Potassium channels: newly found players in synaptic plasticity.

One of the major issues for modern neuroscience research concerns the molecular and cellular mechanisms that underlie the acquisition, storage, and recollection of memories by the brain. Regulation of the strength of individual synaptic inputs (synaptic plasticity) has, for decades, been the front-running candidate mechanism for cellular information storage, with some direct supporting evidence recently obtained. Research into the molecular mechanisms responsible for changing synaptic strength has, to date, primarily focused on trafficking and properties of the neurotransmitter receptors themselves (AMPARs and NMDARs). However, recent evidence indicates that, subsequent to receptor activation, synaptic inputs are subject to regulation by synaptically located K+ channels. It is therefore critical to understand the biophysical properties and subcellular localization (density and distribution) of these channels and how their properties are modulated. Here we will review recent findings showing that two different classes of K+ channels (A-type and small conductance, Ca2+ -activated K+ channels), beyond their traditional role in regulating action potential firing, contribute to the regulation of synaptic strength in the hippocampus. In addition, we discuss how modulation of these channels' properties and expression might contribute to synaptic plasticity.     

Redox modulation of NMDA receptor-mediated synaptic activity in the hippocampus.

The sulfhydryl reducing agent dithiothreitol (DTT) and the oxidizing agent 5,5-dithio-bis-2-nitrobenzoic acid (DTNB) reversibly modulate the component of synaptic potentials mediated by N-methyl-D-aspartate (NMDA) receptors in slices of hippocampal area CA1. DTT (1 mM) reversibly potentiates NMDA receptor-mediated synaptic potentials while DTNB (1 mM) has the opposite effect. However, treatment of the slices with the irreversible sulfhydryl alkylating agent N-ethylmaleimide (300 microM) prevents DTNB from reversing the potentiation induced by DTT. These results further implicate the redox modulatory site as a regulator of the NMDA receptor-channel complex in vivo.     

Facilitated NMDA receptor-mediated synaptic plasticity in the hippocampal CA1 area of dystrophin-deficient mice.

The contribution of the cytoskeletal membrane-associated protein dystrophin in glutamatergic transmission and related plasticity was investigated in the hippocampal CA1 area of wild-type and dystrophin-deficient (mdx) mice, using extracellular recordings in the ex vivo slice preparation. Presynaptic fiber volleys and field excitatory postsynaptic potentials (fEPSPs) mediated through N-methyl-D-Aspartate receptors (NMDAr) or non-NMDAr were compared in both strains. Comparable synaptic responses were observed in wild-type and mdx mice, suggesting that basal glutamatergic transmission is not altered in the mutants. By contrast, the synaptic strengthening induced by a conditioning stimulation of either 10, 30, or 100 Hz was significantly greater in mdx mice during the first minutes posttetanus. Because the posttetanic potentiation induced in the presence of the NMDAr antagonist D-APV was not affected in the mutants, a critical role of NMDAr in this increase was suggested. The magnitude of the potentiation induced by a 30 Hz stimulation in mdx mice was normalized as compared to wild-type mice by increasing the extracellular magnesium concentration from 1.5 to 3 mM. Moreover, the transitory depression of fEPSPs induced by bath-applied NMDA (50 microM for 30s) was more sensitive to an increased extracellular magnesium concentration in wild-type than in mdx mice. Our results suggest that the absence of dystrophin may facilitate NMDAr activation in the CA1 hippocampal subfield of mdx mice, which may be partly due to a reduction of the voltage-dependent block of this receptor by magnesium.     

A role for monomeric G-proteins in synaptic plasticity in the rat dentate gyrus in vitro

Recent studies have implicated Ras signalling in synaptic plasticity. In this study we have investigated a role for the low molecular weight G proteins Ras, Rap, Ra1 and Rac in long-term potentiation and depression using Clostridium Sordelli Lethal Toxin-82 (LT-82), which inactivates Ras, Rap, Ra1 and Rac, and manumycin A, a Ras inhibitor. Perfusion of hippocampal slices with LT-82 (200 ng/ml) attenuated LTP (83±10%, n=5, P<0.01, compared with controls of 160±11% at 60 min post HFS, n=5). LT-82 had no effect on LTD (63±1% at 100 ng/ml, n=5 and 66±1% at 200 ng/ml, n=4, compared to controls of 56±6%, n=6). Manumycin A (2μM) had no effect on LTP (162±2%, n=5, compared to controls of 167±13%, n=5), but significantly attenuated LTD (88±6%, n=5, P<0.01, compared to controls of 63±9%, n=7). LT-82 (200 ng/ml) significantly increased the amplitude of the isolated NMDA-EPSP at 60 min post-drug application (240±40%, n=5, P<0.01, compared with controls of 100±4%, n=5). However, manumycin A, had no significant effect on NMDAR-EPSP amplitude (92±2%, n=5, compared with controls). These results demonstrate an important role for Ras in LTD and a role for Rap, Ra1 and Rac in LTP.     

Multideterminant role of calcium in hippocampal synaptic plasticity

Hippocampal CA1 cells possess several varieties of long-lasting synaptic plasticity: two different forms of long-term potentiation (LTP) and at least one form of long-term depression (LTD). All forms of synaptic plasticity are induced by afferent activation, all involve Ca²⁺ influx, all can be blocked by Ca²⁺ chelators, and all activate Ca²⁺-dependent mechanisms. The question arises as how different physiological responses can be initiated by activation of the same second messenger. We consider two hypotheses which could account for these phenomena: voltage-dependent differences in cytosolic Ca²⁺ concentration acting upon Ca²⁺ substrates of differing Ca²⁺ affinities and compartmentalization of the Ca²⁺ and its substrates. © 1994 Wiley-Liss, Inc.     

The role of acetylcholine in cortical synaptic plasticity

This review examines the role of acetylcholine in synaptic plasticity in archi-, paleo- and neocortex. Studies using microiontophoretic application of acetylcholine in vivo and in vitro and electrical stimulation of the basal forebrain have demonstrated that ACh can produce long-lasting increases in neural responsiveness. This evidence comes mainly from models of heterosynaptic facilitation in which acetylcholine produces a strengthening of a second, noncholinergic synaptic input onto the same neuron. The argument that the basal forebrain cholinergic system is essential in some models of plasticity is supported by studies that have selectively lesioned the cholinergic basal forebrain. This review will examine the mechanisms whereby acetylcholine might induce synaptic plasticity. It will also consider the neural circuitry implicated in these studies, namely the pathways that are susceptible to cholinergic plasticity and the neural regulation of the cholinergic system.     

Permissive role of interneurons in corticostriatal synaptic plasticity

Two different forms of synaptic plasticity have been found at corticostriatal synapses: long-term depression (LTD) and long-term potentiation (LTP). Both these enduring changes in the efficacy of excitatory neurotransmission in the striatum have a major impact on the physiological activity of the basal ganglia and are triggered by the stimulation of complex and independent cascades of intracellular second messenger systems. Striatal LTD and LTP are evoked following the repetitive stimulation of corticostriatal fibers and are dependent on the glutamate ionotropic receptor subtype activated. Recent experimental evidence indicates that two different subtypes of interneurons attend in the correct processing of information flow arising from the cortex and leading to striatal LTD or LTP. Acetylcholine (Ach) and nitric oxide (NO) producing striatal interneurons, in fact, are activated by the cortex during the induction phase of striatal plasticity, and stimulate, in turn, the intracellular changes in projection neurons required for LTD or LTP. Interneurons, therefore, exerts a feed-forward control of the excitability of striatal projection neurons ensuring the coordinate expression of two alternative forms of synaptic plasticity at the same type of excitatory synapse.     

Calcium chelation improves spatial learning and synaptic plasticity in aged rats

Impaired regulation of intracellular calcium is thought to adversely affect synaptic plasticity and cognition in the aged brain. Comparing young (2-3 months) and aged (23-26 months) Fisher 344 rats, stratum radiatum-evoked CA1 field EPSPs were smaller and long-term potentiation (LTP) was diminished in aged hippocampal slices. Resting calcium, in presynaptic axonal terminals in the CA1 stratum radiatum area, was elevated in aged slices. Loading the slice with the calcium chelator, BAPTA-AM, depressed LTP in young slices, but enhanced this plasticity in old slices. Forty-five minutes following LTP-inducing high frequency stimulation, resting calcium levels were significantly increased in both young and old presynaptic terminals, and significantly reduced by pretreatment with BAPTA-AM. In vivo, intraperitoneal administration of BAPTA-AM prior to training in the reference memory version of the Morris water maze test, significantly improved the acquisition of spatial learning in aged animals, without a significant effect in young rats. These results support the hypothesis that increasing intracellular neuronal buffering power for calcium in aged rats ameliorates age-related impaired synaptic plasticity and learning.     

Neuronal and synaptic properties: fundamentals of network plasticity

Neurons, within the nervous system, are organized in different neural networks through synaptic connections. Two fundamental components are dynamically interacting in these functional units. The first one are the neurons themselves, and far from being simple action potential generators, they are capable of complex electrical integrative properties due to various types, number, distribution and modulation of voltage-gated ionic channels. The second elements are the synapses where a similar complexity and plasticity is found. Identifying both cellular and synaptic intrinsic properties is necessary to understand the links between neural networks behavior and physiological function, and is a useful step towards a better control of neurological diseases.     

Cytokines,synaptic plasticity and network dynamics:a matter of balance

The modern view of the immune system as a sensitizing and modulating machinery of the central nervous system is now well recognized. However, the specific mechanisms underlying this fine crosstalk have yet to be fully disentangled. To control cognitive function and behavior, the two systems are engaged in a subtle interacting act. In this scenario, a dual action of pro-inflammatory cytokines in the modulation of brain network connections is emerging. Pro-inflammatory cytokines are indeed require...     

The neurobiology of opiate tolerance,dependence and sensitization: Mechanisms of NMDA receptor-dependent synaptic plasticity

Long-term administration of opiates leads to changes in the effects of these drugs, including tolerance, sensitization and physical dependence. There is, as yet, incomplete understanding of the neural mechanisms that underlie these phenomena. Tolerance, sensitization and physical dependence can be considered adaptive processes similar to other experience-dependent changes in the brain, such as learning and neural development. There is considerable evidence demonstrating that N-methyl-D-aspartate (NMDA) receptors and downstream signaling cascades may have an important role in different forms of experience-dependent changes in the brain and behavior. This review will explore evidence indicating that NMDA receptors and downstream messengers may be involved in opiate tolerance, sensitization and physical dependence. This evidence has been used to develop a cellular model of NMDA receptor/opiate interactions. According to this model, mu opioid receptor stimulation leads to a protein kinase C-mediated activation of NMDA receptors. Activation of NMDA receptors leads to influx of calcium and activation of calcium-dependent processes. These calcium-dependent processes have the ability to produce critical changes in opioid-responsive neurons, including inhibition of opioid receptor/second messenger coupling. This model is similar to cellular models of learning and neural development in which NMDA receptors have a central role. Together, the evidence suggests that the mechanisms that underlie changes in the brain and behavior produced by long-term opiate use may be similar to other central nervous system adaptations. The experimental findings and the resulting model may have implications for the treatment of pain and addiction.     

Protein kinase activity and synaptic plasticity in a chick brain slice.

In an in vitro slice preparation of the chick brain it is possible to record responses to single electrical stimuli from within the intermediate and medial part of the hyperstriatum ventrale (IMHV), a region known to be involved in learning. The amplitude of such responses is significantly increased by superfusion of the slice with 10 microM 4 beta-phorbol 12,13 diacetate (PDAc), a phorbol ester which stimulates protein kinase activity. The ability of PDAc to induce potentiation is greatest in chicks less than 6 days old. Administration of the kinase antagonist H7 prevents the induction of persistent potentiation and in fact produces a long lasting depression of response amplitude. H7 also produces a short term increase in excitability within the IMHV and results in increased expression of N-methyl-D-aspartate receptor activity.     

NMDA receptor-dependent synaptic activation of TRPC channels in olfactory bulb granule cells

Canonical transient receptor potential (TRPC) channels are widely expressed throughout the nervous system including the olfactory bulb where their function is largely unknown. Here, we describe their contribution to central synaptic processing at the reciprocal mitral and tufted cell-granule cell microcircuit, the most abundant synapse of the mammalian olfactory bulb. Suprathreshold activation of the synapse causes sodium action potentials in mouse granule cells and a subsequent long-lasting depolarization (LLD) linked to a global dendritic postsynaptic calcium signal recorded with two-photon laser-scanning microscopy. These signals are not observed after action potentials evoked by current injection in the same cells. The LLD persists in the presence of group I metabotropic glutamate receptor antagonists but is entirely absent from granule cells deficient for the NMDA receptor subunit NR1. Moreover, both depolarization and Ca2? rise are sensitive to the blockade of NMDA receptors. The LLD and the accompanying Ca2? rise are also absent in granule cells from mice deficient for both TRPC channel subtypes 1 and 4, whereas the deletion of either TRPC1 or TRPC4 results in only a partial reduction of the LLD. Recordings from mitral cells in the absence of both subunits reveal a reduction of asynchronous neurotransmitter release from the granule cells during recurrent inhibition. We conclude that TRPC1 and TRPC4 can be activated downstream of NMDA receptor activation and contribute to slow synaptic transmission in the olfactory bulb, including the calcium dynamics required for asynchronous release from the granule cell spine.     

Synaptic structural plasticity: role of synaptic shape

Recent research has indicated that synaptic curvature is an important and potentially critical plastic feature of the synapse. Alterations in synaptic shape are related to synaptic function, being found both during maturation and in adulthood following neuronal activation. In this paper we review the evidence supporting synaptic shape as a plastic feature of synaptic structure. We also propose several mechanisms which might underlie these changes in shape. Finally, we suggest the possible functional role of alterations in synaptic curvature, including its potential in altering synaptic transmission efficacy.     

The role of monosialoganglioside GM1 in the synaptic plasticity: in vitro study on rat hippocampal slices

Rat hippocampal slices were incubated with neuraminidase from Vibrio Cholerae. This enzyme liberates sialic acid from polysialogangliosides converting them into monosialoganglioside GM1. Thus, the tissue is enriched in GM1 content. Another set of slices was incubated with GM1 itself. Both treatments increased the magnitude of potentiation of synaptic response recorded from pyramidal cell layer following high frequency stimulation of Schaffer collateral-commissural fibers. It is concluded that enrichment of synaptic membranes in GM1 enhances the ability of these nerve endings to be potentiated.     

Calcium dependency of excitatory chemical synaptic transmission in the frog cerebellum in vitro.

Chemical synaptic transmission was studied with microelectrode techniques in isolated frog cerebella maintained in vitro. Purkinje cell (PC) EPSPs, elicited by selective monosynaptic electrical stimulation of both the parallel fiber (PF) and climbing fiber (CF) inputs, could be inverted by depolarizing (outward) current injections. Evoked synaptic transmission at both junctions was reduced by lowering the extracellular concentration of calcium ions ([Ca2+]) below 2 mM. Raising [Ca2+] above 2 mM to 8 mM did not further increase synaptic transmission. Mg2+, Sr2+, and Ba2+ did not substitute for Ca2+ in the transmission process.     

Elements of a neurobiological theory of hippocampal function: the role of synaptic plasticity, synaptic tagging and schemas

The 2004 EJN Lecture was an attempt to lay out further aspects of a developing neurobiological theory of hippocampal function [Morris, R.G.M., Moser, E.I., Riedel, G., Martin, S.J., Sandin, J., Day, M. & O'Carroll, C. (2003) Phil. Trans. R. Soc. Lond. B Biol. Sci., 358, 773-786.] These are that (i) activity-dependent synaptic plasticity plays a key role in the automatic encoding and initial storage of attended experience; (ii) the persistence of hippocampal synaptic potentiation over time can be influenced by other independent neural events happening closely in time, an idea with behavioural implications for memory; and (iii) that systems-level consolidation of memory traces within neocortex is guided both by hippocampal traces that have been subject to cellular consolidation and by the presence of organized schema in neocortex into which relevant newly encoded information might be stored. Hippocampal memory is associative and, to study it more effectively than with previous paradigms, a new learning task is described which is unusual in requiring the incidental encoding of flavour-place paired associates, with the readout of successful storage being successful recall of a place given the flavour with which it was paired. NMDA receptor-dependent synaptic plasticity is shown to be critical for the encoding and intermediate storage of memory traces in this task, while AMPA receptor-mediated fast synaptic transmission is necessary for memory retrieval. Typically, these rapidly encoded traces decay quite rapidly over time. Synaptic potentiation also decays rapidly, but can be rendered more persistent by a process of cellular consolidation in which synaptic tagging and capture play a key part in determining whether or not it will be persistent. Synaptic tags set at the time of an event, even many trivial events, can capture the products of the synthesis of plasticity proteins set in train by events before, during or even after an event to be remembered. Tag-protein interactions stabilize synaptic potentiation and, by implication, memory. The behavioural implications of tagging are explored. Finally, using a different protocol for flavour-place paired associate learning, it is shown that rats can develop a spatial schema which represents the relative locations of several different flavours of food hidden at places within a familiar space. This schema is learned gradually but, once acquired, enables new paired associates to be encoded and stored in one trial. Their incorporation into the schema prevents rapid forgetting and suggests that schema play a key and hitherto unappreciated role in systems-level memory consolidation. The elements of what may eventually mature into a more formal neurobiological theory of hippocampal memory are laid out as specific propositions with detailed conceptual discussion and reference to recent data.     

Lipid signaling and synaptic plasticity.

Lipids are essential components of plasma- and organelle-membranes, not only providing a frame for embedded proteins (e.g., receptors and ion channels) but also functioning as reservoirs for lipid mediators. Increasing evidence indicates that bioactive lipids such as eicosanoids, endocannabinoids, and lysophospholipids serve as intercellular and intracellular signaling molecules participating in physiological and pathological functions in the brain. The discovery of some of these lipid receptors and novel lipid signaling mediators has sparked an intense interest in lipidomic neurobiology research. Classic prostaglandins (PGD(2), PGE(2), PGF(2alpha), PGI(2), and TXA(2)), catalyzed by cyclooxygenases (COX), are synthesized from arachidonic acid (AA). Experimental studies demonstrate that prostaglandin E(2) (PGE(2)), mainly derived from the COX-2 reaction, is an important mediator, acting as a retrograde messenger via a presynaptic PGE(2) subtype 2 receptor (EP(2)) in modulation of synaptic events. Novel prostaglandins (prostaglandin glycerol esters and prostaglandin ethanolamides) are COX-2 oxidative metabolites of endogenous cannabinoids (2-arachidonyl glycerol and arachidonyl ethanolamide). Recent evidence suggests that these new types of prostaglandins are likely novel signaling mediators involved in synaptic transmission and plasticity. This means that COX- 2 plays a central role in metabolisms of AA and endocannabinoids (eCBs) and productions of AA- and eCB- derived prostaglandins. Thus, in the present review article, the authors will mainly discuss COX-2 regulation of prostaglandin signaling in modulation of hippocampal synaptic transmission and plasticity.