Corticosteroids

Glucocorticoid hormones, released from the adrenal glands, easily access the brain where they can affect neural structure and function through the binding to two types of intracellular receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Secretion of these steroids is activated by exposure to stressful situations, and growing evidence indicates that they can interact with the neurobiological mechanisms subserving memory formation. After a brief description of...

Conclusion

We have reviewed strong evidence that K+ channel modulation influences neuronal spiking and or synaptic transmission and appears to contribute to memory formation (and maybe even retrieval). Considering the results from different model organisms, continuities and changes among them are apparent. Conditioning in two species of mollusc leads to prolonged action potentials. The affected K+ currents are not identical in each case, perhaps a matter of different circuits. In both species,...

Ligand Gated Ion Channel

The 5-HT3 receptor is the only ligand-gated ion channel among the 5-HT receptors. Inactivation of 5-HT3 receptors has been found to increase the frequency of the hippocam-pal theta rhythm and the magnitude and duration of long-term potentiation (LTP) in the CA1 of the hippocampus of freely moving rats.121 These neurophysiological effects have been correlated with improved retention in both spatial and olfactory memory tasks, behaviors which require the integrity of the hippocampus.121 Systemic...

Necessity for ERK Activation for Mammalian Learning

As described in section two of this book, two paradigms that have been used extensively in studying learning are the conditioned fear task6 and the Morris water task.74 In fear conditioning, animals learn to associate neutral stimuli with a foot shock. In the spatial learning version of the Morris water task, animals learn to utilize various distal visual cues to navigate through a pool of water to locate a hidden escape platform. Lesions of the hippocampus has previously been shown to impair...

Abbreviations

acid acid 11-HSD 11beta-Hydroxysteroid dehydrogenase acid acid ibuprofen acid ACE angiotensin converting enzyme acid ACTH adrenocorticotropic hormone acid acid receptor AP5 2-amino-5-phosphonovaleric acid Arc activity-regulated cytoskeleton associated protein BDNF brain-derived neurotrophic factor BLA basolateral nucleus of the amygdala BOC tert-butoxycarbonyloxiimino protective group CaMk calmodulin-calcium dependent kinase protein kinase CaMK-II calcium-calmodulin dependent kinase-type II...

Adenosine and Purines

Nikbakht and E. Martin O'Kane Abstract Adenosine can act on four subtypes of receptor, of which the Ai and A2A subtypes have received the most attention experimentally. The Ai receptors are primarily inhibitory by depressing transmitter release or causing hyperpolarisation, while the A2A receptors often cause overall excitation by direct depolarisation or the facilitation of transmitter release. Activation of these receptors can also modulate neuronal sensitivity to...

Adenylyl Cyclases

Nicole Mons and Jean-Louis Guillou Abstract Although a number of signal transduction pathways have been implicated in short- and long-term adaptative changes in neuronal plasticity and memory formation, there is increasing evidence that cross-talk between the cAMP- and Ca2+-regulatory pathways may play a pivotal role in learning and memory processes. The fact that adenylyl cyclases (AC), in both invertebrates and mammals, are potentially subject to a wide range of influences has given rise to...

Alzheimers Disease

Abnormal Ca2+ homeostasis characterizes pathophysiology ofAlzheimer's disease (AD). For instance, in AD fibroblasts, bombesin- and bradykinin-induced Ca2+ release (through IP3Rs) is greatly enhanced, compared with those from control groups.55'61 The Ca2+-mediated acetylcholine release from rat hippocampal slice is potently and acutely inhibited by low concentration (10-8 M) of P-amyloid.64 P-Amyloid (AP) causes the death of cortical neurons at micromolar concentrations38 and can directly form...

Anatomy of Brain Cholinergic Pathways

Muscarinic acetylcholine receptors (mAChRs) are the targets of ACh released from the cholinergic nerve endings and in some cases, are located on cholinergic neurons and nerve endings (autoreceptors). For this reason, a short description of the brain cholinergic system is deemed useful.The central cholinergic system was characterized in the eighties using an anti-choline acetyltransferase (ChAT) antibody99 and it was divided into 10 relatively well defined populations of cholinergic neurons...

Animal and Human Amnesia

The Cholinergic Hypothesis Revisited Robert Jaffard and Aline Marighetto Identifying Memory Dysfunction The net effect of an experimentally-induced or naturally occurring alteration in learning and memory is generally determined by the type of neurological dysfunction (from focal lesions to gene expression) and or the nature of the learning task. Accordingly, memory systems are defined as distinct, but interactive, psychological and biological entities that still need specification. Within this...

Avoidance Learning

Avoidance training is widely used and has several advantages compared with spatial learning. Animals have to learn a specific stimulus-response association and this enables better control over the actual learning process. Moreover, the reinforcer used in most studies is a mild footshock. As a consequence, only few trials are necessary to induce long-lasting memory and drug-treatment can therefore selectively target the different stages of memory processing. In inhibitory or passive avoidance...

Ca2 Influx

The ultimate Ca2+ source for neurons exits outside the neurons. Entry of Ca2+ across the plasma membrane is known to be important in generating neuronal Ca2+ signals, resulting in membrane depolarization and an increased Ca2+ c. Ca2+ channel expression at the cell surface is regulated by intracellular signaling molecules.13 The latter leads to activation of Ca2+-dependent intracellular signal cascades. There is a large gradient of Ca2+ concentration across the plasma membrane extracellular Ca2+...

CaMKII Synaptic Plasticity and Memory Processing

Over the last decades a multidisciplinary effort has been made in the search of the molecular and cellular mechanisms responsible for learning and memory. Most of these studies have utilised as a working hypothesis that postulated by Donald Hebb in 1949 which proposes that a given synapse would be strengthened when the pre and postsynaptic neurons were coinciden-tally activated. Today it is an almost universally accepted hypothesis that the storage of new information under the form of long term...

CaMkiv A New and Important Player in the Plasticity Team

Translocation of CaMKII into the nucleus is thought to be regulated by the phosphorylation of a Ser residue adjacent to the NLS sequence in the nuclear-targeted isoforms. The finding that both CaMKI and CaMKIV are able to phosphorylate that site and hinder the accessibility of CaMKII to the nucleus shows the existence of complicated interrelation mechanisms among the different members of the Ca2+ CaM-dependent kinases family.36 As it happens with CaMKII, both CaMKI and CaMKIV are able to bind...

Cannabinoid Receptor Ligands

Endogenous cannabinoid receptor ligands (endocannabinoids) such as anandamide and 2-arachidonoyl glycerol have been isolated20,70 and are able to bind and activate the cloned cannabinoid receptors. A common property of these endocannabinoids, sometimes referred to as eicosanoids, is that they are chemical derivatives of the polyunsaturated fatty acid, arachi-donic acid. They serve as neurotransmitters neuromodulators, are not stored in vesicles but instead are synthesised on demand and released...

Cannabinoid Receptors Modulate Memory Formation

Most of the animal research summarised below has been guided by work on human subjects, for which disruption of short-term memory is a widely acknowledged effect of marijuana or A9THC.11-13'24,29'72,95 Direct effects on memory storage, however, have not been found.3'24 Interestingly, marijuana increased cerebral blood flow predominantly in paralimbic regions of the frontal lobes and the cerebellum, but reduced blood flow in the temporal lobe. 2 Such hypoactivity may be the neural basis of...

Capacity to Prolong Changes and Induce Permanent Functional Alterations

While phosphorylation and dephosphorylation events are, in many cases, quite transient, the activity of most kinases and some phosphatases can be prolonged via several means including, in particular, autophosphorylation, through which an activated kinase phosphorylates itself as well as other substrates. Autophosphorylated kinases continue to phosphorylate substrates following degradation of the message responsible for their activation. Provided phosphatase activity is constrained, therefore,...

Cell Adhesion Molecules

The molecular cascade of events associated with hippocampal processing of information for long-term storage is a time-limited event. Learning sets in motion neural processes that continue to evolve after training, a phenomenon known as consolidation. The consolidation process has been proposed to involve the translation of neural activity into enduring synaptic change by a cascade of sequential molecular steps involving gene induction, increased protein synthesis and synaptic growth mediated,...

CNS Distribution of the Muscarinic Receptors

While a great diversity of behavioral, physiological and biochemical effects is mediated by mAChRs, the identities of the molecular subtypes responsible for any given neuronal function remain elusive. The complex pharmacology of the mAChR subtypes, together with the lack of drugs with high selectivity has made it difficult to determine the individual roles of m1-m5 receptors in the brain. Identification of the mAChR subtypes in the brain has been accomplished using in situ hybridization to...

Cognitive Alteration Induced by Lesions in the Cholinergic Pathways

The prerequisite of lesion studies is the selectivity of the lesion. In order to investigate their role in learning and memory, the lesions must damage only the cholinergic neurons, a condition which is not easily obtained. The first difficulty is represented by the anatomy of the cholin-ergic system since the basal forebrain cholinergic neurons are not clustered together in a well localized nucleus that can be lesioned easily.22 For many years the second difficulty was the tool for making the...

Cognitive Alterations Induced by the Blockade of Muscarinic Receptors

The nonselective muscarinic antagonist scopolamine has been extensively used to study the cognitive alterations induced by the blockade of muscarinic receptors.112 The interpretation of the pharmacological data is not straightforward, as scopolamine blocks postsynaptic receptors as well as presynaptic autoreceptors, this latter effect being responsible for an increase in ACh.197 Scopolamine administered to human subjects impairs rapid information processing209 and encoding of new memories in...

Cognitive Processes Associated with Changes in Cholinergic Activity

The development of the in vivo microdialysis technique191 coupled to sensitive analytical systems for the quantification of ACh levels in the nanomolar range has made it feasible to correlate changes in ACh extracellular levels in the brain with cognitive processes in the animal. Using this approach, it has been possible to study the behaviorally-induced activation of the cholinergic system ascending from the NB to the cortex, from the septum to the hippocampus or in other structures, during...

Conclusions

In summary, the aforementioned behavioural data seem to provide strong evidence for a role of cannabinoids in learning and formation of different forms of memory. However, it could be argued that because systemic infusion of A9THC or other synthetic cannabinoid receptor agonists has numerous unspecific effects, hard proof is difficult to obtain and many studies may be flawed by the overshadowing effects of CB1 activation-induced changes in activity or reward rather than learning. While this may...

Conclusions and Remaining Questions

Collectively, how can these data be summarised Several themes seem to emerge from the data set presented here. 1) Interpretation of pharmacological experiments using AMPA receptor antagonists are somewhat flawed in their interpretation since this treatment results at least in the majority of cases in the blockade of fast synaptic transmission and thus silencing of the whole brain or one brain region in particular. Such a treatment is reminiscent of local anaesthetics such as lidocain or...

Contents

Preface Ca2+ Neurotransmitter Modulation of Channel Signal Transduction Cascades Jeffrey Vernon and Karl Peter Giese How Can K+ Channels Contribute to Learning and Memory 22 Section 2. Principle Neurotransmitters 2.1. Glutamate Gernot Riedel, Jacques Micheau and Bettina Platt Glutamate Receptor Function in Learning and Memory 2.2. y-Amino-Butyric Acid Claudio Castellano, Vincenzo Cestari and Alessandro Ciamei GABAergic Drugs and Memory Formation Peripheral GABAergic Drugs and Memory...

Creb

Josselyn Abstract The cAMP Responsive Element Binding Protein (CREB) is an activity regulated transcription factor that modulates the transcription of genes with cAMP responsive elements (CRE) located in their promoter regions. A variety of signaling pathways converge to phosphorylate CREB at Ser133 and induce transcription. Here, we review the key features of CREB-dependent transcription and evaluate evidence suggesting that CREB plays a key role in different...

DA Receptors and Cognition

When discussing DA receptors and locomotor activity we already pointed at the role of DA receptors in cognitive performance. This subject has been intensively studied by Goldman-Rakic, Arnsten, and co-workers in the nineties, using both monkeys and rats as experimental subjects. In a study with rhesus monkeys, Arnsten et al5 have provided compelling evidence that cognitive performance depends on DA D1 receptor mechanisms. In this study both young and aged monkeys were used. In aged primates...

Delayed MatchtoPosition

Several studies have tested for short-term memory in delayed-match-to-position (DMTP) or delayed-match-to-sample (DMTS) tasks. They are usually performed in a conditioning chamber and animals learn to press a lever during the sample phase and press the same (match) or opposite (nonmatch) lever during the choice phase. These tasks have a spatial component (right or left). In addition, task difficulty can be modified by increasing the delay between the sample and the choice phase with rats coming...

Dopaminergic Depletions and Cognitive Impairments

Ever since the availability of drugs that specifically destroy dopaminergic cells and fibres, the technique of local DA depletion has been a powerful tool in examining the contribution of dopaminergic systems in behavioural performance. The most widely used drug in such studies is 6-OHDA (6-hydroxy-dopamine) that will destroy dopaminergic cells and fibres, while leaving postsynaptic terminals intact. Unfortunately, 6-OHDA is not specific for dopamine but will also damage noradrenergic cells and...

Effects of Opioid Receptor Ligands on Long Term Potentiation in Hippocampal Regions Table

LTP is characterized by the enhancement of synaptic responses that are induced by a particular event, such as high-frequency stimulation, and lasts for hours or days. It is widely regarded as a cellular substrate for learning and memory processes. The mechanisms of LTP are beyond the scope of this review and have been thoroughly reviewed elsewhere.19,25 Here, we will focus on the roles of opioids in LTP of the hippocampal mossy fiber. There have been many demonstrations of and S-opioid receptor...

ERK in Hippocampal Synaptic Plasticity

Considerable evidence already exists implicating ERK in various forms of synaptic plasticity in a wide variety of systems. Long-term facilitation of the sensory-motor neuron synapse in Aplysia causes translocation of ERK into the nucleus of presynaptic neurons. Furthermore, inhibition of ERK by either anti-MAPK antibodies or PD098059 blocks long-term, but not short-term, facilitation of the sensory-motor synapse.67,72 ERK has also been shown to be activated during an in vitro Pavlovian...

From Messengers to Molecules Memories Are Made of These

Bettina Platt, Ph.D. School of Medical Sciences College of Life Sciences and Medicine University of Aberdeen Foresterhill, Aberdeen, U.K. Kluwer Academic Plenum Publishers New York, New York U.S.A. From Messengers to Molecules Memories Are Made of These Landes Bioscience Eurekah.com Kluwer Academic Plenum Publishers Copyright 2004 Eurekah.com and Kluwer Academic Plenum Publishers No part of this book may be reproduced or transmitted in any form or by any means, electronic...

GABAergic Antagonists Picrotoxin

The first study showing a possible involvement of the GABAergic system in memory was carried out by Breen and McGaugh11 with rats tested in an appetitively-motivated multiple T-maze. Posttraining intraperitoneal (i.p.) administrations of picrotoxin reduced significantly the number of errors made by the animals. This initial finding was confirmed by the observation of other investigators, using aversively-motivated as well as appetitively-motivated tasks. Studies carried out by Bovet et al9...

GABAergic Drugs and Memory Formation Administrations into Brain Structures

The possibility that GABAergic agonists and antagonists exert their effects on memory as a consequence of specific actions on central GABAergic receptors has been examined by a number of studies. The first brain structure considered has been the amygdala. It is known that retention can be modulated by posttraining intra-amygdala injections of drugs affecting several neurotrans- Figure 3. Effect of immediately posttraining intra-amygdala administrations of baclofen on retention of a one-trial...

GABAergic Drugs and Memory Genotype Dependent Effects

Studies carried out with the inbred strains of mice C57BL 6 (C57) and DBA 2 (DBA) have shown that the genetic makeup plays an important role in modulating responses to drug administration. As concerns memory processes, strain-dependent effects have been observed, in C57 and DBA mice, following posttraining injections of a number of drugs, such as opioid agonists and antagonists, corticosterone, nicotine and dopaminergic agents. For a review see reference 20. Experiments have recently been...

GABAergic Drugs and the State Dependency Hypothesis

The results of some studies have suggested that the retrograde amnesia which follows some posttraining treatments may be based on state-dependency. According to this hypothesis, the newly acquired informations may be stored in a state induced by the posttraining treatment, and are not subsequently accessible when retention is assessed while the animals are in a normal state. Several studies have reported that, while posttraining administration of P-endorphin or enkephalin impairs retention of...

Giancarlo Pepeu and Maria Grazia Giovannini Abstract

The study of brain muscarinic receptors began more than a century ago, long before the existence of muscarinic receptors was postulated and then demonstrated. However, the effects of drugs acting on these receptors, such as atropine, eserine, pilocarpine and arecoline had been studied much earlier. This chapter is an overview of these studies with the purpose of defining the roles that different subtypes of muscarinic receptors play in the cognitive process. Background information on the...

Histamine

Huston Abstract Histamine is an important but largely neglected modulator in the central nervous system. Histaminergic neurons are located exclusively in the posterior hypothalamus, the tuberomammillary nucleus (TM), from where they project to almost all brain regions, with ventral areas (hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation. Here we summarize behavioural data based on TM-lesions as well as on...

HT Receptors and Linkage to Second Messenger Signaling Pathways

Among the fourteen different 5-HT receptor types or subtypes, only 5-HT3 is a transmitter-gated cation channel, all other 5-HT receptors are linked to guanine nucleotide-binding proteins (G proteins) and members of the seven transmembrane (7TM) domain receptors. 5 The class of 5-HT1 receptor is coupled to Gi o, the 5-HT2 to Gq 11, the 5-HT4 6 7 to Gs (Fig. 2 for reviews see Hoyer and Martin,64 Barnes and Sharp11). The Gi o and Gs linkages decrease and increase adenylyl cyclase (AC) activity,...

Intracerebral Infusion of Dopaminergic Drugs and Cognitive Processes

An important progress in the search for dopaminergic involvement in cognitive processes has been the development of the technique of chronic intracerebral cannulae providing the possibility of infusing dopaminergic drugs into small, well-defined areas of the brain. The areas targeted in this manner have been especially the striatal and prefrontal cortical areas. We will focus on the prefrontal cortical areas. We will first review studies using local administration of dopaminergic drugs...

Introduction

Excitatory neurotransmission in the central nervous system is dominated by one transmitter glutamate. Due to its now well-established role in many aspects of neuronal communication, plasticity and pathology, it has been the focus of intense research in many laboratories around the world. As a consequence, the amount of literature relevant to glutamate and neuronal function has reached a size that most researchers (especially those at the start of their career) will probably consider...

Joyce Besheer and Rick A Bevins Abstract

The nicotinic cholinergic system has been widely implicated in mediating learning and or memory processes in human and nonhuman animals. This chapter highlights various areas of basic research in which stimulation or blockade of nicotinic acetylcholine receptors (nAChRs) has been shown to affect an animal's performance in a variety of tasks thought to measure learning and memory. For example, under certain conditions, stimulation of nAChRs by nicotine (or other nAChRs agonists) can enhance...

Kinases and Phosphatases in Chick Memory Formation

For the past three decades Ng, Gibbs, and their colleagues have investigated memory formation in groups of day-old-chicks trained using a single-trial PAL task in which chicks learn to avoid a red coloured bead which has been coated during a single, ten second training trial, with an aversive chemical, methylanthranilate (reviewed in ref. 144). By testing groups of chicks at precise times relative to learning, it has been possible to document the temporal characteristics of the memory trace...

Kv42 As an Effector for ERK

Recent research suggests that ERK modifies transient A-type potassium currents. Johnston and colleagues have demonstrated that MEK inhibitor application leads to downregulation of A-type K+ currents in CA1 hippocampal dendrites. Both PD098059 and U0126 produce a hyperpolarizing shift in the activation curve for this current and block the enhancement in back-propagating action potential amplitude observed in response to activators of PKA and PKC (Yuan, et al, submitted). These findings suggest a...

Learning Induced Synaptogenesis and Structural Synaptic Remodeling

Berry and Olga T. Ganeshina Abstract This chapter analyzes the results of quantitative electron microscopic studies of the vertebrate brain aimed at the elucidation of changes in synaptic unltrastructure that may underlie learning and memory. It has been reported that behavioral learning promotes new synapse formation, including both a net synaptogenesis, which causes a net gain in synapse number, and a specific synaptogenesis. The latter either accompanies a...

Long Term Potentiation A Model for Increasing Synaptic Efficacy

Long-term potentiation (LTP) is a phenomenon observed when brief trains of high-frequency stimulation (HFS) are delivered to monosynaptic excitatory pathways in hippocampal neurons, resulting in a persistent increase in synaptic efficacy. First reported in 1973, 8,19 this phenomenon is consistent with the proposal that neurons may store information as changes in synaptic efficacy and has been extensively studied as a putative memory-related brain process. While tissue from various brain areas...

LTP As a Model for Learning and Memory

Countless hours and dollars of scientific resources have been spent in an exhaustive effort to better understand the considerable complexities of synaptic plasticity, yet one overriding and critical question remains does LTP equal memory 94 In other words, does LTP have any natural physiological relevance to behavior Conclusive answers to these questions are most certainly beyond the reach of this chapter, but we do want to evaluate some of the currently available data (reviewed in refs. 10,...

Marie Christine Buhot Mathieu Wolff and Louis Segu Abstract

The serotonergic system is widely distributed in the central nervous system and plays a role in many behavioral and physiological processes. However, converging data indicate that serotonin (5-HT) is specifically involved in learning and memory by interacting with major neurotransmitters. Thus, 5-HT modulates acetylcholine and glutamate release in the pathways of first importance for memory functions. The use of global strategies aimed at modifying the 5-HT level allows to estimate the...

Memory Studies with Adrenoceptor Agonists and Antagonists in Chicks

We have systematically investigated the roles of adrenoceptors in the action of noradrena-line in a one trial learning task (discriminated avoidance learning) in the young chick, where the chick discriminates between red and blue beads. The chick at one to two days of age has a number of distinct advantages over rodents in the study of memory, including limited development of the blood brain barrier, the ability to learn about coloured beads in one short trial without any prior knowledge of...

Modulation of Channel Activity

Increases in Ca2+ c activate the Ca2+-dependent K+ channel, either large (BK) or small (SK) conductance, (Kca2+),7,105,124 limiting the firing frequency of repetitive action potentials. In hippocampal neurons, activation of BK channels underlies the falling phase of the action potential and generation of the fast afterhyperpolarization. In contrast, SK channel activation underlies generation of the slow afterhyperpolarization after a burst of action potentials. The source of Ca2+ for BK channel...

Natriuretic Peptides Angiotensin

The natriuretic peptide family is composed of at least three ligands atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). ANP and BNP regulate body fluid homeostasis and blood pressure.22,72 CNP acts mainly as a vasodilator with little natriuretic activity, and is found principally in the central nervous system and endothelial cells.123 The natriuretic peptides have a widespread distribution in the brain. They possess a variety of CNS...

Nerve Growth Factor and the Basal Forebrain Cholinergic System

NGF is the most widely studied and characterized polypeptide growth factor capable of influencing survival and differentiation of neural cells during development.44,45 Although, this prototype neurotrophic factor is well known to regulate the survival of neuronal populations, its function in the control of nerve growth remains unclear. Investigations on newborn and Figure 1. Schematic representation of neurotrophin binding showing that NGF binds to trkA, BDNF and NT4 to trkB, NT3 to trkC while...

Nitric Oxide

Ltp And Ltd Nmda

Kiyofumi Yamada and Toshitaka Nabeshima Abstract Among three isoforms of nitric oxide (NO) synthase, both neuronal and endothelial NO synthases may play an important role in learning and memory. NO production in the brain increases, in an activity-dependent manner, following an increase in intracellular Ca2+ levels. Electrophysiological studies revealed that the NO cGMP pathway plays an important role as an intercellular messenger in the long-term potentiation and long-term depression, which is...

Olfactory and Gustatory Learning Paradigms

Although data using smell and taste-related memory paradigms confirm the importance of the glutamatergic system, interpretation of results need caution due to the limited number of studies, which may only give a preliminary and fragmented picture (Table 5). For olfactory learning such as odour discrimination, odour memory and taste-potentiated odour aversion, pretraining administration of NMDA receptor antagonists via several routes caused memory impairments. Post-training administration of the...

P a

Preferentially dephosphorylates the p-subunit of phosphorylase kinase. 2. Sensitive to INH-1 and INH-2 3. Sensitive to Okadaic acid (IC50 < 10 nM) 4. Does not require divalent cations for activation PP2A 1. Preferentially dephosphorylates the (Polycation- a-subunit of phosphorylase kinase. stimulated 2. Insensitive to INH-1 and INH-2 protein 3. Sensitive to Okadaic acid (IC50 < 0.1 nM) phosphatase) 4. Does not require divalent cations for activation 5. Broad specificity 1. Targeted to...

Phospholipases and Oxidases

Memory formation is dependent on a series of biochemical cascades that alter synaptic transmission and neuronal activity. Phospholipases are key enzymes in these cascades that produce second messengers, which interact with a host of target systems, such as transmitter uptake systems, transmitter release, and intracellular calcium stores. One of the main second messengers is arachidonic acid, which also acts as a substrate for lipoxygenases and cyclooxygenases. These enzymes metabolise...

Posterior Pituitary Peptides Vasopressin Oxytocin

Vasopressin exerts a long-term facilitating effect on learning and memory processes, which can be clearly demonstrated in aversive-conditioning. The influence of vasopressin is time-dependent, i.e., the effectiveness of neuropeptide treatment depends on the time interval between the learning or retention trial and the treatment. Vasopressin and related peptides facilitate consolidation as well as retrieval processes. These neuropeptides also prevent and reverse retrograde amnesia induced by...

Potassium Channel Modulation

As described by Vernon and Giese in this book, potassium (K+) channels serve as the principal regulators of membrane excitability in the central nervous system. These channels flux K+ currents that can influence the likelihood of spike generation in a variety of ways. Certain K+ currents, such as the transient A-type and inward rectifier currents, contribute to the establishment of the resting membrane potential (Vm). Transient K+ currents also act to raise the threshold for action potential...

Protein Kinase A

Vianna and Ivan Izquierdo Abstract Memories are believed to rely upon enduring morphologic and functional changes at synapses activated by learning events. Experiments carried out in the past two decades have indicated that several cellular mechanisms need to be activated in order for the synaptic changes to take place. Among these general cellular mechanisms, enzymatic cascades including the cAMP-dependent protein kinase (protein kinase A, PKA) signaling pathway in CA1 region of...

Protein Kinase C

Xavier Nogues, Alessia Pascale, Jacques Micheau and Fiorenzo Battaini Abstract This chapter reviews the involvement of PKC in cognition and in the brain pathologies affecting cognition. PKC is a family of enzymes. Its activation process is described in the first part. In the second part, we analyse the role of PKC in synaptic plasticity, a neuronal property which may be required for the acquisition of information. Both electrophysiological data and behavioural pharmacology suggest the...

Protein Phosphatases in Aplysia Learning and Memory

Aplysia has been used to study various forms of learning (reviewed in ref. 27). Sensitisation of the gill-and-siphon-withdrawal-reflex has been most extensively studied and provides evidence of a role for PKA-mediated phosphorylation in non-associative memory processes. PKC is also indirectly implicated in learning in Aplysia.26 but the exact role for this enzyme is less clear and it is not discussed here. Sensitisation occurs when Aplysia learns to strengthen a reflex withdrawal response to...

Protein Phosphatases in LTD

Lisman's model has received a great deal of theoretical and empirical support (reviewed in refs. 106 and 222). In the interests of brevity, only evidence examining the involvement of phosphatases in relevant forms of synaptic plasticity is considered here. During LTD in the adult hippocampus in vivo, there is a transient (< one hour) increase in PP1 activity and a more persistent (> one hour) increase in PP2A activity.191 LTD in the CA1 region can be blocked by bath-application of...

Protein Phosphatases in LTP

The fact that numerous kinase-mediated events contribute to LTP justifies examination of whether phosphatases may be similarly involved' and several studies have now addressed this issue (reviewed in ref. 213). NMDA GluR subunits are reported to be closely associated with PP2A29 and decreased PP2A activity' possibly associated with increased phosphorylation of a non-catalytic PP2A subunit' has been reported in hippocampal slices following induction of LTP.57 There is also evidence to suggest...

Protein Phosphatases in Rodent Learning and Memory

Pharmacological studies examining phosphatase involvement in memory formation in rodents have emerged only recently. One of these found that rats infused with OA for several weeks developed learning difficulties.4 The rats also demonstrated gross morphological changes, however, making it difficult to determine whether phosphatase inhibition was responsible for the learning deficits or whether these deficits may have reflected a secondary problem.136 In another study, microinjection of OA into...

Protein Phosphorylation What Is It and Why Is It Significant

The cells that make up biological organisms comprise numerous components. Many are proteins, the sequence of which is encoded genetically. Proteins carry small, localized, electrostatic charges that force each molecule to adopt a three-dimensional configuration specific for that protein. This configuration determines its function. Several mechanisms have evolved by which the configuration and function of proteins can be altered. Some are irreversible, resulting in permanent structural and...

Protein Serine Threonine Phosphatases in the Brain

Phosphatases have not been as intensively studied as kinases and, even fifteen years ago, no firm conclusions could be drawn regarding how they were regulated or about their physiological roles.141 This was due mainly to a mistaken assumption that phosphatases, by generally turning things 'off', act merely to restore homeostasis. Turning things 'on' via kinase activity was thought to be the primary means of effecting change. Consistent with this view, phos-phatases were not typically observed...

Protein Synthesis I Pharmacology

Oliver Stork and Hans Welz Abstract The formation of long-lasting memory traces depends on the de novo synthesis of proteins. For more than 30 years substantial experimental evidence has been collected in species ranging from insects to mammals, in support of this hypothesis. A pharmacological approach to investigate the dependence of long-term memory formation on de novo protein synthesis is to administer drugs that prevent protein synthesis on the transcriptional or translational level. When...

Protein Synthesis II New Proteins

The role of protein synthesis in long-term memory formation is still an area of intense scientific interest, which encompasses the study of mechanisms involved in gene expression and molecular mechanisms underlying synaptic plasticity. A number of low molecular weight compounds have been used to inhibit or enhance this fundamental cellular process. The pivotal role of protein synthesis in long-term memory formation suggest yet again that an understanding of how protein synthesis can be...

Receptors

There are important differences in the pattern of opioid receptor expression among species. In rats, -opioid receptor mRNA has been demonstrated in neurons scattered in both granule cell and pyramidal cell layer, but also in stratum oriens and radiatum.2,20 Similarly, receptor autoradiography, using 3H DAMGO, has revealed a high density of -opioid binding sites in the stratum lacunosum moleculare and the pyramidal cell layer. The binding sites are moderately dense in CA3 stratum radiatum but...

References

Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 1997 88 615-626. 2. Abeliovich A, Chen C, Goda Y et al. Modified hippocampal long-term potentiation in PKCg-mutant mice. Cell 1993 75 1253-1262. 3. Abeliovich A, Paylor R, Chen C et al. PKCg mutant mice exhibit mild deficits in spatial and contextual learning. Cell 1993 75 1263-1271. 4. Adams JP, Anderson AE, Varga AW et al. The A-type potassium...

Role of 5HT in Memory Global Strategies

Serotonergic projections from the raphe nuclei, where cell bodies are concentrated, are widespread and terminate in brain structures thought to underly memory processes such as the hippocampus, the prefrontal cortex, cortical associative areas, basal ganglia, or thalamus. The projections to the frontal cortex predominantly originate in the dorsal raphe nucleus (DRN), whereas the projections to the hippocampus arise from the median raphe nucleus (MRN). The DRN regulates the excitability of...

Signal Transduction Cascades

One critical role of Ca2+ in neuronal signaling is to couple electrical excitation to the activation of intracellular enzymes, such as various tyrosine protein kinases,128'130 and signal trans-duction cascades (Fig. 1). Ca2+ regulates a wide variety of biological functions through binding to proteins, so to confine it neatly to one predominant role in mediating effects of signal transduction on synaptic plasticity may be unrealistic. Most Ca2+-binding proteins can be grouped into families with...

Signal Transduction Pathways of PAdrenoceptors

P-ARs are coupled by Gs to adenylate cyclase and produce alterations in cellular activity by raising intracellular levels of cyclic AMP (Fig. 3). Pharmacologically, the classical P-ARs have been defined as receptors at which (-)-isoprenaline acts as an agonist and (-)-propranolol as an antagonist. In addition to the classical P1- and P2-ARs there is a third subtype, the P3-AR, Figure 1. Signal transduction pathways for aj-adrenocceptors. Gq jj couples aj-adrenenoceptor to PIP2 (phosphatidyl...

Spatial Learning

Many thoughtfully developed spatial testing procedures are available to date and the most popular ones are the water maze, the 8-arm radial maze and T- or Y-mazes. These paradigms allow for spatial reference and or working memory to be assessed and there are also some Table 2. Effects of glutamate receptor blockade on spatial learning and memory formation i.c.v. (minipump), i.HC, i.IC, s.c., i.p. (postnatal d8- d19), i.v. N AP5,CPP, MK801, ketamine 7Cl-kynurenate 5,11,53,68,76, 76,78,83,125,...

Spatial Learning Requires ERK

Administration of SL327 to mice during training in the Morris water maze produced significant spatial learning deficits. SL327-treated mice took significantly longer to locate the escape platform during training compared to vehicle-treated controls (Fig. 5). Furthermore, vehicle-treated control mice performed significantly better than drug-treated animals in probe trials conducted following training suggesting that SL327 impairs spatial learning performance (Figs. 6 and 7). These results...

Spatial Learning Water Maze

Training in an open water-filled tank containing a submerged platform is a popular learning paradigm tackling spatial and thus hippocampal-dependent memory.75 Animals learn to find the submerged platform in the opaque water in relation to distal cues and reduce their latency to swim and climb onto it over days. Despite its long tradition as a behavioural test, reports on the effects of cannabinoids are relatively recent. The initial report by Ferrari and colleagues28 revealed evidence for...

Specific Contributions of ERK Isoforms to LTP and Learning

Taken together, these findings described above build a convincing argument for a requirement of the ERK isoforms of MAPK in the molecular events that underlie information storage at both the synaptic and behavioral levels. However, these inhibitor studies do not address the specific contribution of one versus the other ERK isoforms, i.e., ERK1 versus ERK2. To this end, ERK1 knockout mice were tested in various behavioral and physiological paradigms in order to elucidate the role of this...

Subtypes

Nicotinic acetylcholine receptors are ligand-gated ion channels. This receptor is composed of five polypeptide subunits that form a barrel-like structure around a central ion channel.21 In contrast to nAChRs located in the periphery which are composed of al, (31, 6, e, Y subunits, the standard configuration of the neuronal nAChRs include combinations of a and ( sub-units. However, a7, a8, and a9 subunits can also form functional nAChRs that consist of a single subunit type.25 Presently, the...

T

MR antagonist altered pecking pattern diminished avoidance GR antagonist no effect diminished avoidance Figure 3. Schematic representation of the one-trial passive avoidance task in the day-old chick and the effects of the administration of mineralocorticoid (MR) and glucocorticoid (GR) receptor antagonists on memory for this task. On the training session, due to their innate tendency to peak salient objects in their environment, chicks peck at a bright bead which has been coated in an aversive...

T t

Basolateral nucleus Inhibition of glucocortrcoid-induced Figure 5. Role of amygdala nuclei in the memory-facilitating effect of glucocorticoids. Cartoon showing neural circuits involved in the communication among different amygdala nuclei. When the central nucleus is lesioned in rats before being exposed to a training session in the passive avoidance task, the enhancement ofmemory induced by a posttraining glucocorticoid injection is preserved. However, when it is the basolateral nucleus which...

T t t t t t t t

TIME OF EXPOSURE TO ELEVATED GLUCOCORTICOIDS Figure 7. Schematic representation of the effect of sustained exposure to elevated levels of glucocorticoids on hippocampal CA3 neurons. Animal studies have shown that pyramidal CA3 neurons undergo a time-dependent neurodegeneration process when expossed to excessive glucocorticoids or to sustained stress. When these conditions are mantained for 3-4 weeks, a reversible atrophy of apical dendrites is observed. However, if they last for longer time...

Table 2 Shortest active amino acid sequences of neuropeptides modulating learning and memory processes

The anatomical substrate of facilitating retrieval of information activity of AII(3-7) is closely related to the dopaminergic projection from the ventral tegmental area and substantia nigra to the central amygdala and to the hippocampus.147 Delorenzi et al29 in the crab Chasmagnathus found that Ang IV enhances long-term memory stronger than Ang II. The effect was dose dependent and salarasin reversible. Kramar et al 6 investigated the effects of two Ang IV analogs, Nle(1)-AngIV (an AT4 receptor...

The Erkmapk Cascade

As described in several preceding chapters, recent advances have given us a much more detailed understanding of the signal transduction mechanisms subserving learning in the intact animal and one fact that has become clear is that protein kinases play a critical role in these processes. Most recently, the Mitogen-Activated Protein Kinase (MAPK) superfamily of signaling cascades has achieved some notoreity as a player in learning and memory. The MAPK superfamily includes three subfamilies the...

Why Phosphorylation Might Be Critical for Memory Formation

The demonstrated involvement of phosphorylative regulation in almost every facet of cell functioning provides justification for examining the contributions made by this process to memory formation. One of the difficulties inherent with research in this area, however, lies in distinguishing brain processes that play a direct role in retaining information from those that play a less direct, but equally critical, role, perhaps being necessary for general cell functioning, without which memory...

Immediate Early Genes

Jeffrey Greenwood, Pauline Curtis, Barbara Logan, Wickliffe Abraham and Mike Dragunow How long-term memories are formed in the brain is one of the principal targets of contemporary neuroscience research. This work is important from a fundamental perspective, because memory is a vital component of virtually all cognitive activity. It is also important from a clinical perspective since the early and most dramatic symptoms of Alzheimer's disease (AD) are an impairment of memory formation. Diseases...

Muscarinic Receptors in Aging and Alzheimers Disease

Whether or not the mild cognitive deficits associated with aging or the severe memory loss in AD depend, at least partly, on the loss of muscarinic receptors or change in their function is a controversial topic. Age-related loss of muscarinic receptors in rat neocortex and hippocampus is still a matter of debate, with the majority of the studies reporting no changes, and a few reporting a decrease or even an increase in binding sites.44,196 In a recent PET study using N- 11C methyl-4-piperidyl...

Table 3 Effects of opioid receptor ligands on the various learning and memory tasks

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Downstream Effectors of the CaMKII Cascade

What are the consequences of CaMKII translocation How does the activation of this kinase contribute to the establishment of LTP and in which way is this contribution related to the formation of new memories CaMKII phosphorylates several PSD-associated proteins, including PSD-95, a and P tubulin, the GTPase dynamin, the type IV intermediate filament protein a-internexin and cAMP phosphodiesterase,120 although the functional consequences of most of these phosphorylations are not known. Despite...

Brain Gut Peptides CCK Neuropeptide Y Galanin

Cholecystokinin (CCK) is a peptide originally discovered in the gastorintestinal tract but also found in high density in the mammalian brain. The C-terminal sulphated octapeptide fragment of cholecystokinin (CCK-8) constitutes one of the major neuropeptides in the brain CCK-8 has been shown to be involved in numerous physiological functions such as feeding behavior, central respiratory control and cardiovascular tonus, vigilance states, memory processes, nociception, emotional and motivational...

Receptors that Inhibit Adenylyl Cyclase

The 5-HT1A receptor is characterized by its high concentration in the hippocampus (Fig. 3), as well as in the raphe, where autoreceptors are also likely to exert an indirect influence on cognitive functions. This receptor subtype interacts with other neurotransmitter systems, such as the cholinergic, glutamatergic, GABAergic ones.52 8-OH-DPAT, a specific 5-HT1A agonist, dose-dependently impairs the retention of a well-learned maze, as well as acquisition of a novel configuration of the maze.67...

How Can K Channels Contribute to Learning and Memory

It is generally accepted that synaptic inputs trigger L& M mechanisms. Synaptic receptors activate signalling pathways resulting in the phosphorylation of proteins such as ion channels, modulating their properties. Phosphorylation is a recognised mechanism of channel modula-tion74 and the data discussed in this paper show that kinases are implicated in L& M in both invertebrates and vertebrates. K+ channels may contribute to L& M in three ways, as shown by Figure 2. (1) Modulation of...

Pp2a

Initial studies employed the drugs Okadaic Acid (OA) and Calyculin A (CalA), agents widely acknowledged to be specific and selective phosphatase inhibitors.54 Both drugs disrupted retention from two different time points depending on the concentration of drug administered and the time relative to training at which administration took place.17,224 At concentrations of OA that might be expected to selectively inhibit PP2A (0.5 nM per hemisphere), bilateral intracranial administration of either...

Eph Receptors and Their Ephrin Ligands in Neural Plasticity

Spontaneous Alternation Maze

Eph receptor tyrosine kinases are largely known for their involvement in brain development. But, as these receptors are also expressed in the adult, their possible role in the mature nervous system has begun to be explored. Emerging evidence for the involvement of Eph receptors in synaptic plasticity, learning and memory is discussed in this chapter. It is forecast that the actions of Eph receptors in the adult brain will attract significant attention, and research into their roles will have...