Role of the synaptic microenvironment in functional modification of synaptic transmission

Experiments on hippocampal slices showed that perfusion with a dextran solution more effectively facilitates AMPA-mediated transmission in structurally complex synapses of mossy fibers of Shaffer collaterals. Estimates for changes in the extracellular Ca²⁺ concentration in the close vicinity of a reconstructed synapse during the action potential development are obtained. The results together with data about the rather small (0.5 μm) characteristics distance between neighboring synapses showed that the probability of mutual intersynaptic influence via the microenvironment is high. A probable functional role of such influences is discussed.     

A non-linear model for the synaptic basis of neuronal memory.

We propose a mathematical model for the synaptic basis of neuronal memory. The model incorporates non-linear effects in analogy with population growth problems of human beings, animals, biological species, crystal growth, etc., and provides a mechanism whereby the excitatory and inhibitory inputs produce alterations in a neurone which result in a long-lasting increase in transmitter release at a synapse.     

Syntaxin-1通过激活突触递质传递加速早期突触的形成

Syntaxin-1是一种多结构域蛋白,通过与synaptobrevin-2和SNAP-25形成SNARE复合体调节囊泡融合.然而,syntaxin-1在突触形成过程中是否发挥作用,目前尚不清楚.本研究显示syntaxin-1的表达水平与突触形成过程高度相关.Syntaxin-1的R151A和I155A突变影响其在突触形成中的促进作用,而Habc结构域或跨膜结构域在突触形成中无显著作用.结果表明,syntaxin-1通过激活突触囊泡释放来加速突触的形成.     

A model of synaptic memory: a CaMKII/PP1 switch that potentiates transmission by organizing an AMPA receptor anchoring assembly

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is localized in the postsynaptic density (PSD) and is necessary for LTP induction. Much has been learned about the autophosphorylation of CaMKII and its dephosphorylation by PSD protein phosphatase-1 (PP1). Here, we show how the CaMKII/PP1 system could function as an energy-efficient, bistable switch that could be activated during LTP induction and remain active despite protein turnover. We also suggest how recently discovered binding interactions could provide a structural readout mechanism: the autophosphorylated state of CaMKII binds tightly to the NMDAR and forms, through CaMKII-actinin-actin-(4.1/SAP97) linkages, additional sites for anchoring AMPARs at synapses. The proposed model has substantial experimental support and elucidates principles by which a local protein complex could produce stable information storage and readout.     

Learning-related long-term synaptic facilitation in snails: Possible mechanisms of long-term memory formation

The long-term changes in the electrical activity of command neurons related to sensitization and elaboration of associative defensive behavioral habit (food rejection) were studied inHelix snail. The long-term effects consisted of facilitation of synaptic components in neuronal responses to the test stimulations. Variations were found in the dynamics of long-term synaptic facilitation of responses to the applied chemical and tactile stimuli in the course of sensitization, as well as dependence of the degree of long-term facilitation of responses to the test stimulation at the site of its application with respect to the site of the sensitizing stimulation (site-specific sensitization). After conditioning, the synaptic response of command neurons to the conditioning stimulation appeared approximately 30 min later than did the long-term sensitization in these cells. The minimum duration of long-term synaptic facilitation of responses to the test stimulation varied from 1 h (for tactile stimulation) to 3 h (for chemical stimulation). The maximum duration of effects exceeded 4 h. It is suggested that the observed features of the synaptic plasticity in command neurons during learning are based on the selective regulation of synaptic inputs by specific protein regulators, whose lifespan does not exceed 1 h to 3 h.Neirofiziologiya/Neurophysiology, Vol. 25, No. 5, pp. 383–389, September–October, 1993.     

Statistical analysis of synaptic transmission: model discrimination and confidence limits.

Procedures for discriminating between competing statistical models of synaptic transmission, and for providing confidence limits on the parameters of these models, have been developed. These procedures were tested against simulated data and were used to analyze the fluctuations in synaptic currents evoked in hippocampal neurones. All models were fitted to data using the Expectation-Maximization algorithm and a maximum likelihood criterion. Competing models were evaluated using the log-likelihood ratio (Wilks statistic). When the competing models were not nested, Monte Carlo sampling of the model used as the null hypothesis (H0) provided density functions against which H0 and the alternate model (H1) were tested. The statistic for the log-likelihood ratio was determined from the fit of H0 and H1 to these probability densities. This statistic was used to determine the significance level at which H0 could be rejected for the original data. When the competing models were nested, log-likelihood ratios and the chi 2 statistic were used to determine the confidence level for rejection. Once the model that provided the best statistical fit to the data was identified, many estimates for the model parameters were calculated by resampling the original data. Bootstrap techniques were then used to obtain the confidence limits of these parameters.     

Distinct neuronal coding schemes in memory revealed by selective erasure of fast synchronous synaptic transmission

Neurons encode information by firing spikes in isolation or bursts and propagate information by spike-triggered neurotransmitter release that initiates synaptic transmission. Isolated spikes trigger neurotransmitter release unreliably but with high temporal precision. In contrast, bursts of spikes trigger neurotransmission reliably (i.e., boost transmission fidelity), but the resulting synaptic responses are temporally imprecise. However, the relative physiological importance of different spike-firing modes remains unclear. Here, we show that knockdown of synaptotagmin-1, the major Ca(2+) sensor for neurotransmitter release, abrogated neurotransmission evoked by isolated spikes but only delayed, without abolishing, neurotransmission evoked by bursts of spikes. Nevertheless, knockdown of synaptotagmin-1 in the hippocampal CA1 region did not impede acquisition of recent contextual fear memories, although it did impair the precision of such memories. In contrast, knockdown of synaptotagmin-1 in the prefrontal cortex impaired all remote fear memories. These results indicate that different brain circuits and types of memory employ distinct spike-coding schemes to encode and transmit information.     

Cyclin E constrains Cdk5 activity to regulate synaptic plasticity and memory formation

Cyclin E is a component of the core cell cycle machinery, and it drives cell proliferation by regulating entry and progression of cells through the DNA synthesis phase. Cyclin E expression is normally restricted to proliferating cells. However, high levels of cyclin E are expressed in the adult brain. The function of cyclin E in quiescent, postmitotic nervous system remains unknown. Here we use a combination of in?vivo quantitative proteomics and analyses of cyclin E knockout mice to demonstrate that in terminally differentiated neurons cyclin E forms complexes with Cdk5 and controls synapse function by restraining Cdk5 activity. Ablation of cyclin E led to?a decreased number of synapses, reduced number and volume of dendritic spines, and resulted in impaired synaptic plasticity and memory formation in cyclin E-deficient animals. These results reveal a cell cycle-independent role for a core cell cycle protein, cyclin E, in synapse function and memory.     

Gene control of synaptic plasticity and memory formation: implications for diseases and therapeutic strategies

There has been nearly a century of interest in the idea that information is stored in the brain as changes in the efficacy of synaptic connections between neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular and molecular bases of learning and memory. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. Here we briefly review these mechanisms and illustrate with a few examples of animal models of neurological disorders how new knowledge about these mechanisms can provide valuable insights into identifying the mechanisms that go awry when memory is deficient, and how, in turn, characterisation of the dysfunctional mechanisms offers prospects to design and evaluate molecular and biobehavioural strategies for therapeutic prevention and rescue.     

Long-lasting synaptic potentials and the modulation of synaptic transmission.

Long-lasting postsynaptic potentials (PSPs) generated by decreases in membrane conductance (permeability) have been reported in many types of neurons. We investigated the possible role of such long-lasting decreases in membrane conductance in the modulation of synaptic transmission in the sympathetic ganglion of the bullfrog. The molecular basis by which such conductance-decrease PSPs are generated was also investigated. Synaptic activation of muscarinic cholinergic receptors on these sympathetic neurons results in the generation of a slow EPSP (excitatory postsynaptic potential), which is accompanied by a decrease in membrane conductance. We found that the conventional "fast" EPSPs were increased in amplitude and duration during the iontophoretic application of methacholine, which activates the muscarinic postsynaptic receptors. A similar result was obtained when a noncholinergic conductance-decrease PSP--the late-slow EPSP--was elicited by stimulation of a separate synaptic pathway. The enhancement of fast EPSP amplitude increased the probability of postsynaptic action potential generation, thus increasing the efficacy of impulse transmission across the synapse. Stimulation of one synaptic pathway is therefore capable of increasing the efficacy of synaptic transmission in a second synaptic pathway by a postsynaptic mechanism. Furthermore, this enhancement of synaptic efficacy is long-lasting by virtue of the long duration of the slow PSP. Biochemical and electrophysiological techniques were used to investigate whether cyclic nucleotides are intracellular second messengers mediating the membrane permeability changes underlying slow-PSP generation. Stimulation of the synaptic inputs, which lead to the generation of the slow-PSPs, increased the ganglionic content of both cyclic AMP and cyclic GMP. However, electrophysiological analysis of the actions of these cyclic nucleotides and the actions of agents that affect their metabolism does not provide support for such a second messenger role for either cyclic nucleotide.     

Homeostatic control of synaptic rewiring in recurrent networks induces the formation of stable memory engrams

Brain networks store new memories using functional and structural synaptic plasticity. Memory formation is generally attributed to Hebbian plasticity, while homeostatic plasticity is thought to have an ancillary role in stabilizing network dynamics. Here we report that homeostatic plasticity alone can also lead to the formation of stable memories. We analyze this phenomenon using a new theory of network remodeling, combined with numerical simulations of recurrent spiking neural networks that exhibit structural plasticity based on firing rate homeostasis. These networks are able to store repeatedly presented patterns and recall them upon the presentation of incomplete cues. Storage is fast, governed by the homeostatic drift. In contrast, forgetting is slow, driven by a diffusion process. Joint stimulation of neurons induces the growth of associative connections between them, leading to the formation of memory engrams. These memories are stored in a distributed fashion throughout connectivity matrix, and individual synaptic connections have only a small influence. Although memory-specific connections are increased in number, the total number of inputs and outputs of neurons undergo only small changes during stimulation. We find that homeostatic structural plasticity induces a specific type of “silent memories”, different from conventional attractor states.     

Spatial memory formation induces recruitment of NMDA receptor and PSD-95 to synaptic lipid rafts

NMDA receptors (NMDARs) activation in the hippocampus and insular cortex is necessary for spatial memory formation. Recent studies suggest that localization of NMDARs to lipid rafts enhance their signalization, since the kinases that phosphorylate its subunits are present in larger proportion in lipid raft membrane microdomains. We sought to determine the possibility that NMDAR translocation to synaptic lipid rafts occurs during plasticity processes such as memory formation. Our results show that water maze training induces a rapid recruitment of NMDAR subunits (NR1, NR2A, NR2B) and PSD-95 to synaptic lipid rafts and decrease in the post-synaptic density plus an increase of NR2B phosphorylation at tyrosine 1472 in the rat insular cortex. In the hippocampus, spatial training induces selective translocation of NR1 and NR2A subunits to lipid rafts. These results suggest that NMDARs translocate from the soluble fraction of post-synaptic membrane (non-raft PSD) to synaptic lipid raft during spatial memory formation. The recruitment of NMDA receptors and other proteins to lipid rafts could be an important mechanism for increasing the efficiency of synaptic transmission during synaptic plasticity process.