The role of synaptic ion channels in synaptic plasticity

The nervous system receives a large amount of information about the environment through elaborate sensory routes. Processing and integration of these wide-ranging inputs often results in long-term behavioural alterations as a result of past experiences. These relatively permanent changes in behaviour are manifestations of the capacity of the nervous system for learning and memory. At the cellular level, synaptic plasticity is one of the mechanisms underlying this process. Repeated neural activity generates physiological changes in the nervous system that ultimately modulate neuronal communication through synaptic transmission. Recent studies implicate both presynaptic and postsynaptic ion channels in the process of synapse strength modulation. Here, we review the role of synaptic ion channels in learning and memory, and discuss the implications and significance of these findings towards deciphering the molecular biology of learning and memory.     

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.     

活性依赖的突触抑制和突触稳态的分子机制

常规RNA干涉或基因敲除的功能缺失手段仅仅只是简单地移除某个基因或蛋白,而这个过程常常会掩盖磷酸化对某个特定蛋白的调节。在树突发育和突触功能活性依赖的调节过程中,突触后致密蛋白磷酸化的机制仍然是未知的领域。突触后Rap GTP酶激活蛋白SPAR与PSD95结合,可以促进树突棘的生长并加强突触。Plk2（polo-like kinase2,也称为Snk）是一种受突触活性诱导表达的蛋白激酶,它可以磷酸化SPAR,磷酸化的SPAR通过泛素化．蛋白酶体途径降解,从而导致树突棘和突触的减少。Plk2的诱导表达和随后SPAR的降解是长时间神经活性增强过程中突触强度的稳态抑制（突触剥落）所必需的。有趣的是,SPAR需要被另外一种激酶cDK5磷酸化后才能被Plk2所降解。这种机制通过CDK5对一部分突触进行标记,为由Plk2-SPAR通路抑制或去除这些突触提供了可能的途径,但其分子机制在神经退行性疾病突触丢失中的作用仍需进一步探讨。     

Influence of active synaptic pools on the single synaptic event

The activity of the single synapse is the base of information processing and transmission in the brain as well as of important phenomena as the Long Term Potentiation which is the main mechanism for learning and memory. Although usually considered as independent events, the single quantum release gives variable postsynaptic responses which not only depend on the properties of the synapses but can be strongly influenced by the activity of other synapses. In the present paper we show the results of a series of computational experiments where pools of active synapses, in a compatible time window, influence the response of a single synapse of the considered pool. Moreover, our results show that the activity of the pool, by influencing the membrane potential, can be a significant factor in the NMDA unblocking from \(Mg^{2+}\) increasing the contribution of this receptor type to the Excitatory Post Synaptic Current. We consequently suggest that phenomena like the LTP, which depend on NMDA activation, can occur also in subthreshold conditions due to the integration of the dendritic synaptic activity.     

Retaining synaptic AMPARs

Endocytosis, exocytosis, and lateral diffusion are key mechanisms for AMPA receptor trafficking. Endocytosis of AMPARs and other postsynaptic proteins has been proposed to occur at specific endocytic zones (EZs), but the mechanisms that regulate this process are not at all clear. In this issue of Neuron, Lu et al. show that correct synaptic EZ positioning requires links between the GTPase dynamin-3 and the Homer/Shank complex.     

The kinetics of synaptic vesicle pool depletion at CNS synaptic terminals

During sustained action potential (AP) firing at nerve terminals, the rates of endocytosis compared to exocytosis determine how quickly the available synaptic vesicle pool is depleted, in turn influencing presynaptic efficacy. Mechanisms, including rapid kiss-and-run endocytosis as well as local, preferential recycling of docked vesicles, have been proposed as a means to allow endocytosis and recycling to keep up with stimulation. We show here that, for CNS nerve terminals at physiological temperatures, endocytosis is sufficiently fast to avoid vesicle pool depletion during continuous AP firing at 10 Hz. This endocytosis-exocytosis balance persists for turnover of the entire releasable pool of vesicles and allows for efficient escape of FM 4-64, indicating that it is a non-kiss-and-run endocytic event. Thus, under physiological conditions, the sustained speed of vesicle membrane retrieval for the entire releasable pool appears to be sufficiently fast to compensate for exocytosis, avoiding significant vesicle pool depletion during robust synaptic activity.     

Newly produced synaptic vesicle proteins are preferentially used in synaptic transmission

Aged proteins can become hazardous to cellular function, by accumulating molecular damage. This implies that cells should preferentially rely on newly produced ones. We tested this hypothesis in cultured hippocampal neurons, focusing on synaptic transmission. We found that newly synthesized vesicle proteins were incorporated in the actively recycling pool of vesicles responsible for all neurotransmitter release during physiological activity. We observed this for the calcium sensor Synaptotagmin 1, for the neurotransmitter transporter VGAT, and for the fusion protein VAMP2 (Synaptobrevin 2). Metabolic labeling of proteins and visualization by secondary ion mass spectrometry enabled us to query the entire protein makeup of the actively recycling vesicles, which we found to be younger than that of non‐recycling vesicles. The young vesicle proteins remained in use for up to ~ 24 h, during which they participated in recycling a few hundred times. They were afterward reluctant to release and were degraded after an additional ~ 24–48 h. We suggest that the recycling pool of synaptic vesicles relies on newly synthesized proteins, while the inactive reserve pool contains older proteins.     

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.     

Separation of enriched synaptosomes, synaptic vesicles and synaptic plasma membranes]

A rapid and simple method is described for separation of intact synaptosomes, synaptic plasma membranes and vesicles. Two synaptosome fractions were obtained by modified differential centrifugation. The rate zonal zentrifugation in a linear sucrose gradient (very low density) is suitable to obtain fractions highly enriched in synaptic plasma membranes and vesicles. Examination of the prepared fractions was done by enzyme marker activities and electron microscopy     

Drosophila Futsch regulates synaptic microtubule organization and is necessary for synaptic growth

We present evidence that Futsch, a novel protein with MAP1B homology, controls synaptic growth at the Drosophila neuromuscularjunction through the regulation of the synaptic microtubule cytoskeleton. Futsch colocalizes with microtubules and identifies cytoskeletal loops that traverse the lateral margin of select synaptic boutons. An apparent rearrangement of microtubule loop architecture occurs during bouton division, and a genetic analysis indicates that Futsch is necessary for this process. futsch mutations disrupt synaptic microtubule organization, reduce bouton number, and increase bouton size. These deficits can be partially rescued by neuronal overexpression of a futsch MAP1B homology domain. Finally, genetic manipulations that increase nerve-terminal branching correlate with increased synaptic microtubule loop formation, and both processes require normal Futsch function. These data suggest a common microtubule-based growth mechanism at the synapse and growth cone.     

Interaction of isolated synaptic vesicles with synaptic contacts in the rat brain

The effects of Mg-ATP, EGTA, EDTA and dicyclohexylcarbodiimide on the changes in the intensity of light scattering were studied in rat brain synaptic vesicles (SV) suspended in saccharose-buffer medium. Specific interactions between SV and isolated synaptic junctional complex were observed in the presence of Mg-ATP and calmodulin. An in vitro model of exocytosis is discussed.     

MPTP modulates hippocampal synaptic transmission and activity-dependent synaptic plasticity via dopamine receptors

Parkinson's disease (PD)-like symptoms and cognitive deficits are inducible by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Since cognitive abilities, including memory formations rely also on hippocampus, we set out to clarify the effects of MPTP on hippocampal physiology. We show that bath-application of MPTP (25?μM) to acute hippocampal slices enhanced AMPA receptor-mediated field excitatory postsynaptic potentials (AMPAr-fEPSPs) transiently, whereas N-methyl-D-aspartate (NMDA) receptor-mediated fEPSPs (NMDAr-fEPSPs) were facilitated persistently. The MPTP-mediated transient AMPAr-fEPSP facilitation was antagonized by the dopamine D2-like receptor antagonists, eticlopride (1?μM) and sulpiride (1 and 40?μM). In contrast, the persistent enhancement of NMDAr-fEPSPs was prevented by the dopamine D1-like receptor antagonist SCH23390 (10?μM). In addition, we show that MPTP decreased paired-pulse facilitation of fEPSPs and mEPSCs frequency. Regarding activity-dependent synaptic plasticity, 25?μM MPTP transformed short-term potentiation (STP) into a long-term potentiation (LTP) and caused a slow onset potentiation of a non-tetanized synaptic input after induction of LTP in a second synaptic input. This heterosynaptic slow onset potentiation required activation of dopamine D1-like and NMDA-receptors. We conclude that acute MPTP application affects basal synaptic transmission by modulation of presynaptic vesicle release and facilitates NMDAr-fEPSPs as well as activity-dependent homo- and heterosynaptic plasticity under participation of dopamine receptors.     

BCL-xL regulates synaptic plasticity

Mitochondria are the predominant organelle within many presynaptic terminals. During times of high synaptic activity, they affect intracellular calcium homeostasis and provide the energy needed for synaptic vesicle recycling and for the continued operation of membrane ion pumps. Recent discoveries have altered our ideas about the role of mitochondria in the synapse. Mitochondrial localization, morphology, and docking at synaptic sites may indeed alter the kinetics of transmitter release and calcium homeostasis in the presynaptic terminal. In addition, the mitochondrial ion channel BCL-xL, known as a protector against programmed cell death, regulates mitochondrial membrane conductance and bioenergetics in the synapse and can thereby alter synaptic transmitter release and the recycling of pools of synaptic vesicles. BCL-xL, therefore, not only affects the life and death of the cell soma, but its actions in the synapse may underlie the regulation of basic synaptic processes that subtend learning, memory and synaptic development.