Teneurins instruct synaptic partner matching in an olfactory map

Neurons are interconnected with extraordinary precision to assemble a functional nervous system. Compared to axon guidance, far less is understood about how individual pre- and postsynaptic partners are matched. To ensure the proper relay of olfactory information in the fruitfly Drosophila, axons of ～50 classes of olfactory receptor neurons (ORNs) form one-to-one connections with dendrites of ～50 classes of projection neurons (PNs). Here, using genetic screens, we identified two evolutionarily conserved, epidermal growth factor (EGF)-repeat containing transmembrane Teneurin proteins, Ten-m and Ten-a, as synaptic-partner-matching molecules between PN dendrites and ORN axons. Ten-m and Ten-a are highly expressed in select PN-ORN matching pairs. Teneurin loss- and gain-of-function cause specific mismatching of select ORNs and PNs. Finally, Teneurins promote homophilic interactions in vitro, and Ten-m co-expression in non-partner PNs and ORNs promotes their ectopic connections in vivo. We propose that Teneurins instruct matching specificity between synaptic partners through homophilic attraction.     

An SCF-like ubiquitin ligase complex that controls presynaptic differentiation

During synapse formation, specialized subcellular structures develop at synaptic junctions in a tightly regulated fashion. Cross-signalling initiated by ephrins, Wnts and transforming growth factor-beta family members between presynaptic and postsynaptic termini are proposed to govern synapse formation. It is not well understood how multiple signals are integrated and regulated by developing synaptic termini to control synaptic differentiation. Here we report the identification of FSN-1, a novel F-box protein that is required in presynaptic neurons for the restriction and/or maturation of synapses in Caenorhabditis elegans. Many F-box proteins are target recognition subunits of SCF (Skp, Cullin, F-box) ubiquitin-ligase complexes. fsn-1 functions in the same pathway as rpm-1, a gene encoding a large protein with RING finger domains. FSN-1 physically associates with RPM-1 and the C. elegans homologues of SKP1 and Cullin to form a new type of SCF complex at presynaptic periactive zones. We provide evidence that T10H9.2, which encodes the C. elegans receptor tyrosine kinase ALK (anaplastic lymphoma kinase), may be a target or a downstream effector through which FSN-1 stabilizes synapse formation. This neuron-specific, SCF-like complex therefore provides a localized signal to attenuate presynaptic differentiation.     

Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis

Synapses are specialized intercellular junctions in which cell adhesion molecules connect the presynaptic machinery for neurotransmitter release to the postsynaptic machinery for receptor signalling. Neurotransmitter release requires the presynaptic co-assembly of Ca2+ channels with the secretory apparatus, but little is known about how synaptic components are organized. Alpha-neurexins, a family of >1,000 presynaptic cell-surface proteins encoded by three genes, link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins. Using triple-knockout mice, we show that alpha-neurexins are not required for synapse formation, but are essential for Ca2+-triggered neurotransmitter release. Neurotransmitter release is impaired because synaptic Ca2+ channel function is markedly reduced, although the number of cell-surface Ca2+ channels appears normal. These data suggest that alpha-neurexins organize presynaptic terminals by functionally coupling Ca2+ channels to the presynaptic machinery.     

The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans.

At synaptic junctions, specialized subcellular structures occur in both pre- and postsynaptic cells. Most presynaptic termini contain electron-dense membrane structures, often referred to as active zones, which function in vesicle docking and release. The components of those active zones and how they are formed are largely unknown. We report here that a mutation in the Caenorhabditis elegans syd-2 (for synapse-defective) gene causes a diffused localization of several presynaptic proteins and of a synaptic-vesicle membrane associated green fluorescent protein (GFP) marker. Ultrastructural analysis revealed that the active zones of syd-2 mutants were significantly lengthened, whereas the total number of vesicles per synapse and the number of vesicles at the prominent active zones were comparable to those in wild-type animals. Synaptic transmission is partially impaired in syd-2 mutants. syd-2 encodes a member of the liprin (for LAR-interacting protein) family of proteins which interact with LAR-type (for leukocyte common antigen related) receptor proteins with tyrosine phosphatase activity (RPTPs). SYD-2 protein is localized at presynaptic termini independently of the presence of vesicles, and functions cell autonomously. We propose that SYD-2 regulates the differentiation of presynaptic termini in particular the formation of the active zone, by acting as an intracellular anchor for RPTP signalling at synaptic junctions.     

Presynaptic glycine receptors enhance transmitter release at a mammalian central synapse

Glycine and GABAA (gamma-aminobutyric acid A) receptors are inhibitory neurotransmitter-gated Cl- channels localized in postsynaptic membranes. In some cases, GABAA receptors are also found presynaptically, but they retain their inhibitory effect as their activation reduces excitatory transmitter release. Here we report evidence for presynaptic ionotropic glycine receptors, using pre- and postsynaptic recordings of a calyceal synapse in the medial nucleus of the trapezoid body (MNTB). Unlike the classical action of glycine, presynaptic glycine receptors triggered a weakly depolarizing Cl- current in the nerve terminal. The depolarization enhanced transmitter release by activating Ca2+ channels and increasing resting intraterminal Ca2+ concentrations. Repetitive activation of glycinergic synapses on MNTB neurons also enhanced glutamatergic synaptic currents, indicating that presynaptic glycine receptors are activated by glycine spillover. These results reveal a novel site of action of the transmitter glycine, and indicate that under certain conditions presynaptic Cl- channels may increase transmitter release.     

Lrp4 is a retrograde signal for presynaptic differentiation at neuromuscular synapses

Motor axons receive retrograde signals from skeletal muscle that are essential for the differentiation and stabilization of motor nerve terminals. Identification of these retrograde signals has proved elusive, but their production by muscle depends on the receptor tyrosine kinase, MuSK (muscle, skeletal receptor tyrosine-protein kinase), and Lrp4 (low-density lipoprotein receptor (LDLR)-related protein 4), an LDLR family member that forms a complex with MuSK, binds neural agrin and stimulates MuSK kinase activity. Here we show that Lrp4 also functions as a direct muscle-derived retrograde signal for early steps in presynaptic differentiation. We demonstrate that Lrp4 is necessary, independent of MuSK activation, for presynaptic differentiation in vivo, and we show that Lrp4 binds to motor axons and induces clustering of synaptic-vesicle and active-zone proteins. Thus, Lrp4 acts bidirectionally and coordinates synapse formation by binding agrin, activating MuSK and stimulating postsynaptic differentiation, and functioning in turn as a muscle-derived retrograde signal that is necessary and sufficient for presynaptic differentiation.     

Arachidonic acid induces a long-term activity-dependent enhancement of synaptic transmission in the hippocampus

Long-term potentiation (LTP) is a widely studied model of the synaptic basis of information storage in the mammalian brain. The induction of LTP is triggered by the postsynaptic entry of calcium through the channel associated with the N-methyl-D-aspartate (NMDA) receptor, whereas its maintenance is mediated, at least in part, by presynaptic mechanisms. To explain how postsynaptic events can lead to an increase in transmitter release, we have postulated the existence of a retrograde messenger to carry information from the postsynaptic side of the synapse to recently active presynaptic terminals. Candidates for a retrograde messenger include arachidonic acid or one of its lipoxygenase metabolites. Here we report that weak activation of the perforant path, when given in the presence of arachidonic acid, leads to a slow-onset persistent increase in synaptic efficacy both in vivo and in vitro. The activity-dependent potentiation thus produced is accompanied by an increase in the release of glutamate, and is non-additive with tetanus-induced LTP. These observations indicate a role for arachidonic acid as a retrograde messenger in the later, but not the initial, stages of LTP.     

Presynaptic release probability influences the locus of long-term potentiation.

The quantal hypothesis proposes that chemical synaptic transmission involves the probabilistic release of multimolecular packets of transmitter. Analysis of the resulting trial-to-trial fluctuations in postsynaptic response can provide estimates both of the number of quanta released and of the size of their postsynaptic effect. This in turn permits the quantification of the relative contributions of pre- and postsynaptic factors to the strength of a given synapse. Quantal analysis of excitatory synapses in the hippocampus has proved difficult and has led to contradictory conclusions when applied to long-term potentiation. Here we report the use of a combination of quantal analysis procedures to provide evidence that both pre- and postsynaptic changes can contribute substantially to the maintenance of long-term potentiation in the CA1 region of the hippocampus. The initial setting of the presynaptic release mechanism seems to determine their relative importance.     

Possible role of acetylcholinesterase in regulation of postsynaptic receptor efficacy at a central inhibitory synapse of Aplysia

Most of the effects of acetylcholinesterase (AChE) on synaptic transmission are considered to be related to its acetylcholine (ACh) hydrolysing properties. This is clearly apparent from changes which occur in the characteristics of the miniature endplate potential and of the endplate potential at neuromuscular junctions when AChE is inhibited1-4 and during the development of enzymatic AChE activity at maturing synapses5. However, we report here that after inhibiting AChE in a cholinergic synapse in Aplysia, we found an increase not only in postsynaptic responses to presynaptic stimulation and to ionophoretic application of ACh on postsynaptic receptors, but also to ionophoretic application of carbachol. This could not be explained by the inhibition of the ACh hydrolysing function of the enzyme, as carbachol is not hydrolysed by AChE. A possible explanation of these observations is that inhibition of the enzyme affects a property of the ACh receptor (AChR) itself.     

Neuroligins and neurexins link synaptic function to cognitive disease

The brain processes information by transmitting signals at synapses, which connect neurons into vast networks of communicating cells. In these networks, synapses not only transmit signals but also transform and refine them. Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions. In humans, alterations in genes encoding neurexins or neuroligins have recently been implicated in autism and other cognitive diseases, linking synaptic cell adhesion to cognition and its disorders.     

The architecture of active zone material at the frog's neuromuscular junction

Active zone material at the nervous system's synapses is situated next to synaptic vesicles that are docked at the presynaptic plasma membrane, and calcium channels that are anchored in the membrane. Here we use electron microscope tomography to show the arrangement and associations of structural components of this compact organelle at a model synapse, the frog's neuromuscular junction. Our findings indicate that the active zone material helps to dock the vesicles and anchor the channels, and that its architecture provides both a particular spatial relationship and a structural linkage between them. The structural linkage may include proteins that mediate the calcium-triggered exocytosis of neurotransmitter by the synaptic vesicles during synaptic transmission.     

Postsynaptic hyperpolarization during conditioning reversibly blocks induction of long-term potentiation

Activity-induced changes in the efficacy of synaptic transmission between neurones are central to several prominent theories of learning. In both in vivo and in vitro preparations of the hippocampus, a conditioning high-frequency stimulus delivered to afferent fibres results in a long-term potentiation of synaptic transmission at those inputs. Evidence has been provided supporting both presynaptic and postsynaptic sites as loci where critical events occur in the development of potentiation. In this study we report that long-term potentiation is reversibly blocked by intracellular injection of hyperpolarizing current in the postsynaptic cell during the conditioning high-frequency stimulus, suggesting the involvement of a voltage-dependent postsynaptic mechanism.     

短时程突触可塑性的简化模型

给出了一类包含抑制和易化的短时程突触可塑性的简化模型.分别讨论了突触前发放为周期和Poisson电位脉冲串时,突触后的神经元的抑制和易化机制,并给出了定性分析和数值结果的比较.进一步发现在相同的突触前发放频率下,随机模型使得突触后神经元发放的易化和抑制的参数范围比周期模型的参数范围大.     

Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition

Synaptic activity drives synaptic rearrangement in the vertebrate nervous system; indeed, this appears to be a main way in which experience shapes neural connectivity. One rearrangement that occurs in many parts of the nervous system during early postnatal life is a competitive process called 'synapse elimination'. At the neuromuscular junction, where synapse elimination has been analysed in detail, muscle fibres are initially innervated by multiple axons, then all but one are withdrawn and the 'winner' enlarges. In support of the idea that synapse elimination is activity dependent, it is slowed or speeded when total neuromuscular activity is decreased or increased, respectively. However, most hypotheses about synaptic rearrangement postulate that change depends less on total activity than on the relative activity of the competitors. Intuitively, it seems that the input best able to excite its postsynaptic target would be most likely to win the competition, but some theories and results make other predictions. Here we use a genetic method to selectively inhibit neurotransmission from one of two inputs to a single target cell. We show that more powerful inputs are strongly favoured competitors during synapse elimination.     

The mechanism of rectification at the electrotonic motor giant synapse of the crayfish

The synapse between the giant interneurone and the motor giant axon of the crayfish is a well-known example of the rare class of current-rectifying electrotonic synapses. One early proposal for the basis of this rectification was that rectifying junctions are like diodes. Biological correlates of diodes can exist, such as constant-field channels which rectify by very high-speed rearrangements of charge carriers, but these require high selectivity and large concentration gradients. Electrotonic synapses are believed to be composed of wide-bore (1-2 nm) gap-junction channels which have poor selectivity and bridge similar intracellular compartments. An alternative mechanism for rectification would be by voltage-dependent gates that sense trans-synaptic potential. These two mechanisms can be distinguished because a diode should rectify instantaneously (on a biological time-scale) while a gated channel should show kinetic processes. Although a gating model is more consistent with the known behaviour of channels than a diode model, previous work has failed to find any time course for the rectification. We have now developed a high-quality voltage clamp and by working at reduced temperatures we are able to demonstrate channel kinetics. These results support the hypothesis that this rectifying synapse contains voltage-dependent gates.     

RIM1alpha forms a protein scaffold for regulating neurotransmitter release at the active zone.

Neurotransmitters are released by synaptic vesicle fusion at the active zone. The active zone of a synapse mediates Ca2+-triggered neurotransmitter release, and integrates presynaptic signals in regulating this release. Much is known about the structure of active zones and synaptic vesicles, but the functional relation between their components is poorly understood. Here we show that RIM1alpha, an active zone protein that was identified as a putative effector for the synaptic vesicle protein Rab3A, interacts with several active zone molecules, including Munc13-1 (ref. 6) and alpha-liprins, to form a protein scaffold in the presynaptic nerve terminal. Abolishing the expression of RIM1alpha in mice shows that RIM1alpha is essential for maintaining normal probability of neurotransmitter release, and for regulating release during short-term synaptic plasticity. These data indicate that RIM1alpha has a central function in integrating active zone proteins and synaptic vesicles into a molecular scaffold that controls neurotransmitter release.     

Dendritic spines as individual neuronal compartments for synaptic Ca2+ responses.

The possibility that postsynaptic spines on neuronal dendrites are discrete biochemical compartments for Ca(2+)-activated processes involved in synaptic plasticity is a widely proposed concept that has eluded experimental demonstration. Using microfluorometry on CA3 neurons in hippocampal slices, we show here that with weak presynaptic stimulation of associative/commissural fibres, Ca2+ accumulates in single postsynaptic spines but not in the parent dendrite. Stronger stimulation also promotes changes in dendrites. The NMDA-receptor antagonist AP-5 blocks changes in Ca2+ in spines. Sustained steep Ca2+ gradients between single spines and the parent dendrite, often lasting several minutes, develop with repeated stimulation. The observed compartmentalization allows for the specificity, cooperativity and associativity displayed by memory models such as long-term potentiation.     

High-fidelity transmission of sensory information by single cerebellar mossy fibre boutons

Understanding the transmission of sensory information at individual synaptic connections requires knowledge of the properties of presynaptic terminals and their patterns of firing evoked by sensory stimuli. Such information has been difficult to obtain because of the small size and inaccessibility of nerve terminals in the central nervous system. Here we show, by making direct patch-clamp recordings in vivo from cerebellar mossy fibre boutons-the primary source of synaptic input to the cerebellar cortex-that sensory stimulation can produce bursts of spikes in single boutons at very high instantaneous firing frequencies (more than 700 Hz). We show that the mossy fibre-granule cell synapse exhibits high-fidelity transmission at these frequencies, indicating that the rapid burst of excitatory postsynaptic currents underlying the sensory-evoked response of granule cells can be driven by such a presynaptic spike burst. We also demonstrate that a single mossy fibre can trigger action potential bursts in granule cells in vitro when driven with in vivo firing patterns. These findings suggest that the relay from mossy fibre to granule cell can act in a 'detonator' fashion, such that a single presynaptic afferent may be sufficient to transmit the sensory message. This endows the cerebellar mossy fibre system with remarkable sensitivity and high fidelity in the transmission of sensory information.     

A dynamical system-Markov model for active postsynaptic responses of muscle spindle afferent nerve

Motoneuron is the control unit of skeletal muscles,and the dynamic frequency-regulating feedback from the afferent nerve of receptors like muscle spindles forms the physical basis of its closed-loop regulation.Focused on the synapses of muscle spindle afferents,this paper established a dynamical system-Markov model starting from presynaptic stimulations to postsynaptic responses,and further verified the model via comparisons between theoretical results and relevant experimental data.With the purpose of describing the active features of dendritic membrane,we employed the methods of dynamical systems rather than the traditional passive cable theory,and identified the physical meaning of parameters involved.For the dynamic behavior of postsynaptic currents,we adopted simplified Markov models so that the analytical solutions for the open dynamics of postsynaptic receptors can be obtained.The model in this paper is capable of simulating the actual non-uniformity of channel density,and is suitable for complex finite element analysis of neurons;thus it facilitates the exploration of the frequency-regulating feedback and control mechanisms of motoneurons.     

Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain

The induction of associative synaptic plasticity in the mammalian central nervous system classically depends on coincident presynaptic and postsynaptic activity. According to this principle, associative homosynaptic long-term potentiation (LTP) of excitatory synaptic transmission can be induced only if synaptic release occurs during postsynaptic depolarization. In contrast, heterosynaptic plasticity in mammals is considered to rely on activity-independent, non-associative processes. Here we describe a novel mechanism underlying the induction of associative LTP in the lateral amygdala (LA). Simultaneous activation of converging cortical and thalamic afferents specifically induced associative, N-methyl-D-aspartate (NMDA)-receptor-dependent LTP at cortical, but not at thalamic, inputs. Surprisingly, the induction of associative LTP at cortical inputs was completely independent of postsynaptic activity, including depolarization, postsynaptic NMDA receptor activation or an increase in postsynaptic Ca2+ concentration, and did not require network activity. LTP expression was mediated by a persistent increase in the presynaptic probability of release at cortical afferents. Our study shows the presynaptic induction and expression of heterosynaptic and associative synaptic plasticity on simultaneous activity of converging afferents. Our data indicate that input specificity of associative LTP can be determined exclusively by presynaptic properties.