemically mediated synaptic actions can significantly modulate the strength of electrical coupling in a highly dynamical fashion [ 5 , 75 ]. In fact, as these synaptic actions usually involve changes of membrane permeability to different ion species, they are accompanied by corresponding changes in membrane resistance of the postsynaptic cell and hence of the strength of electrical coupling.

    Usually, synaptic actions are defined by the sign of its effect on membrane potential of the postsynaptic cell depolarization versus hyperpolarization. What is remarkable is that although both synaptic actions are depolarizing shifts of membrane voltage they have opposite effects on the efficacy of electrical transmission. Whereas synaptic actions involving an increase in Rm enhance the strength of coupling, a reduction in Rm elicits an uncoupling of electrically connected cells [ 76 ].

    A similar shunting effect by nearby GABAergic inputs has been proposed to underlie decoupling in pairs of inferior olivary neurons [ 77 , 78 ]. These results indicate that the membrane resistance of the postsynaptic cell is a key element for regulating electrical coupling, being as important as the junctional resistance. This means that changes in the efficacy of electrical synapses might be accomplished through modification of either of these two resistances.

    Alternatively, when electrical coupling is expected to be constant in order to assure stable network function, changes in electrophysiological properties of coupled cells require corresponding changes of junctional resistance. In fact, concurrent changes of the junctional and membrane resistances of coupled cells in a homeostatic fashion has been proposed to underlie the stability of electrical coupling strength between neurons of the thalamic reticular nucleus during development [ 79 ].

    In fact, while a simple ohmic resistor responds to a step current with a similar voltage step, cells show voltage responses that rise and decay more slowly than the current step Fig. This property of the membrane can be modeled by a resistor connected in parallel to a capacitor. The ability of this circuit to slow down changes in voltage results from the fact that a discharged capacitance offers no resistance to current flow, determining that at the beginning of the current step all current will flow through the capacitance and nothing through the resistance.

    As the capacitance gets charged it progressively develops more resistance to current and more current will flow through the resistance [ 80 ]. This circuit comprises a simple low pass filter for input currents characterized by its time constant. Indeed, the resistance of the gap junction connected in series to the parallel resistance and capacitance of the postsynaptic cell behaves as a low-pass filter determining that the high-frequency components of presynaptic signals are comparatively more attenuated.

    That is, slow fluctuations of membrane voltage pass more effectively between cells than do fast signals [ 7 , 81 ]. This is a characteristic property of electrical transmission and underlies the fact that coupling potentials present a slower time course in comparison to the presynaptic signals that generated them Fig. As a result of this property, a delay of postsynaptic responses is introduced with respect to the presynaptic signals. This property of low-pass filters, known as phase lag, represents the synaptic delay of electrical synapses.

    Although current begins to flow across the junction without delay, time is required for charging the postsynaptic capacitance to a significant level to generate a detectable voltage change above the noise level [ 81 ]. Early descriptions of electrical synapses in invertebrates already proposed that these contacts present low-pass filtering characteristics [ 4 , 82 , 83 ].

    More recently, filtering characteristics of electrical transmission between mammalian central neurons have been demonstrated by using dual whole cell patch recordings and injecting sinusoidal currents of different frequencies Fig. Under these experimental conditions, coupling coefficients and phase lag were determined as a function of sinusoidal frequency.

    This experimental approach in different cell types like GABAergic interneurons of the neocortex [ 84 — 86 ], neurons of the thalamic reticular nucleus [ 59 ], Golgi cells of the cerebellum [ 87 ], retinal AII amacrine cells [ 88 ] among others, confirmed that electrical transmission presents low-pass filter characteristics, allowing the passage of low frequency signals but strongly attenuating and delaying signals of higher frequency [ 6 ]. Frequency selectivity of electrical transmission. Middle, Superimposed are depicted the voltage membrane responses of the presynaptic cell Vm Cell 1 and of the postsynaptic cell Vm Cell 2 for a pair of coupled cells which include only passive elements RC circuit, black elements in circuit in A.

    Both responses are characteristics of a low-pass filter where amplitude of membrane response decreases monotonically as sinusoidal frequency increases. Bottom, By contrast, when cells present passive and active voltage-dependent currents IK and INap membrane responses present certain frequency selectivity where signals close to the characteristic frequency are of bigger amplitude compared to signals whose frequency lie far from this value.

    Whereas transfer function when cells present only passive elements show the typical profile of a low-pass filter gray trace , the presence of voltage-dependent currents determines that transmission of signals near the characteristic frequency vertical dashed line is less attenuated, determining a maximum in the function red trace. This property of electrical synapses determines that slow potential changes typically subthreshold are preferentially transmitted over action potentials, endowing electrical synapses with the ability to transmit different information than the spikes transmitted via chemical synapses.

    This phenomenon results from the low-pass filter properties of electrical transmission. In fact, because the high-frequency components of the fast presynaptic action potential are more attenuated than the slow AHP, the coupling potential results in a net hyperpolarizing signal, inhibiting neural activity rather than promoting activation of the postsynaptic neuron [ 85 , 87 , 89 ].

    In the cerebellar cortex, this effect has been involved in the desynchronization of the population of Golgi cells due to sparse depolarizing synaptic inputs [ 90 ]. In addition to the passive membrane properties those that are linear with respect to the membrane voltage , excitable cells like neurons present active membrane properties, which are highly non-linear mechanisms due to complex time and voltage dependent processes.

    Despite these spike-generating mechanisms which allow neurons to communicate over long distances in a non-decremental fashion, excitable cells usually present a large variety of subthreshold active properties. These active mechanisms along with the passive properties establish the way neurons integrate spatially and temporally distributed synaptic inputs, and how these inputs are translated or encoded into a time series of action potentials.

    The active membrane properties of neurons depend on the kind, density and distribution of voltage operated ion channels in the surface membrane of the different cellular compartments. Central neurons present a rich repertoire of voltage operated membrane ion channels that endow them with powerful encoding capabilities represented by the ability to transform their inputs into complex firing patterns. Indeed, neurons express tens of different voltage operated membrane conductances according to their ion selectivity, voltage range of activation, kinetics, presence of inactivation, and modulation by intracellular second messengers giving rise to a wide variety of electrophysiological phenotypes [ 92 — 95 ].

    Despite the limited voltage gating of connexin intercellular channels imposed by its slow kinetics, electrical coupling between neurons might present marked voltage-dependency.

    http://cpanel.amosautomotive.com/kogab-azithromycin-und.php However, this phenomenon does not represent a voltage dependent property of the gap junctions but instead are supported by the active properties of the non-junctional membrane of the postsynaptic cell. For instance, in fish a pair of gigantic command neurons, the Mauthner cells, which are responsible for the initiation of escape responses, are contacted by a special class of auditory afferents through mixed electrical and chemical synaptic contacts [ 96 ].

    These electrical contacts not only allow the forward transmission of signals from afferents to the Mauthner cell , but also support retrograde transmission by allowing the spread of dendritic postsynaptic depolarizations to the presynaptic afferents. Moreover, retrograde coupling potentials in the afferents present a marked voltage dependency.

    In fact, depolarization of the membrane potential of these afferents evokes a dramatic increase in coupling potential amplitude, eventually enough to activate them, and hence supporting a mechanism of lateral excitation whereby the sound-evoked activation of some afferents can recruit more afferents to reinforce the synaptic action on Mauthner cells [ 97 , 98 ]. Additionally, its subthreshold voltage range of activation, among other properties, indicates that the persistent sodium current INap of these afferents is the underlying mechanism of this amplification [ 98 ].

    This cell population is coupled mostly in pairs and activation of one neuron of an electrically coupled pair produces a spikelet in the postsynaptic cell Fig. This coupling potential critically depends on the membrane potential, being enhanced by depolarization of the postsynaptic cell and eventually triggering an action potential in this cell.

    This spikelet exhibits a positive correlation with the membrane potential of the postsynaptic cell, and because of its voltage range of activation and sensitivity to sodium channel blockers it represent the activation of a persistent sodium current [ 99 ].

    Similar amplifying mechanism has been proposed in the cerebellar cortex [ 87 , ] and the thalamic reticular nucleus [ ]. Thus, the INap endows electrical coupling with voltage-dependent amplification, suggesting a relevant contribution of active membrane conductances in regulating the efficacy of electrical transmission between neurons. Moreover, as such amplification of electrotonic potentials might be enough to recruit the postsynaptic cell, it tends to synchronize the activity of networks of neurons, emphasizing the role of active conductances in the dynamics of networks of electrically coupled neurons.

    Most typically electrical transmission between neurons possesses low-pass filter properties imposed by the RC circuit of the postsynaptic cell. Accordingly, transmission of spikes through these contacts is significantly more efficient than in electrical contacts between FS or LTS interneurons of the neocortex, whose frequency transfer resembles a low-pass filter [ 86 ]. This suggests that electrical transmission between MesV neurons is well suited for the transmission of action potentials, which most probably constitute the main signal source for coupling and promotes the synchronic activation of pairs of MesV neurons [ 99 ].

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    Sunday, September 08, Friday, September 06, Our research is focused on understanding the physiology of presynaptic terminals. We believe that this is important for identifying the first principles underlying biological computation. Specifically: We are developing a new conceptual framework for the dynamic changes in connection strength that occur at essentially every type of chemical synapse during normal use. The dynamic changes are also known as short-term plasticity.

    They are cell autonomous, have a presynaptic origin, and occur with timing of milliseconds to tens of minutes, depending on the recent history of use. The idea is that the new framework will provide a comprehensive method for categorizing the variation, and that this is needed for understanding how information is encoded, processed, stored, and decoded in neural circuits, and may also help elucidate what goes wrong in some diseases. We began by developing assays for each of the rate-limiting steps in vesicle cycling at a variety of central synapses using electrophysiological and optical imaging techniques.