CiteULike: tmk's library [270 articles]

Single-neuron labeling with inducible Cre-mediated knockout in transgenic mice.

Paul Young — 2008-05-09T08:59:37-00:00

Nature neuroscience (4 May 2008)

To facilitate a functional analysis of neuronal connectivity in a mammalian nervous system that is tightly packed with billions of cells, we developed a new technique that uses inducible genetic manipulations in fluorescently labeled single neurons in mice. Our technique, single-neuron labeling with inducible Cre-mediated knockout (SLICK), is achieved by coexpressing a drug-inducible form of Cre recombinase and a fluorescent protein in a small subsets of neurons, thus combining the powerful Cre recombinase system for conditional genetic manipulation with fluorescent labeling of single neurons for imaging. Here, we demonstrate efficient inducible genetic manipulation in several types of neurons using SLICK. Furthermore, we applied SLICK to eliminate synaptic transmission in a small subset of neuromuscular junctions. Our results provide evidence for the long-term stability of inactive neuromuscular synapses in adult animals and demonstrate a Cre-loxP compatible system for dissecting gene functions in single identifiable neurons.

Noise in the nervous system

Aldo Faisal — 2008-03-20T11:26:51-00:00

Nat Rev Neurosci, Vol. 9, No. 4. (April 2008), pp. 292-303.

Modulation of voltage-dependent calcium currents by serotonin in acutely isolated rat amygdala neurons.

CH Lin — 2008-01-23T06:53:02-00:00

Synapse, Vol. 41, No. 4. (15 September 2001), pp. 351-359.

The modulation of voltage-dependent calcium currents (I(Ca)) by serotonin (5-HT) was studied in rat acutely dissociated amygdala neurons using whole-cell patch-clamp recording techniques. 5-HT inhibited I(Ca) in a concentration-dependent manner with a ED50 of approximately 1 microM and a maximal inhibition of approximately 50%. The inhibition was mimicked by the selective 5-HT1A agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and was reduced by the 5-HT1A antagonist NAN-190, indicating its mediation by 5-HT1A receptors. Pretreatment of neurons with the alkylating agent N-ethylmaleimide (NEM) or pertussis toxin (PTX) markedly reduced the action of 5-HT. The modulation was partially reversed by strong depolarization and was not seen in cell-attached patches when the agonist was applied outside the recorded patch, suggesting a membrane-delimited, G-protein-mediated signaling pathway. Nimodipine (1 microM) reduced the I(Ca) by approximately 30% without reducing inhibition of current by 5-HT significantly, ruling out L-type channels as the target of modulation. 5-HT-mediated inhibition after exposure to omega-conotoxin-GVIA (omega-CgTX, 1 microM) or omega-agatoxin-IV (omega-AgTX, 200 nM), which blocked 26% and 21% of the total I(Ca), respectively, was significantly decreased, suggesting involvement of the N- and P/Q-type channels. In the combined presence of omega-CgTX and omega-AgTX, 5-HT still caused a small but significant reduction of I(Ca), suggesting a possible involvement of R-type channels. Stimulation of beta-adrenergic receptor with isoproterenol (Iso) or activation of adenylyl cyclase with forskolin resulted in an enhancement of I(Ca). 5-HT caused the same degree of inhibition with or without Iso or forskolin pretreatment. On the other hand, application of 8-OH-DPAT inhibited I(Ca) and blocked Iso- and Sp-cAMPS-induced enhancement. These results provide the first evidence showing a dominant effect of 5-HT-mediated inhibition over Iso-mediated enhancement of I(Ca).

Selective muscarinic regulation of functional glutamatergic Schaffer collateral synapses in rat CA1 pyramidal neurons.

D Fernández de Sevilla — 2008-01-22T06:46:28-00:00

J Physiol, Vol. 545, No. Pt 1. (15 November 2002), pp. 51-63.

Analysis of the cholinergic regulation of glutamatergic neurotransmission is an essential step in understanding the hippocampus because it can influence forms of synaptic plasticity that are thought to underlie learning and memory. We studied in vitro the cholinergic regulation of excitatory postsynaptic currents (EPSCs) evoked in rat CA1 pyramidal neurons by Schaffer collateral (SC) stimulation. Using "minimal" stimulation, which activates one or very few synapses, the cholinergic agonist carbamylcholine (CCh) increased the failure rate of functional more (36 %) than of silent synapses (7 %), without changes in the EPSC amplitude. These effects of CCh were insensitive to manipulations that increased the probability of release, such as paired pulse facilitation, increases in temperature and increases in the extracellular Ca(2+) : Mg(2+) ratio. Using "conventional" stimulation, which activates a large number of synapses, CCh inhibited more the pharmacologically isolated non-NMDA (86 %) than the NMDA (47 %) EPSC. The changes in failure rate, EPSC variance and the increased paired pulse facilitation that paralleled the inhibition imply that CCh decreased release probability. Muscarine had similar effects. The inhibition by both CCh and by muscarine was prevented by atropine. We conclude that CCh reduces the non-NMDA component of SC EPSCs by selectively inhibiting transmitter release at functional synapses via activation of muscarinic receptors. The results suggest that SCs have two types of terminals, one in functional synapses, selectively sensitive to regulation through activation of muscarinic receptors, and the other in silent synapses less sensitive to that regulation. The specific inhibition of functional synapses would favour activity-dependent plastic phenomena through NMDA receptors at silent synapses without the activation of non-NMDA receptors and functional synapses.

The amygdala.

J LeDoux — 2007-12-06T12:03:25-00:00

Curr Biol, Vol. 17, No. 20. (23 October 2007)

LTP leads to rapid surface expression of NMDA but not AMPA receptors in adult rat CA1.

DR Grosshans — 2007-09-14T01:59:18-00:00

Nat Neurosci, Vol. 5, No. 1. (January 2002), pp. 27-33.

In the CA1 region of the rat hippocampus, long-term potentiation (LTP) requires the activation of NMDA receptors (NMDARs) and leads to an enhancement of AMPA receptor (AMPAR) function. In neonatal hippocampus, this increase in synaptic strength seems to be mediated by delivery of AMPARs to the synapse. Here we studied changes in surface expression of native AMPA and NMDA receptors following induction of LTP in the adult rat brain. In contrast to early postnatal rats, we find that LTP in the adult rat does not alter membrane association of AMPARs. Instead, LTP leads to rapid surface expression of NMDARs in a PKC- and Src-family-dependent manner. The present study suggests a developmental shift in the LTP-dependent trafficking of AMPA receptors. Moreover, our results indicate that insertion of NMDA receptors may be a key step in regulating synaptic plasticity.

Rapid Bidirectional Switching of Synaptic NMDA Receptors.

Camilla Bellone — 2007-09-12T06:46:11-00:00

Neuron, Vol. 55, No. 5. (6 September 2007), pp. 779-785.

Synaptic NMDA-type glutamate receptors (NMDARs) play important roles in synaptic plasticity, brain development, and pathology. In the last few years, the view of NMDARs as relatively fixed components of the postsynaptic density has changed. A number of studies have now shown that both the number of receptors and their subunit compositions can be altered. During development, the synaptic NMDARs subunit composition changes, switching from predominance of NR2B-containing to NR2A-containing receptors, but little is known about the mechanisms involved in this developmental process. Here, we report that, depending on the pattern of NMDAR activation, the subunit composition of synaptic NMDARs is under extremely rapid, bidirectional control at neonatal synapses. This switching, which is at least as rapid as that seen with AMPARs, will have immediate and dramatic consequences on the integrative capacity of the synapse.

Protein kinase signaling in synaptic plasticity and memory.

M Mayford — 2007-09-06T09:26:31-00:00

Curr Opin Neurobiol, Vol. 17, No. 3. (June 2007), pp. 313-317.

The relay of extracellular signals into changes in cellular physiology involves a Byzantine array of intracellular signaling pathways, of which cytoplasmic protein kinases are a crucial component. In the nervous system, a great deal of effort has focused on understanding the conversion of patterns of synaptic activity into long-lasting changes in synaptic efficacy that are thought to underlie memory. The goal is both to understand synaptic plasticity mechanisms, such as long-term potentiation, at a molecular level and to understand the relationship of these synaptic mechanisms to behavioral memory. Although both involve the activation of multiple signaling pathways, recent studies are beginning to define discrete roles and mechanisms for individual kinases in the different temporal phases of both synaptic and behavioral plasticity.

NEUROSCIENCE: The Threatened Brain

Stephen Maren — 2007-09-04T15:56:45-00:00

Science, Vol. 317, No. 5841. (24 August 2007), pp. 1043-1044.

10.1126/science.1147797

A stream of cells migrating from the caudal telencephalon reveals a link between the amygdala and neocortex

Ryan Remedios — 2007-08-29T00:24:44-00:00

Nature Neuroscience, Vol. 10, No. 9. (12 August 2007), pp. 1141-1150.

Synaptically released zinc gates long-term potentiation in fear conditioning pathways.

SA Kodirov — 2007-08-31T12:06:06-00:00

Proc Natl Acad Sci U S A, Vol. 103, No. 41. (10 October 2006), pp. 15218-15223.

The functional role of releasable Zn2+ in the central nervous system remains unknown. Here we show that zinc transporter 3 (ZnT-3), which maintains a high concentration of Zn2+ in synaptic vesicles and serves as a marker for zinc-containing neurons, is enriched in the lateral nucleus of the amygdala and in the temporal area 3 of the auditory cortex, an area that conveys information about the auditory conditioned stimulus to the lateral nucleus of the amygdala, but not in other conditioned stimulus areas located in the auditory thalamus. Using whole-cell recordings from amygdala slices, we demonstrated that activity-dependent release of chelatable Zn2+ is required for the induction of spike timing-dependent long-term potentiation in cortical input to the amygdala implicated in fear learning. Our data indicate that synaptically released Zn2+ enables long-term potentiation at the cortico-amygdala synapses by depressing feed-forward GABAergic inhibition of principal neurons. This regulatory mechanism, implicating pathway-dependent release of Zn2+, may serve an essential control function in assuring spatial specificity of long-lasting synaptic modifications in the neural circuit of a learned behavior.

A deletion variant of the alpha2b-adrenoceptor is related to emotional memory in Europeans and Africans.

Dominique J-F de Quervain — 2007-07-31T18:12:48-00:00

Nat Neurosci (29 July 2007)

Emotionally arousing events are recalled better than neutral events. This phenomenon, which helps us to remember important and potentially vital information, depends on the activation of noradrenergic transmission in the brain. Here we show that a deletion variant of ADRA2B, the gene encoding the alpha2b-adrenergic receptor, is related to enhanced emotional memory in healthy Swiss subjects and in survivors of the Rwandan civil war who experienced highly aversive emotional situations.

A thin slice preparation for patch clamp recordings from neurones of the mammalian central nervous system.

FA Edwards — 2007-08-13T13:59:07-00:00

Pflugers Arch, Vol. 414, No. 5. (September 1989), pp. 600-612.

(1) A preparation is described which allows patch clamp recordings to be made on mammalian central nervous system (CNS) neurones in situ. (2) A vibrating tissue slicer was used to cut thin slices in which individual neurones could be identified visually. Localized cleaning of cell somata with physiological saline freed the cell membrane, allowing the formation of a high resistance seal between the membrane and the patch pipette. (3) The various configurations of the patch clamp technique were used to demonstrate recording of membrane potential, whole cell currents and single channel currents from neurones and isolated patches. (4) The patch clamp technique was used to record from neurones filled with fluorescent dyes. Staining was achieved by filling cells during recording or by previous retrograde labelling. (5) Thin slice cleaning and patch clamp techniques were shown to be applicable to the spinal cord and almost any brain region and to various species. These techniques are also applicable to animals of a wide variety of postnatal ages, from newborn to adult.

Patch-clamp recording from mossy fiber terminals in hippocampal slices.

J Bischofberger — 2007-08-13T13:55:31-00:00

Nat Protoc, Vol. 1, No. 4. (2006), pp. 2075-2081.

Rigorous analysis of synaptic transmission in the central nervous system requires access to presynaptic terminals. However, cortical terminals have been largely inaccessible to presynaptic patch-clamp recording, due to their small size. Using improved patch-clamp techniques in brain slices, we recorded from mossy fiber terminals in the CA3 region of the hippocampus, which have a diameter of 2-5 microm. The major steps of improvement were the enhanced visibility provided by high-numerical aperture objectives and infrared illumination, the development of vibratomes with minimal vertical blade vibrations and the use of sucrose-based solutions for storage and cutting. Based on these improvements, we describe a protocol that allows us to routinely record from hippocampal mossy fiber boutons. Presynaptic recordings can be obtained in slices from both rats and mice. Presynaptic recordings can be also obtained in slices from transgenic mice in which terminals are labeled with enhanced green fluorescent protein.

Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system.

MD Ehlers — 2007-08-01T13:51:32-00:00

Nat Neurosci, Vol. 6, No. 3. (March 2003), pp. 231-242.

Experience-dependent remodeling of the postsynaptic density (PSD) is critical for synapse formation and plasticity in the mammalian brain. Here, in cultured rat hippocampal neurons, I found long-lasting, global changes in the molecular composition of the PSD dictated by synaptic activity. These changes were bidirectional, reversible, modular, and involved multiple classes of PSD proteins. Moreover, activity-dependent remodeling was accompanied by altered protein turnover, occurred with corresponding increases or decreases in ubiquitin conjugation of synaptic proteins and required proteasome-mediated degradation. These modifications, in turn, reciprocally altered synaptic signaling to the downstream effectors CREB (cyclic AMP response element binding protein) and ERK-MAPK (extracellular signal regulated kinase-MAP kinase). These results indicate that activity regulates postsynaptic composition and signaling through the ubiquitin-proteasome system, providing a mechanistic link between synaptic activity, protein turnover and the functional reorganization of synapses.

The NR2B subtype of NMDA receptor: a potential target for the treatment of alcohol dependence.

J Nagy — 2007-07-31T06:53:43-00:00

Curr Drug Targets CNS Neurol Disord, Vol. 3, No. 3. (June 2004), pp. 169-179.

Ethanol is a small molecule acting on several neurotransmitter systems in the brain. Accumulating evidences suggest that the primary excitatory--i.e. the glutamatergic--neurotransmitter system is a particularly important site of ethanol's action. Several studies showed that ethanol is a potent and selective inhibitor of the N-methyl-D-aspartate (NMDA) receptors and prolonged ethanol exposition leads to a compensatory "up-regulation" of these receptors resulting in enhanced NMDA receptor-mediated functions after removal of ethanol. These alterations are supposed to contribute to the development of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal. In recent papers, alterations in subunit composition of NMDA receptors were reported after long term ethanol exposure. mRNA and/or protein levels of NR2A and NR2B types of subunits were found elevated both by in vivo and in vitro experiments. Our results showed that especially the NR2B subunit expression is increased in cultured hippocampal and cortical neurones after 3 days of intermittent ethanol treatment. According to the high calcium permeability, the increased agonist sensitivity and the relatively slow closing kinetics of NMDA ion channels composed of NR2B subunits, the above mentioned changes may underlie the enhanced NMDA receptor activation observed after long term ethanol exposure. Accordingly, we have tested NR2B subunit selective NMDA receptor antagonists in primary cultures of rat cortical neurones pre-treated with ethanol intermittently for 3 days and found that these compounds potently inhibited the neurotoxic effect of ethanol withdrawal. Hypothesising the involvement of enhanced NR2B subunit expression in development of alcohol dependence and withdrawal symptoms and considering the tolerable side effect profile of the NR2B subunit selective NMDA receptor antagonists, the NR2B type of NMDA receptor subunit may serve as a possible drug target in pharmacological interventions for alcoholism. The aim of this review is to give an update on the role of altered structure and function of NMDA receptors after ethanol exposure and to summarise the recent data about the activity of NR2B subunit selective NMDA receptor antagonists in model systems related to alcoholism.

Homeostatic plasticity and NMDA receptor trafficking.

I Pérez-Otaño — 2007-07-31T03:14:24-00:00

Trends Neurosci, Vol. 28, No. 5. (May 2005), pp. 229-238.

Learning, memory and brain development are associated with long-lasting modifications of synapses that are guided by specific patterns of neuronal activity. Such modifications include classical Hebbian plasticities (such as long-term potentiation and long-term depression), which are rapid and synapse-specific, and others, such as synaptic scaling and metaplasticity, that work over longer timescales and are crucial for maintaining and orchestrating neuronal network function. The cellular mechanisms underlying Hebbian plasticity have been well studied and involve rapid changes in the trafficking of highly mobile AMPA receptors. An emerging concept is that activity-dependent alterations in NMDA receptor trafficking contribute to homeostatic plasticity at central glutamatergic synapses.

A functional genetic variation of the 5-HT2a receptor affects human memory.

DJ de Quervain — 2007-07-25T02:40:15-00:00

Nat Neurosci, Vol. 6, No. 11. (November 2003), pp. 1141-1142.

Human memory capacity is highly variable across individuals and is influenced by both genetic and environmental factors. A roughly 50% heritability estimate indicates that naturally occurring genetic variations have an important impact on this cognitive ability. Therefore, we investigated a functional variation of a memory-related serotonin receptor in 349 healthy young volunteers, and found 21% poorer memory performance in subjects with the rare variant.

The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.

MF Egan — 2007-07-25T02:36:41-00:00

Cell, Vol. 112, No. 2. (24 January 2003), pp. 257-269.

Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein. In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal n-acetyl aspartate (NAA), assayed with MRI spectroscopy. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF and its val/met polymorphism in human memory and hippocampal function and suggest val/met exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF.

Identification of a genetic cluster influencing memory performance and hippocampal activity in humans

Dominique de Quervain — 2006-03-21T12:11:38-00:00

PNAS, Vol. 103, No. 11. (14 March 2006), pp. 4270-4274.

Experimental work in animals has shown that memory formation depends on a cascade of molecular events. Here we show that variability of human memory performance is related to variability in genes encoding proteins of this signaling cascade, including the NMDA and metabotrobic glutamate receptors, adenylyl cyclase, CAMKII, PKA, and PKC. The individual profile of genetic variability in these signaling molecules correlated significantly with episodic memory performance (P < 0.00001). Moreover, functional MRI during memory formation revealed that this genetic profile correlated with activations in memory-related brain regions, including the hippocampus and parahippocampal gyrus. The present study indicates that genetic variability in the human homologues of memory-related signaling molecules contributes to interindividual differences in human memory performance and memory-related brain activations.

Tissue-specific and reversible RNA interference in transgenic mice

Ross Dickins — 2007-06-28T22:35:21-00:00

Nature Genetics, Vol. 39, No. 7. (17 June 2007), pp. 914-921.

Natural polymorphism affecting learning and memory in Drosophila.

Frederic Mery — 2007-07-23T11:33:21-00:00

Proc Natl Acad Sci U S A (19 July 2007)

Knowing which genes contribute to natural variation in learning and memory would help us understand how differences in these cognitive traits evolve among populations and species. We show that a natural polymorphism at the foraging (for) locus, which encodes a cGMP-dependent protein kinase (PKG), affects associative olfactory learning in Drosophila melanogaster. In an assay that tests the ability to associate an odor with mechanical shock, flies homozygous for one natural allelic variant of this gene (for(R)) showed better short-term but poorer long-term memory than flies homozygous for another natural allele (for(s)). The for(s) allele is characterized by reduced PKG activity. We showed that for(R)-like levels of both short-term learning and long-term memory can be induced in for(s) flies by selectively increasing the level of PKG in the mushroom bodies, which are centers of olfactory learning in the fly brain. Thus, the natural polymorphism at for may mediate an evolutionary tradeoff between short- and long-term memory. The respective strengths of learning performance of the two genotypes seem coadapted with their effects on foraging behavior: for(R) flies move more between food patches and so could particularly benefit from fast learning, whereas for(s) flies are more sedentary, which should favor good long-term memory.

Spatiotemporal asymmetry of associative synaptic plasticity in fear conditioning pathways.

RM Shin — 2007-07-17T12:26:38-00:00

Neuron, Vol. 52, No. 5. (7 December 2006), pp. 883-896.

Input-specific long-term potentiation (LTP) in afferent inputs to the amygdala serves an essential function in the acquisition of fear memory. Factors underlying input specificity of synaptic modifications implicated in information transfer in fear conditioning pathways remain unclear. Here we show that the strength of naive synapses in two auditory inputs converging on a single neuron in the lateral nucleus of the amygdala (LA) is only modified when a postsynaptic action potential closely follows a synaptic response. The stronger inhibitory drive in thalamic pathway, as compared with cortical input, hampers the induction of LTP at thalamo-amygdala synapses, contributing to the spatial specificity of LTP in convergent inputs. These results indicate that spike timing-dependent synaptic plasticity in afferent projections to the LA is both temporarily and spatially asymmetric, thus providing a mechanism for the conditioned stimulus discrimination during fear behavior.

Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear.

GP Shumyatsky — 2007-07-17T12:25:54-00:00

Cell, Vol. 111, No. 6. (13 December 2002), pp. 905-918.

We identified the Grp gene, encoding gastrin-releasing peptide, as being highly expressed both in the lateral nucleus of the amygdala, the nucleus where associations for Pavlovian learned fear are formed, and in the regions that convey fearful auditory information to the lateral nucleus. Moreover, we found that GRP receptor (GRPR) is expressed in GABAergic interneurons of the lateral nucleus. GRP excites these interneurons and increases their inhibition of principal neurons. GRPR-deficient mice showed decreased inhibition of principal neurons by the interneurons, enhanced long-term potentiation (LTP), and greater and more persistent long-term fear memory. By contrast, these mice performed normally in hippocampus-dependent Morris maze. These experiments provide genetic evidence that GRP and its neural circuitry operate as a negative feedback regulating fear and establish a causal relationship between Grpr gene expression, LTP, and amygdala-dependent memory for fear.

GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity.

F Duprat — 2007-06-21T02:32:21-00:00

Philos Trans R Soc Lond B Biol Sci, Vol. 358, No. 1432. (29 April 2003), pp. 715-720.

AMPA-type glutamate receptors mediate most fast excitatory synaptic transmissions in the mammalian brain. They are critically involved in the expression of long-term potentiation and long-term depression, forms of synaptic plasticity that are thought to underlie learning and memory. A number of synaptic proteins have been identified that interact with the intracellular C-termini of AMPA receptor subunits. Here, we review recent studies and present new experimental data on the roles of these interacting proteins in regulating the AMPA receptor function during basal synaptic transmission and plasticity.

Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation.

Ammar H Hawasli — 2007-06-04T11:48:57-00:00

Nat Neurosci (27 May 2007)

Learning is accompanied by modulation of postsynaptic signal transduction pathways in neurons. Although the neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) has been implicated in cognitive disorders, its role in learning has been obscured by the perinatal lethality of constitutive knockout mice. Here we report that conditional knockout of Cdk5 in the adult mouse brain improved performance in spatial learning tasks and enhanced hippocampal long-term potentiation and NMDA receptor (NMDAR)-mediated excitatory postsynaptic currents. Enhanced synaptic plasticity in Cdk5 knockout mice was attributed to reduced NR2B degradation, which caused elevations in total, surface and synaptic NR2B subunit levels and current through NR2B-containing NMDARs. Cdk5 facilitated the degradation of NR2B by directly interacting with both it and its protease, calpain. These findings reveal a previously unknown mechanism by which Cdk5 facilitates calpain-mediated proteolysis of NR2B and may control synaptic plasticity and learning.

The Neuregulin-1 Receptor ErbB4 Controls Glutamatergic Synapse Maturation and Plasticity.

B Li — 2007-05-31T04:23:11-00:00

Neuron, Vol. 54, No. 4. (24 May 2007), pp. 583-597.

Neuregulin-1 (NRG1) signaling participates in numerous neurodevelopmental processes. Through linkage analysis, nrg1 has been associated with schizophrenia, although its pathophysiological role is not understood. The prevailing models of schizophrenia invoke hypofunction of the glutamatergic synapse and defects in early development of hippocampal-cortical circuitry. Here, we show that the erbB4 receptor, as a postsynaptic target of NRG1, plays a key role in activity-dependent maturation and plasticity of excitatory synaptic structure and function. Synaptic activity leads to the activation and recruitment of erbB4 into the synapse. Overexpressed erbB4 selectively enhances AMPA synaptic currents and increases dendritic spine size. Preventing NRG1/erbB4 signaling destabilizes synaptic AMPA receptors and leads to loss of synaptic NMDA currents and spines. Our results indicate that normal activity-driven glutamatergic synapse development is impaired by genetic deficits in NRG1/erbB4 signaling leading to glutamatergic hypofunction. These findings link proposed effectors in schizophrenia: NRG1/erbB4 signaling perturbation, neurodevelopmental deficit, and glutamatergic hypofunction.

Remote control of neuronal activity with a light-gated glutamate receptor.

S Szobota — 2007-05-31T05:15:44-00:00

Neuron, Vol. 54, No. 4. (24 May 2007), pp. 535-545.

The ability to stimulate select neurons in isolated tissue and in living animals is important for investigating their role in circuits and behavior. We show that the engineered light-gated ionotropic glutamate receptor (LiGluR), when introduced into neurons, enables remote control of their activity. Trains of action potentials are optimally evoked and extinguished by 380 nm and 500 nm light, respectively, while intermediate wavelengths provide graded control over the amplitude of depolarization. Light pulses of 1-5 ms in duration at approximately 380 nm trigger precisely timed action potentials and EPSP-like responses or can evoke sustained depolarizations that persist for minutes in the dark until extinguished by a short pulse of approximately 500 nm light. When introduced into sensory neurons in zebrafish larvae, activation of LiGluR reversibly blocks the escape response to touch. Our studies show that LiGluR provides robust control over neuronal activity, enabling the dissection and manipulation of neural circuitry in vivo.

Recovery of learning and memory is associated with chromatin remodelling

Andre Fischer — 2007-04-30T23:48:55-00:00

Nature (29 April 2007)

The amygdala modulates the consolidation of memories of emotionally arousing experiences.

JL McGaugh — 2007-04-18T17:12:56-00:00

Annu Rev Neurosci, Vol. 27 (2004), pp. 1-28.

Converging findings of animal and human studies provide compelling evidence that the amygdala is critically involved in enabling us to acquire and retain lasting memories of emotional experiences. This review focuses primarily on the findings of research investigating the role of the amygdala in modulating the consolidation of long-term memories. Considerable evidence from animal studies investigating the effects of posttraining systemic or intra-amygdala infusions of hormones and drugs, as well as selective lesions of specific amygdala nuclei, indicates that (a) the amygdala mediates the memory-modulating effects of adrenal stress hormones and several classes of neurotransmitters; (b) the effects are selectively mediated by the basolateral complex of the amygdala (BLA); (c) the influences involve interactions of several neuromodulatory systems within the BLA that converge in influencing noradrenergic and muscarinic cholinergic activation; (d) the BLA modulates memory consolidation via efferents to other brain regions, including the caudate nucleus, nucleus accumbens, and cortex; and (e) the BLA modulates the consolidation of memory of many different kinds of information. The findings of human brain imaging studies are consistent with those of animal studies in suggesting that activation of the amygdala influences the consolidation of long-term memory; the degree of activation of the amygdala by emotional arousal during encoding of emotionally arousing material (either pleasant or unpleasant) correlates highly with subsequent recall. The activation of neuromodulatory systems affecting the BLA and its projections to other brain regions involved in processing different kinds of information plays a key role in enabling emotionally significant experiences to be well remembered.

Involvement of the amygdala in memory storage: interaction with other brain systems.

JL McGaugh — 2005-08-10T17:56:00-00:00

Proc Natl Acad Sci U S A, Vol. 93, No. 24. (26 November 1996), pp. 13508-13514.

There is extensive evidence that the amygdala is involved in affectively influenced memory. The central hypothesis guiding the research reviewed in this paper is that emotional arousal activates the amygdala and that such activation results in the modulation of memory storage occurring in other brain regions. Several lines of evidence support this view. First, the effects of stress-related hormones (epinephrine and glucocorticoids) are mediated by influences involving the amygdala. In rats, lesions of the amygdala and the stria terminalis block the effects of posttraining administration of epinephrine and glucocorticoids on memory. Furthermore, memory is enhanced by posttraining intraamygdala infusions of drugs that activate beta-adrenergic and glucocorticoid receptors. Additionally, infusion of beta-adrenergic blockers into the amygdala blocks the memory-modulating effects of epinephrine and glucocorticoids, as well as those of drugs affecting opiate and GABAergic systems. Second, an intact amygdala is not required for expression of retention. Inactivation of the amygdala prior to retention testing (by posttraining lesions or drug infusions) does not block retention performance. Third, findings of studies using human subjects are consistent with those of animal experiments. beta-Blockers and amygdala lesions attenuate the effects of emotional arousal on memory. Additionally, 3-week recall of emotional material is highly correlated with positronemission tomography activation (cerebral glucose metabolism) of the right amygdala during encoding. These findings provide strong evidence supporting the hypothesis that the amygdala is involved in modulating long-term memory storage.

Exploration of signal transduction pathways in cerebellar long-term depression by kinetic simulation.

S Kuroda — 2007-05-09T10:44:54-00:00

J Neurosci, Vol. 21, No. 15. (1 August 2001), pp. 5693-5702.

Because multiple molecular signal transduction pathways regulate cerebellar long-term depression (LTD), which is thought to be a possible molecular and cellular basis of cerebellar learning, the systematic relationship between cerebellar LTD and the currently known signal transduction pathways remains obscure. To address this issue, we built a new diagram of signal transduction pathways and developed a computational model of kinetic simulation for the phosphorylation of AMPA receptors, known as a key step for expressing cerebellar LTD. The phosphorylation of AMPA receptors in this model consists of an initial phase and an intermediate phase. We show that the initial phase is mediated by the activation of linear cascades of protein kinase C (PKC), whereas the intermediate phase is mediated by a mitogen-activated protein (MAP) kinase-dependent positive feedback loop pathway that is responsible for the transition from the transient phosphorylation of the AMPA receptors to the stable phosphorylation of the AMPA receptors. These phases are dually regulated by the PKC and protein phosphatase pathways. Both phases also require nitric oxide (NO), although NO per se does not show any ability to induce LTD; this is consistent with a permissive role as reported experimentally (Lev-Ram et al., 1997). Therefore, the kinetic simulation is a powerful tool for understanding and exploring the behaviors of complex signal transduction pathways involved in cerebellar LTD.

Inositol 1,4,5-trisphosphate-dependent Ca2+ threshold dynamics detect spike timing in cerebellar Purkinje cells.

T Doi — 2006-12-01T08:35:58-00:00

J Neurosci, Vol. 25, No. 4. (26 January 2005), pp. 950-961.

Large Ca2+ signals essential for cerebellar long-term depression (LTD) at parallel fiber (PF)-Purkinje cell synapses are known to be induced when PF activation precedes climbing fiber (CF) activation by 50-200 ms, consistent with cerebellar learning theories. However, large Ca2+ signals and/or LTD can also be induced by massive PF stimulation alone or by photolysis of caged Ca2+ or inositol 1,4,5-trisphosphate (IP3). To understand the spike-timing detection mechanisms in cerebellar LTD, we developed a kinetic model of Ca2+ dynamics within a Purkinje dendritic spine. In our kinetic simulation, IP3 was first produced via the metabotropic pathway of PF inputs, and the Ca2+ influx in response to the CF input triggered regenerative Ca2+-induced Ca2+ release from the internal stores via the IP3 receptors activated by the increased IP3. The delay in IP3 increase caused by the PF metabotropic pathway generated the optimal PF-CF interval. The Ca2+ dynamics revealed a threshold for large Ca2+ release that decreased as IP3 increased, and it coherently explained the different forms of LTD. At 2.5 microM IP3, CF activation after PF activation was essential to reach the threshold for the regenerative Ca2+ release. At 10 microM IP3, the same as achieved experimentally by strong IP3 photolysis, the threshold was lower, and thus large Ca2+ release was generated even without CF stimulation. In contrast, the basal 0.1 microM IP3 level resulted in an extremely high Ca2+ threshold for regenerative Ca2+ release. Thus, the results demonstrated that Ca2+ dynamics can detect spike timing under physiological conditions, which supports cerebellar learning theories.

Multimodal fast optical interrogation of neural circuitry

Feng Zhang — 2007-04-05T10:04:24-00:00

Nature, Vol. 446, No. 7136., pp. 633-639.

5-Hydroxytryptamine induces a protein kinase A/mitogen-activated protein kinase-mediated and macromolecular synthesis-dependent late phase of long-term potentiation in the amygdala.

YY Huang — 2007-03-27T10:08:21-00:00

J Neurosci, Vol. 27, No. 12. (21 March 2007), pp. 3111-3119.

The amygdala is a critical site for the acquisition of learned fear memory in mammals, and the formation and long-term maintenance of fear memories are thought to be associated with changes of synaptic strength in the amygdala. Here we report that serotonin (5-hydroxytryptamine; 5-HT), a modulatory neurotransmitter known to be linked to learned fearful and emotional behavior, has dual effects on excitatory synaptic transmission in the basolateral amygdala. There is an early depression of synaptic transmission lasting 30-50 min, mediated by 5-HT1A, and a late, long-lasting facilitation lasting >5 h in slice recordings, mediated by the 5-HT4 receptor. 5-HT late phase long-term potentiation (L-LTP) is blocked by inhibitors of either protein kinase A (PKA) and/or mitogen-activated kinase (MAPK) and requires new protein synthesis and gene transcription. Moreover, the 5-HT-induced L-LTP in neurons of amygdala is blocked by the actin inhibitor cytochalasin D, suggesting that 5-HT stimulates a cytoskeletal rearrangement. These results show, for the first time, that 5-HT can produce long-lasting facilitation of synaptic transmission in the amygdala and provides evidence for the possible synaptic role of 5-HT in long-term memory for learned fear.

Presynaptic autoreceptors in the third decade: focus on alpha2-adrenoceptors.

K Starke — 2007-03-26T07:01:25-00:00

J Neurochem, Vol. 78, No. 4. (August 2001), pp. 685-693.

Calcium-permeable AMPA receptors mediate long-term potentiation in interneurons in the amygdala.

NK Mahanty — 2007-03-15T11:45:55-00:00

Nature, Vol. 394, No. 6694. (13 August 1998), pp. 683-687.

Fear conditioning is a paradigm that has been used as a model for emotional learning in animals. The cellular correlate of fear conditioning is thought to be associative N-methyl-D-aspartate (NMDA) receptor-dependent synaptic plasticity within the amygdala. Here we show that glutamatergic synaptic transmission to inhibitory interneurons in the basolateral amygdala is mediated solely by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast to AMPA receptors at inputs to pyramidal neurons, these receptors have an inwardly rectifying current-voltage relationship, indicative of a high permeability to calcium. Tetanic stimulation of inputs to interneurons caused an immediate and sustained increase in the efficacy of these synapses. This potentiation required a rise in postsynaptic calcium, but was independent of NMDA receptor activation. The potentiation of excitatory inputs to interneurons was reflected as an increase in the amplitude of the GABA(A)-mediated inhibitory synaptic current in pyramidal neurons. These results demonstrate that excitatory synapses onto interneurons within a fear conditioning circuit show NMDA-receptor independent long-term potentiation. This plasticity might underlie the increased synchronization of activity between neurons in the basolateral amygdala after fear conditioning.

Synapse-specific reconsolidation of distinct fear memories in the lateral amygdala.

Valérie Doyère — 2007-03-15T11:23:53-00:00

Nat Neurosci (11 March 2007)

When reactivated, memories enter a labile, protein synthesis-dependent state, a process referred to as reconsolidation. Here, we show in rats that fear memory retrieval produces a synaptic potentiation in the lateral amygdala that is selective to the reactivated memory, and that disruption of reconsolidation is correlated with a reduction of synaptic potentiation in the lateral amygdala. Thus, both retrieval and reconsolidation alter memories via synaptic plasticity at selectively targeted synapses.

Anti-Hebbian long-term potentiation in the hippocampal feedback inhibitory circuit.

KP Lamsa — 2007-03-14T07:40:18-00:00

Science, Vol. 315, No. 5816. (2 March 2007), pp. 1262-1266.

Long-term potentiation (LTP), which approximates Hebb's postulate of associative learning, typically requires depolarization-dependent glutamate receptors of the NMDA (N-methyl-D-aspartate) subtype. However, in some neurons, LTP depends instead on calcium-permeable AMPA-type receptors. This is paradoxical because intracellular polyamines block such receptors during depolarization. We report that LTP at synapses on hippocampal interneurons mediating feedback inhibition is "anti-Hebbian":Itis induced by presynaptic activity but prevented by postsynaptic depolarization. Anti-Hebbian LTP may occur in interneurons that are silent during periods of intense pyramidal cell firing, such as sharp waves, and lead to their altered activation during theta activity.

Obligatory Role of NR2A for Metaplasticity in Visual Cortex.

BD Philpot — 2007-02-16T06:22:37-00:00

Neuron, Vol. 53, No. 4. (15 February 2007), pp. 495-502.

Light deprivation lowers the threshold for long-term depression (LTD) and long-term potentiation (LTP) in visual cortex by a process termed metaplasticity, but the mechanism is unknown. The decreased LTD/P threshold correlates with a decrease in the ratio of NR2A to NR2B subunits of cortical NMDA receptors (NMDARs) and a slowing of NMDAR-mediated excitatory postsynaptic currents (EPSCs). However, whether and how changes in NR2 subunit expression contribute to LTD and LTP have been controversial. In the present study, we used an NR2A knockout (KO) mouse to examine the role of this subunit in the experience-dependent modulation of NMDAR properties, LTD, and LTP. We found that deletion of NR2A abrogates the effects of visual experience on NMDAR EPSCs and prevents metaplasticity of LTP and LTD. These data support the hypothesis that experience-dependent changes in NR2A/B are functionally significant and yield a mechanism for an adjustable synaptic modification threshold in visual cortex.

Regulatory mechanisms of AMPA receptors in synaptic plasticity

Victor Derkach — 2007-01-22T15:45:40-00:00

Nature Reviews Neuroscience, Vol. 8, No. 2., pp. 101-113.

The molecular basis of CaMKII function in synaptic and behavioural memory.

J Lisman — 2007-02-14T07:32:23-00:00

Nat Rev Neurosci, Vol. 3, No. 3. (March 2002), pp. 175-190.

Long-term potentiation (LTP) in the CA1 region of the hippocampus has been the primary model by which to study the cellular and molecular basis of memory. Calcium/calmodulin-dependent protein kinase II (CaMKII) is necessary for LTP induction, is persistently activated by stimuli that elicit LTP, and can, by itself, enhance the efficacy of synaptic transmission. The analysis of CaMKII autophosphorylation and dephosphorylation indicates that this kinase could serve as a molecular switch that is capable of long-term memory storage. Consistent with such a role, mutations that prevent persistent activation of CaMKII block LTP, experience-dependent plasticity and behavioural memory. These results make CaMKII a leading candidate in the search for the molecular basis of memory.

The neuronal microRNA system

Kenneth Kosik — 2006-11-20T22:53:28-00:00

Nature Reviews Neuroscience, Vol. 7, No. 12., pp. 911-920.

Synaptic Protein Synthesis Associated with Memory Is Regulated by the RISC Pathway in Drosophila

Shovon Ashraf — 2006-01-13T14:45:49-00:00

Cell, Vol. 124, No. 1. (13 January 2006), pp. 191-205.

SummaryLong-lasting forms of memory require protein synthesis, but how the pattern of synthesis is related to the storage of a memory has not been determined. Here we show that neural activity directs the mRNA of the Drosophila Ca2+, Calcium/Calmodulin-dependent Kinase II (CaMKII), to postsynaptic sites, where it is rapidly translated. These features of CaMKII synthesis are recapitulated during the induction of a long-term memory and produce patterns of local protein synthesis specific to the memory. We show that mRNA transport and synaptic protein synthesis are regulated by components of the RISC pathway, including the SDE3 helicase Armitage, which is specifically required for long-lasting memory. Armitage is localized to synapses and lost in a memory-specific pattern that is inversely related to the pattern of synaptic protein synthesis. Therefore, we propose that degradative control of the RISC pathway underlies the pattern of synaptic protein synthesis associated with a stable memory.

A brain-specific microRNA regulates dendritic spine development

Gerhard Schratt — 2006-01-19T04:33:05-00:00

Nature, Vol. 439, No. 7074., pp. 283-289.

Different types of calcium channels mediate central synaptic transmission.

T Takahashi — 2007-01-29T09:01:48-00:00

Nature, Vol. 366, No. 6451. (11 November 1993), pp. 156-158.

Synaptic transmission is mediated by calcium entry through voltage-dependent calcium channels in presynaptic nerve terminals. Various types of calcium channel have been characterized in neuronal somata, but it is not clear which subtypes induce transmitter release at central synapses. The N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CgTx) suppresses the excitatory postsynaptic responses only partially, whereas potassium-induced release of glutamate from brain synaptosomes can be blocked by omega-Aga-VIA (ref. 9), a blocker of P-type calcium channels and possibly of other types of calcium channels. Here we test type-specific calcium-channel blockers on postsynaptic currents recorded from neurons in thin slices of rat central nervous system. Inhibitory postsynaptic currents in cerebellar and spinal neurons and excitatory postsynaptic currents in hippocampal neurons are markedly suppressed by omega-Aga-IVA and reduced to a lesser extent by omega-CgTx. The L-type calcium channel blocker nicardipine had no effect. Our results indicate that at least two types of calcium channel mediate synaptic transmission in the mammalian central nervous system.

Coactivation of beta-adrenergic and cholinergic receptors enhances the induction of long-term potentiation and synergistically activates mitogen-activated protein kinase in the hippocampal CA1 region.

AM Watabe — 2007-01-19T11:40:57-00:00

J Neurosci, Vol. 20, No. 16. (15 August 2000), pp. 5924-5931.

Interactions between noradrenergic and cholinergic receptor signaling may be important in some forms of learning. To investigate whether noradrenergic and cholinergic receptor interactions regulate forms of synaptic plasticity thought to be involved in memory formation, we examined the effects of concurrent beta-adrenergic and cholinergic receptor activation on the induction of long-term potentiation (LTP) in the hippocampal CA1 region. Low concentrations of the beta-adrenergic receptor agonist isoproterenol (ISO) and the cholinergic receptor agonist carbachol had no effect on the induction of LTP by a brief train of 5 Hz stimulation when applied individually but dramatically facilitated LTP induction when coapplied. Although carbachol did not enhance ISO-induced increases in cAMP, coapplication of ISO and carbachol synergistically activated p42 mitogen-activated protein kinase (p42 MAPK). This suggests that concurrent beta-adrenergic and cholinergic receptor activation enhances LTP induction by activating MAPK and not by additive or synergistic effects on adenylyl cyclase. Consistent with this, blocking MAPK activation with MEK inhibitors suppressed the facilitation of LTP induction produced by concurrent beta-adrenergic and cholinergic receptor activation. Although MEK inhibitors also suppressed the induction of LTP by a stronger 5 Hz stimulation protocol that induced LTP in the absence of ISO and carbachol, they had no effect on LTP induced by high-frequency synaptic stimulation or low-frequency synaptic stimulation paired with postsynaptic depolarization. Our results indicate that MAPK activation has an important, modulatory role in the induction of LTP and suggest that coactivation of noradrenergic and cholinergic receptors regulates LTP induction via convergent effects on MAPK.

Downregulation of transient K+ channels in dendrites of hippocampal CA1 pyramidal neurons by activation of PKA and PKC.

DA Hoffman — 2007-01-19T11:34:24-00:00

J Neurosci, Vol. 18, No. 10. (15 May 1998), pp. 3521-3528.

We have reported recently a high density of transient A-type K+ channels located in the distal dendrites of CA1 hippocampal pyramidal neurons and shown that these channels shape EPSPs, limit the back-propagation of action potentials, and prevent dendritic action potential initiation (). Because of the importance of these channels in dendritic signal propagation, their modulation by protein kinases would be of significant interest. We investigated the effects of activators of cAMP-dependent protein kinase (PKA) and the Ca2+-dependent phospholipid-sensitive protein kinase (PKC) on K+ channels in cell-attached patches from the distal dendrites of hippocampal CA1 pyramidal neurons. Inclusion of the membrane-permeant PKA activators 8-bromo-cAMP (8-br-cAMP) or forskolin in the dendritic patch pipette resulted in a depolarizing shift in the activation curve for the transient channels of approximately 15 mV. Activation of PKC by either of two phorbol esters also resulted in a 15 mV depolarizing shift of the activation curve. Neither PKA nor PKC activation affected the sustained or slowly inactivating component of the total outward current. This downregulation of transient K+ channels in the distal dendrites may be responsible for some of the frequently reported increases in cell excitability found after PKA and PKC activation. In support of this hypothesis, we found that activation of either PKA or PKC significantly increased the amplitude of back-propagating action potentials in distal dendrites.

Protein kinase modulation of dendritic K+ channels in hippocampus involves a mitogen-activated protein kinase pathway.

LL Yuan — 2007-01-19T11:32:07-00:00

J Neurosci, Vol. 22, No. 12. (15 June 2002), pp. 4860-4868.

We investigated mitogen-activated protein kinase (MAPK) modulation of dendritic, A-type K+ channels in CA1 pyramidal neurons in the hippocampus. Activation of cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) leads to an increase in the amplitude of backpropagating action potentials in distal dendrites through downregulation of transient K+ channels in CA1 pyramidal neurons in the hippocampus. We show here that both of these signaling pathways converge on extracellular-regulated kinases (ERK)-specific MAPK in mediating this reduction in dendritic K+ current, which is confirmed, in parallel, by biochemical assays using phosphospecific antibodies against the ppERK and pKv4.2. Furthermore, immunostaining indicates dendritic localization of ppERK and pKv4.2. Taken together, these results demonstrate that dendritic, A-type K+ channels are dually regulated by PKA and PKC through a common downstream pathway involving MAPK, and the modulation of these K+ channels may be accounted for by the phosphorylation of Kv4.2 subunits.

Activity-dependent decrease of excitability in rat hippocampal neurons through increases in Ih

Yuan Fan — 2005-10-27T05:37:50-00:00

Nature Neuroscience, Vol. 8, No. 11. (23 October 2005), pp. 1542-1551.