Associative short-term synaptic plasticity mediated by endocannabinoids

Associative learning is important on rapid timescales, but no suitable form of short-term plasticity has been identified that is both associative and synapse specific. Here, we assess whether endocannabinoids can mediate such plasticity. In the cerebellum, bursts of parallel fiber (PF) activity evoke endocannabinoid release from Purkinje cell dendrites that results in retrograde synaptic inhibition lasting seconds. We find that the powerful climbing fiber (CF) to Purkinje cell synapse regulates this inhibition. Compared to PF stimulation alone, coactivation of PF and CF synapses greatly enhanced endocannabinoid-mediated inhibition of PF synapses. Retrograde inhibition was restricted to PFs activated within several hundred milliseconds of CF activation. This associative plasticity reflects two aspects of calcium-dependent endocannabinoid release. First, PF-mediated activation of metabotropic glutamate receptors locally reduced the dendritic calcium levels required for endocannabinoid release. Second, CF and PF coactivation evoked localized supralinear dendritic calcium signals. Thus, endocannabinoids mediate transient associative synaptic plasticity.     

Functional diversity on synaptic plasticity mediated by endocannabinoids

Endocannabinoids (eCBs) act as modulators of synaptic transmission through activation of a number of receptors, including, but not limited to, cannabinoid receptor 1 (CB1). eCBs share CB1 receptors as a common target with Δ⁹-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Although THC has been used for recreational and medicinal purposes for thousands of years, little was known about its effects at the cellular level or on neuronal circuits. Identification of CB1 receptors and the subsequent development of its specific ligands has therefore enhanced our ability to study and bring together a substantial amount of knowledge regarding how marijuana and eCBs modify interneuronal communication. To date, the eCB system, composed of cannabinoid receptors, ligands and the relevant enzymes, is recognized as the best-described retrograde signalling system in the brain. Its impact on synaptic transmission is widespread and more diverse than initially thought. The aim of this review is to succinctly present the most common forms of eCB-mediated modulation of synaptic transmission, while also illustrating the multiplicity of effects resulting from specializations of this signalling system at the circuital level.     

Calcium and endocannabinoids in the modulation of inhibitory synaptic transmission

Synapses in the central nervous system can be highly plastic devices, being able to modify their efficacy in relaying information in response to several factors. Calcium ions are often fundamental in triggering synaptic plasticity. Here, we will shortly review the effects induced by postsynaptic increases of calcium concentration at GABAergic and glycinergic synapses. Both postsynaptic and presynaptic mechanisms mediating changes in synaptic strength will be examined. Particular attention will be devoted to phenomena of retrograde signaling and, specifically, to the recently discovered role, played by the endocannabinoid system in retrograde synaptic modulation.     

Characteristics and plasticity of electrical synaptic transmission

Electrical synapses are an omnipresent feature of nervous systems, from the simple nerve nets of cnidarians to complex brains of mammals. Formed by gap junction channels between neurons, electrical synapses allow direct transmission of voltage signals between coupled cells. The relative simplicity of this arrangement belies the sophistication of these synapses. Coupling via electrical synapses can be regulated by a variety of mechanisms on times scales ranging from milliseconds to days, and active properties of the coupled neurons can impart emergent properties such as signal amplification, phase shifts and frequency-selective transmission. This article reviews the biophysical characteristics of electrical synapses and some of the core mechanisms that control their plasticity in the vertebrate central nervous system.     

Mathematical theory of chemical synaptic transmission

Mathematical theory of chemical synaptic transmission is suggested in which the modes of operation of chemical synapses are given as consequencies of some fundamental theoretical principles presented in the form of systems of quantum and macroscopic postulates. These postulates establish transmitter transfer rules between 3 component parts — cytoplasmic, vesicular and external pools of neurotransmitter. The main features of the transfers are determined by special properties of the dividing membranes (synaptic and vesicle) which show high selectivity towards the direction of the transmitter quantum transfer. The formulation of a previously unknown effect of transmitter quantum transfer from the vesicular pool into the cytoplasmic one is introduced: it is postulated that each arriving presynaptic impulse not only releases a constant fraction of the current contents of the cytoplasmic pool into the synaptic cleft (external pool), but also realizes practically simultaneous transmitter transfer from the vesicular pool into the cytoplasmic one. Zone structure of the vesicular pool is postulated. In accordance with basic equations of the theory a nonlinear control system (dynamic synaptic modulator — DYSYM) of transmitter release from the terminal is constructed.Depending on the parameters relation two types of synapses are classified — those with rapid and slow demobilization. Analytical dependencies of the transmitter pools sizes on the stimulation frequency are introduced. By fitting the frequency dependencies to the empirical data model parameters are determined corresponding to a set of experimentally studied synaptic junctions. Different aspects of the chemical synapse behaviour under the influence of presynaptic stimulation are simulated.     

Effects of transition metal ions on spontaneous electrical activity and chemical synaptic transmission of neurons in the medicinal leech

Leech neurons exposed to salines containing inorganic Ca²⁺-channel blockers generate rhythmic bursts of impulses. According to an earlier model, these blockers unmask persistent Na⁺ currents that generate plateau-like depolarizations, each triggering a burst of impulses. The resulting increase in intracellular Na⁺ activates an outward Na⁺/K⁺ pump current that contributes to burst termination. We tested this model by examining systematically the effects of six transition metal ions (Co²⁺, Ni²⁺, Mn²⁺, Cd²⁺, La³⁺, and Zn²⁺) on the electrical activity of neurons in isolated leech ganglia. Each ion induced bursting activity, but the amplitude, form, and persistence of bursting differed with the ion used and its concentration relative to Ca²⁺. All ions tested suppressed chemical synaptic transmission between identified motor neurons, consistent with block of voltage-dependent Ca²⁺ currents in these cells. In addition, a strong correlation between suppression of synaptic transmission and burst amplitudes was obtained. Finally, burst duration was increased and the rate of repolarization decreased in reduced K⁺ saline, as expected for pump-dependent repolarization. These results provide further support for the hypothesis that a novel form of oscillatory electrical activity driven by persistent Na⁺ currents and the Na⁺/K⁺ pump occurs in leech ganglia exposed to Ca²⁺-channel blockers. Accepted: 15 May 1997     

Rapid and reversible chemical inactivation of synaptic transmission in genetically targeted neurons

Inducible and reversible silencing of selected neurons in vivo is critical to understanding the structure and dynamics of brain circuits. We have developed Molecules for Inactivation of Synaptic Transmission (MISTs) that can be genetically targeted to allow the reversible inactivation of neurotransmitter release. MISTs consist of modified presynaptic proteins that interfere with the synaptic vesicle cycle when crosslinked by small molecule "dimerizers." MISTs based on the vesicle proteins VAMP2/Synaptobrevin and Synaptophysin induced rapid ( approximately 10 min) and reversible block of synaptic transmission in cultured neurons and brain slices. In transgenic mice expressing MISTs selectively in Purkinje neurons, administration of dimerizer reduced learning and performance of the rotarod behavior. MISTs allow for specific, inducible, and reversible lesions in neuronal circuits and may provide treatment of disorders associated with neuronal hyperactivity.     

Potentiation of glutamatergic synaptic input to supraoptic neurons by presynaptic nicotinic receptors

The release of vasopressin and oxytocin from the supraoptic nucleus (SON) neurons is tonically regulated by excitatory glutamatergic and inhibitory GABAergic synaptic inputs. Acetylcholine is known to excite SON neurons and to elicit vasopressin release. Cholinergic receptors are located pre- and postsynaptically in the SON, but their functional significance in the regulation of SON neurons is not fully understood. In this study, we determined the role of presynaptic cholinergic receptors in regulation of the excitatory glutamatergic inputs to the SON neurons. The magnocellular neurons in the rat hypothalamic slices were identified microscopically, and the spontaneous miniature excitatory postsynaptic currents (mEPSCs) were recorded using the whole cell voltage-clamp technique. The mEPSCs were abolished by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (20 microM). Acetylcholine (100 microM) significantly increased the frequency of mEPSCs of 38 SON neurons from 1.87 +/- 0.36 to 3.42 +/- 0.54 Hz but did not alter the amplitude (from 19.61 +/- 0.90 to 19.34 +/- 0.84 pA) and the decay time constant of mEPSCs. Furthermore, the nicotinic receptor antagonist mecamylamine (10 microM, n = 16), but not the muscarinic receptor antagonist atropine (100 microM, n = 12), abolished the excitatory effect of acetylcholine on the frequency of mEPSCs. These data provide new information that the excitatory effect of acetylcholine on the SON neurons is mediated, at least in part, by its effect on presynaptic glutamate release. Activation of presynaptic nicotinic, but not muscarinic, receptors located in the glutamatergic terminals increases the excitatory synaptic input to the SON neurons of the hypothalamus.     

Acute modulation of calcium currents and synaptic transmission by gabapentinoids

Gabapentin and pregabalin are anticonvulsant drugs that are extensively used for the treatment of several neurological and psychiatric disorders. Gabapentinoids (GBPs) are known to have a high affinity binding to α2δ-1 and α2δ-2 auxiliary subunit of specific voltage-gated calcium channels. Despite the confusing effects reported on Ca (2+) currents, most of the studies showed that GBPs reduced release of various neurotransmitters from synapses in several neuronal tissues. We showed that acute in vitro application of pregabalin can reduce in a dose dependent manner synaptic transmission in both neuromuscular junctions and calyx of Held-MNTB excitatory synapses. Furthermore presynaptic Ca (2+) currents treated with pregabalin are reduced in amplitude, do not show inactivation at a clinically relevant low concentration of 100 μM and activate and deactivate faster. These results suggest novel modulatory role of acute pregabalin that might contribute to better understanding its anticonvulsant/analgesic clinical effects.     

突触长时程增强形成与学习记忆的相关研究

突触长时程增强(LTP)的形成与学习记忆有相似特征,将其作为记忆的一种模式加以研究,并深入探索LTP机制产生与静止突触的关系,长时程突触修饰与突触后神经细胞内Ca^2 的作用机制,学习行为后海马内出现的突触效能变化与行为学习之间的关系,以及BDNF对海马突触的LTP调节与长时记忆所涉及关于LTP的相关基因表达。     

Neuronal responses mediated by activation of the non-NMDA receptors: Potentiation by nootropes

Experiments on superfused slices of rat hippocampus showed that the nootropic drugs pyracetam, ethymizol, ambocarb, and nooglutil increase the amplitude of populational EPSP (pEPSP) of neurons of the dentate gyrus evoked by electrical stimulation of the perforant pathway (PP). Nootropes exert no effect on the process of presynaptic glutamate liberation from the PP axons, but increase the chemosensitivity of the postsynaptic AMPA/kainate receptors mediating EPSP generation in the dentate gyrus neurons. Inhibitors of protein kinase (A-buthamide) and guanylatecyclase (methylene blue) do not modify the effects of nootropes. The nootrope-induced potentiation of pEPSP does not develop against the background of the application of calmodulin inhibitor W-7. In the presence of protein kinase inhibitor C, polymixin B, nootropes reversibly depress pEPSP in the dentate gyrus neurons. Blocking of the NMDA receptor ionic channels by ketamine and of the voltage-dependent T-type calcium channels by Ni²⁺ does not significantly modify the effects of nootropic drugs. A blocker of Ca²⁺-ATPase of the Ca²⁺ stores sodium orthovanadate, potentiates the effects of nootropes. Dantrolene, which disrupts Ca²⁺ liberation from the non-mitochondrical depots, blocks the effects of nootropes and diminishes pEPSP depression evoked by nootropes in the presence of polymixin B. On the basis of presented data, it is supposed that nootropic drugs assist Ca²⁺ liberation from the neuronal depots and activate calmodulin-dependent protein kinase and protein kinase C. Protein kinases phosphorylate the intracellular domains of the AMPA/kainate receptors, and this process results in an increase in their sensitivity to excitatory amino acids.Neirofiziologiya/Neurophysiology, Vol. 26, No. 5, pp. 365–372, September–October, 1994.     

Depression of glutamate-mediated synaptic transmission by benzyl alcohol.

The data obtained from this study suggest that the nonionizable anesthetic benzyl alcohol has two prominent actions on GABA- and glutamate-mediated synaptic transmission at the lobster neuromuscular junction. They are as follows: (1) depression of the excitatory end-plate potential and the postsynaptic membrane response to applied glutamate, and (2) a hyperpolarization of the postsynaptic resting membrane potential associated with a decrease in effective membrane resistance. No change in amplitude of the inhibitory end-plate potential or inhibitory reversal potential was seen. Excitatory miniature end-plate potential frequency was also unaffected. The depression of excitatory synaptic transmission appears to be due to a decreased responsiveness of the postsynaptic receptor-ionophore complex.     

Control of neural information transmission by synaptic dynamics.

The computational processing of a neural system is strongly influenced by the dynamical characteristics of the information transmission between neurons. In this work, the control of neural information transmission by synaptic dynamics is investigated by means of a master-equation-based stochastic model of pre-synaptic release of neurotransmitter-containing vesicles. The model incorporates facilitation of vesicle fusion with the pre-synaptic membrane due to intracellular calcium ions and depletion of readily releasable vesicles. The message to be transmitted is coded by the pre-synaptic firing sequence, and the received signal corresponds to the post-synaptic membrane potential response. At the sending end, the stochastic character of the vesicle release contributes to the entropy of the probability distribution of the number of vesicles released and represents noise with respect to information transmission. At the receiving end, the generation of post-synaptic membrane potentials is influenced by the temporal behaviour of ionic currents and membrane charging and is determined by means of a low-dimensional model. The rate and temporal types of neural coding are compatible with limiting cases of the synaptic information transmission as a function of initial vesicle release probability and pre-synaptic firing rate. The effects of the nonlinear dependencies of the vesicle release probability on intracellular calcium concentration and number of available vesicles are analysed. The model is compared with phenomenological and reduced models, a principal advantage being the capability of also determining fluctuations of dynamic variables Copyright 2002 Academic Press.     

Bi-directional modulation of fast inhibitory synaptic transmission by leptin

The hormone leptin has widespread actions in the CNS. Indeed, leptin markedly influences hippocampal excitatory synaptic transmission and synaptic plasticity. However, the effects of leptin on fast inhibitory synaptic transmission in the hippocampus have not been evaluated. Here, we show that leptin modulates GABA_A receptor-mediated synaptic transmission onto hippocampal CA1 pyramidal cells. Leptin promotes a rapid and reversible increase in the amplitude of evoked GABA_A receptor-mediated inhibitory synaptic currents (IPSCs); an effect that was paralleled by increases in the frequency and amplitude of miniature IPSCs, but with no change in paired pulse ratio or coefficient of variation, suggesting a post-synaptic expression mechanism. Following washout of leptin, a persistent depression (inhibitory long-lasting depression) of evoked IPSCs was observed. Whole-cell dialysis or bath application of inhibitors of phosphoinositide 3 (PI 3)-kinase or Akt prevented leptin-induced enhancement of IPSCs indicating involvement of a post-synaptic PI 3-kinase/Akt-dependent pathway. In contrast, blockade of PI 3-kinase or Akt activity failed to alter the ability of leptin to induce inhibitory long-lasting depression, suggesting that this process is independent of PI 3-kinase/Akt. In conclusion these data indicate that the hormone leptin bi-directionally modulates GABA_A receptor-mediated synaptic transmission in the hippocampus. These findings have important implications for the role of this hormone in regulating hippocampal pyramidal neuron excitability.     

Control of excitatory synaptic transmission by C-terminal Src kinase

The induction of long-term potentiation at CA3-CA1 synapses is caused by an N-methyl-d-aspartate (NMDA) receptordependent accumulation of intracellular Ca(2+), followed by Src family kinase activation and a positive feedback enhancement of NMDA receptors (NMDARs). Nevertheless, the amplitude of baseline transmission remains remarkably constant even though low frequency stimulation is also associated with an NMDAR-dependent influx of Ca(2+) into dendritic spines. We show here that an interaction between C-terminal Src kinase (Csk) and NMDARs controls the Src-dependent regulation of NMDAR activity. Csk associates with the NMDAR signaling complex in the adult brain, inhibiting the Src-dependent potentiation of NMDARs in CA1 neurons and attenuating the Src-dependent induction of long-term potentiation. Csk associates directly with Src-phosphorylated NR2 subunits in vitro. An inhibitory antibody for Csk disrupts this physical association, potentiates NMDAR mediated excitatory postsynaptic currents, and induces long-term potentiation at CA3-CA1 synapses. Thus, Csk serves to maintain the constancy of baseline excitatory synaptic transmission by inhibiting Src kinase-dependent synaptic plasticity in the hippocampus.     

Neurotrophin regulation of synaptic transmission

Examples of signaling molecules that are devoted to neuronal development at the exclusion of other functions are scarce. It may then come as no surprise to learn that a family of molecules that promote neuronal survival, differentiation and outgrowth also regulate synaptic transmission at both developing and mature synapses. Indeed, many studies over the past five years have shown that neurotrophins, including nerve growth factor (NGF), neurotrophin-3 (NT-3), NT-4/5 and brain-derived neurotrophic factor (BDNF), have both rapid and long-latency influences on synaptic strength. New research has highlighted the enormous range of neurotrophin actions at both developing and mature synapses, demonstrating that transmission can be enhanced or reduced at excitatory and inhibitory synapses by either pre- or postsynaptic mechanisms.