Effectors Of Pka And Pkc In Aplysia Presynaptic Facilitation

The cAMP-dependent protein kinase phosphorylates and closes the S channel. Closure of this channel has several effects on the electrical properties of the sensory neuron cell membrane. First, as the channels are closed, there is less resting potassium current flowing across the membrane, resulting in a modest depolarization of the membrane. This brings the resting membrane potential closer to the threshold for action potential generation and increases the likelihood of action...

Bqz

ID16 1014 10 -1 10'1< > 1 - 10 s 10' 10 10'MO-10 10 * 10 ' ID16 1014 10 -1 10'1< > 1 - 10 s 10' 10 10'MO-10 10 * 10 ' Concentration (M) Concentration (M) BOX 2, cont'd (B) In other studies, the interaction of Ap peptides with the a7nicotinic ACh receptor was assessed by ligand receptor binding assay using the a7nAChR-selective ligand alpha-bungarotoxin. (Left-hand panel) 125I-a-bungarotoxin (BTX) binding to a7 receptor-containing cell membranes was assessed. Amyloid beta peptide...

I

Ih, see H current IkB Kinase (IKK), 245 Ikv, 381b Immediate early genes, 69-71b Impey, Soren, 47, 239 Implicit memory, see Nondeclarative memory Imprinting, 9, 10, 318 Information processing, 62 complexity of LTP induction, 183 hippocampal role in multimodal information processing, 61 multimodal, 264, 289 relationships, 77-84, 79f, 80f, 81f, role of LTP in, 285-289 role of NMDA receptors, 105-106 space, 65-72, 66-69f time, 65, 72-77 Inhibitor 1, 178, 178f Inhibitor of Kappa B (IkB), 245...

What Is Ad

Of the various dementing illnesses our understanding of AD has progressed the farthest at the molecular level. That is not to say that our molecular understanding of AD is good, but rather that we have at least a few clues as to what is happening. As we will discuss later, a number of specific genes involved with AD have been identified. These genes, when mutated, essentially invariably lead to an individual developing AD. We will discuss these genes and gene products in more detail later, but...

The Nmda Receptor Supramolecular Complex

To localize protein kinases such as CaMKII postsynaptically. However, the ERK, PKA, and src cascades in other cellular domains may achieve effects more broadly, and indeed be subject to additional mechanisms of regulation. This has been demonstrated in studies investigating ERK signaling to the nucleus. At a minimum, it appears that there are at least two (likely more) functional pools of ERK and PKA in neurons one involved in local regulation of the dendritic spine compartment and a second...

Pkc

FIGURE 15 Hippocampal protein kinase activation in fear-conditioning. Two different fear-conditioning paradigms were used, cued and cued plus contextual (see text). Protein kinase activation was assessed using phospho-selective antisera to measure kinase phosphorylation. Percent change in phosphorylation from control for each protein kinase is shown. Number of animals used are in parentheses. All protein phosphorylation measurements were normalized to corresponding protein kinase amounts....

S

Sacktor, Todd, 190, 200, 203, 209, 386 Selcher, Joel, 50, 131, 279-280, 282 Selkoe, Dennis, 349 Senile plaques, 341b, 343 Sensitization, 5, 11, 12f, 13, 14, 55b, 377, 382 Sensory afferents, 55b Sensory input, 295 Sensory-motor gating, 55 Serotonin, 64, 94, 136-138b, 322b, 376 Serum response Factor (SRF), 245 Shank, 168, 168f Sheng, Morgan, 167 Shinnick-Gallagher, Pat, 47, 275-277b Shors, Tracy, 246b Short term synaptic plasticity, 113-114b, 114f paired-pulse facilitation, 113-114b, 114f...

Pi3kinase And Eltp Expression

Anti-apoptotic signaling system that regulates neuronal cell death during development and promotes survival in adult neurons (97, 98). The study by Sanna et al. expands our appreciation of normal physiologic roles for the PI-3-K pathway in mediating synaptic plasticity in the adult CNS. Their work suggests that PI3K activity is one of the processes necessary for the ongoing expression of LTP expressed physiologically. This appears to be one aspect of an emerging picture. For example, Kelly and...

Protectedsite Phosphorylation In

Figure shows several renderings of our model of the PKC catalytic core and C-terminal phosphorylation sites. Our modeling suggests two potential types of protected phosphorylation sites in the C-terminal autophosphorylation domain of PKC. The first type is exemplified by the T641 phosphorylation site. The phosphate at T641 is immersed in a cleft in the upper lobe of the catalytic core, pointed inward toward the center of the molecule (right-hand panels, white arrows). In addition, T641 sits on...

The Cholinergic Hypothesis Of Ad And Current Pharmacotherapies

In the mid to late 1970s and early 1980s, there were a series of landmark papers published describing a loss of cholinergic neurons in the brains of AD patients (11, 83, 84). This led to the formulation of the cholinergic hypothesis of AD (85-87), which briefly stated posited that loss of cholinergic function in the CNS was the basis for the dementia in AD. There was palpable optimism in the papers published during that period, which is poignant in retrospect. The feeling was that this might be...

Spine Anatomy And Biochemical Compartmentalization

So far we have discussed the synapse in abstract terms related largely to its function. However, the synapse is also a physical entity and the structural attributes of this entity confer some interesting properties. In this last section, we will look at certain physical aspects of the synapse that will be important to consider before moving on to the next chapter, where we begin to talk about molecular mechanisms for LTP. In brief, there are three points we will highlight in this section....

V

(VLDL), 355 Vestibulo-ocular reflex, 291-293b Villareal, Desiree, 238b Visual cliff task, 57 Voltage clamp experiments, 98b Voltage-dependent ion channels, modulate dendritic action potentials, 106-107, 107f neuromodulation, 108-109 potassium channels, 108-109 Voltage-Dependent Sodium channels, 160 Voltage-gated calcium channels, 381b Voltage-sensitive Calcium channels, 200 Hz LTP, 110

Coupling Of Receptors To Intracellular Messengers

Neurotransmitters that act by binding to receptors on the cell surface can elicit a wide variety of biochemical effects inside a neuron. How does a signal at the cell's surface manage to alter the activities of enzymatic processes intracellularly In many cases, this is achieved by virtue of the neuro-transmitter receptor coupling to and altering the catalytic activity of second-messenger-generating enzymes on the inner leaflet of the cell membrane. The second messengers thus produced typically...

Targets Of The Persisting Signals

How is it that a persistently activated kinase or other persisting biochemical signal is converted to an enhancement of the coupling between two neurons at Schaffer-collateral synapses This is the essential question concerning the mechanism of expression of E-LTP. Maintenance can be served by an autonomously active kinase, for example, but that persisting signal must be converted to some functional consequence at the synapse in order for synaptic potentiation to occur. This is the issue we will...

Inherited Disorders of Human Memory

Neurofibromatosis, Coffin-Lowry Syndrome, and the ras ERK Cascade II. Angelman Syndrome A. Fragile X Mental Retardation Syndrome Type 1 B. Fragile X Mental Retardation Type 2 As we discussed in the first chapter, our great capacity for learning and remembering plays an enormous role in forming our human potential. Moreover, our personal experiences, where we have learned and remembered specific items and events, define us as individuals. These truths are nowhere more evident than when we...

Lltp Decay Is An Active Process

The idea is that when neighboring synapses undergo LTP, other inactive synapses in the same neuron are simultaneously depressed. This has been directly demonstrated to occur experimentally and to be NMDA receptor-dependent. The general idea is that ongoing formation of new memories triggers a cellular trade-off, causing the erasure of previously stored information. The evolutionary advantage to this might be that it prevents the driving of synapses to...

Modulation Of The Release Machinery

A third, less well-understood mechanism recruited by the PKA and PKC pathways is direct augmentation of the responsiveness of the neurotransmitter release machinery to the action-potential-associated calcium influx. Even though the effect recruited by serotonin to contribute to presynaptic facilitation is quite robust, at present the incompleteness of our understanding of the release process itself precludes a mechanistic description of this component. This is, however, a very active area of...

Apolipoprotein E In The Nervous System

Lipoproteins are complexes of carrier proteins and lipids, including cholesterol, that in the cardiovascular and digestive systems are involved in the trafficking of dietary lipids. Apolipoprotein E is a component of lipoproteins and mediates the uptake of these lipoprotein particles into target tissues. In the liver, ApoE is incorporated into very low density lipopro-teins (VLDLs), which carry triglycerides and cholesterol to peripheral tissues, mainly muscle and adipose tissue. In the gut,...

70

TABLE BOX 4 Summary of molecular composition of the NMDAR supramolecular complex. The component molecule and its molecular weight are list. Adapted from Husi et al. (90). Hebbosome is even bigger than the huge molecular complex already described. In fact, the Hebbosome may be the entire postsynaptic spine compartment. Even this idea leaves out presynaptic factors. Consideration of the NMDA receptor supramolecular complex raises an additional important point to bear in mind. Briefly stated,...

Fragile X Mental Retardation Syndrome Type

In the late 1980s, an interesting new mechanism for gene disruption was discovered as an outgrowth of studies investigating the genetic basis of human degenerative CNS disorders the triplet repeat mechanism. The essential discovery was that in humans there are repetitive DNA sequences, specifically CGG or similar trinucleotide sequences, that can expand in length (i.e., number of CGG repeats) from generation to generation. In general, once a triplet repeat sequence in or around a gene reaches a...

A

343-345b Abraham, Cliff, 223 Acetylcholine receptor, 183 Acetylation, 190 Acetylcholine, 64, 94, 136-138b Acetylcholinesterase, 343b Acoustic startle, 54-55, 56f Actin Depolymerization Factor(ADF) cofilin, 328b Actin matrix, 164-167 Actin turnover, 329b, 370, 371f Actinomycin D, 236 Action potential, 67, 74 potential dendritic, 106-110, 124b increased firing during LTP, 127-130 propagation, 108-109 threshold, 381b Adams, Paige, 156 Adenylyl cyclase, 95b, 162 knockout mice, 198, 199f in PLC PKC...

D

Search time and platform crossings are assessed to characterize a subject's search behavior during the probe trial. The quadrant search measure is obtained by conceptually dividing the pool into four equal quadrants and then measuring the amount of time that the subject spends searching in each quadrant. The platform crossing measure is the number of times a subject crosses the exact place where the platform had been located during training. For comparison, the number of times a subject crosses...

Rett Syndrome

Rett Syndrome is an unusual disorder in girls that manifests itself as an age-dependent progressive decline in cognitive function starting after the first year of life. Among its attributes are diminished brain size, mental retardation, the development of stereotyped hand-wringing movements, and ultimately autism-like features. The gene for Rett Syndrome is on the X chromosome, and embryonic lethality in males (which, of course, have only one copy of the X chromosome) likely leads to the...

Neurogenesis In The Adult

As if the processes for establishing and maintaining long-term memory weren't already complicated enough, recent findings indicate that hitherto unanticipated mechanisms also may play a role. Specifically, neurogenesis has entered the picture. When I was a young scientific sprout, the dogma was that there is no new generation of neurons in the adult CNS. However, fascinating recent results have shown that neurogenesis does indeed continue into the adult, particularly in the dentate gyrus. One...

Three Attributes Of Chemical Reactions Mediating Memory

What do these examples of memory mechanisms in Aplysia tell us about the chemical reactions that support them First, there must be chemical reactions with different time courses that mediate short-term, long-term, and ultralong-term memory. Second, because manifestation of the memory phenotype between shorter-term and longer-term memories is seamless, the various chemical reactions are likely to converge on common effectors. And finally, there must be some unique mechanism to mediate those...

Modulation Of Ltp Induction

BOX 5, cont'd (C) BDNF also modulates LTP induction in response to theta-frequency-type stimulation. Two stimulating electrodes were positioned on either side of a single recording electrode to stimulate two different groups of afferents converging in the same dendritic field in CA1. Stimulation was applied to Schaffer collaterals alternately at low frequency (one per minute). After a period of baseline recording, LTP was induced with a theta-burst stimulation applied at time 0 only to one...

13m

FIGURE 4 PS1 A246E FAD mutant transgene greatly accelerates amyloid plaque pathology of Tg2576 transgenic mice. Brain sections of the hippocampus of transgenic mice co-expressing APP K670N M671L (the Tg 2576 line) and PS1 A246E FAD mutant transgenes were immunostained with Ap specific mAb 6E10 and compared to that of age-matched Tg2576 transgenic animals. Panels are hippocampi of mice 7, 9, and 13 months of age. At all ages examined, both the density and the size of plaques in heterozygous...

Introduction

The study of learning and memory requires the development and use of experimental model systems that can be utilized both to characterize the fundamental behaviors associated with memory and to explore the underlying mechanisms. In this chapter, we will transition from the abstract discussion of the last chapter into a discussion of real-life systems used experimentally and will focus on behavioral model systems for the study of learning and memory. We will limit our discussion to rodent model...

Genesfamilial And Lateonset Ad

AD is broadly divided into two types. The first and relatively better understood category is early-onset familial AD, which I will abbreviate as FAD. FAD is relatively rare, accounting in aggregate for a few percent of total AD cases (see reference 48 for a review). FAD is inherited in an autosomal dominant fashion and is highly penetrant, meaning that if you inherit a single copy of the gene you are highly likely to develop AD before age 60. So far, FAD-causing mutations have been identified...

Ampa

Unpaired control Naive control Fear-conditioned BOX 2, cont'd (B) Fear-conditioning results in potentiation of evoked EPSCs in the amygdala. (a) Plot of percent startle potentiation in fear-conditioned and unpaired control animals. (b) Composite EPSCs in amygdala neurons in trained and untrained animals, evoked with constant input stimulations of 9V. (c) AMPA receptor-mediated EPSCs evoked with input stimulations of 9 V. Reproduced from McKernan and Shinnick-Gallagher (55). (C) The effect of...

Ampar

FIGURE 4 PSD-95 as an anchoring protein for NMDA receptors. See text for explanation. also binds the ras Guanosine triphosphatase Activating Protein synGAP, whose function is still under investigation but which may regulate the ras ERK cascade locally at the synapse (see Box 3). PSD-95 also anchors the cytoskeleton through its interations with a protein termed SPAR, which is a Guanosine triphos-phatase Activating Protein (GAP) for rap and also an actin-interacting protein in its own right. Rap...

Arc And Cellular Reactivation

And Bruce McNaughton has demonstrated that Arc regulation is particularly interesting, and we will return to these studies in later chapters. Of course, in order to make an active product, all genes must be transcribed, processed into mRNA, and then translated into protein. Arc mRNA has the interesting attribute that it is rapidly transported into dendritic processes. In fact, the mRNA is selectively transported and compartmentalized to dendritic regions that have undergone recent excitation....

Ltp May Equal Memory In The Amygdala

In 1997, two groups broke through a long-standing barrier by directly demonstrating the occurrence of LTP in association with behavioral training in animals (55, 56). Thus, the amygdala became the envy of hippocampologists everywhere. These studies were particularly compelling because in this system there is appreciable understanding of the structure of the relevant circuits and how they map onto the behavior (see Panel A). The behavioral system under study by both groups was cued fear...

Peptide Immunization As A Potential Therapy For Ad

In this first study, the investigators documented significant prevention of plaque formation in the immunized mice. This was a very exciting finding concerning a new potential therapy for AD immunization with A , letting the body's normal immune response do the rest. How does the immunization effect a decrease in amyloid plaque formation These immunization procedures produce active anti-A antibodies in the bloodstream, a fraction of which apparently can penetrate into the CNS. The idea is that...

3

FIGURE 1 Summary of functions of the hippocampus. distinguish between memory consolidation and memory storage. The hippocampus generally does not store information for extended periods of time but rather serves as an intermediate-duration memory buffer that is involved in maintaining memories until they are transferred for more permanent storage in various regions of the cerebral cortex. This is referred to as consolidation of memories, that is, consolidation is the process by which memories...

Summary

In this chapter, I have promoted viewing Alzheimer's disease as a memory disorder, as opposed to thinking of AD as a generalized neuropathologic dementia. The basic hypothesis is that, for early stages of AD, which are characterized not by generalized dementia but rather by much more subtle deficits in memory consolidation, there will be derangements of the normal signal transduction machinery that underlies memory. This viewpoint sets me apart from most investigators in the AD field. However,...

Aging Related Memory Disorders

Genes Familial and Late-Onset AD IV. Apolipoprotein E in the Nervous System V. Mouse models for AD A. The Tg2576 Mouse In the last chapter, we talked about human mental retardation syndromes inherited deficiencies in learning and memory that manifest themselves from birth. In this chapter, we move to the other end of the developmental spectrum and will discuss aging-related memory dysfunction. In particular we will focus on Alzheimer's disease (AD) as an...

Info

Hypothesis that LTP occurs in vivo with memory formation. There also have been quite a number of other experiments of exactly the same sort, demonstrating that LTP-associated molecular events occur in the hippocampus and other parts of the CNS with learning (see Table 2). I focused on ERK activation as a specific example of this general category of experiment because it is the system with which I am most familiar. Thus, while it has not been possible so far to directly demonstrate LTP...

Box

SILENT SYNAPSES, WHISPERING SYNAPSES Silent synapses are all-or-none. The popular model for silent synapses is insertion of postsynaptic AMPA receptors into a synapse that previously had only NMDA receptors, activating the synapse (see figure). The prior existence in the synapse of the NMDA receptor is, of course, necessary for the synapse to be capable of sensing the simultaneous presence of synaptic glutamate and membrane depolarization and to trigger the AMPA receptor insertion. The NMDA...

Tea

NMDA receptor-independent LTP in area CA1 can also be induced using tetraethylammonium (TEA+) ion application, a form of LTP that is referred to as LTPk (15, 16). TEA+ is a nonspecific potassium channel blocker, the application of which greatly increases membrane excitability. Like 200-Hz LTP, LTPK is insensitive to NMDA receptor antagonists and is blocked by blockade of voltage-sensitive calcium channels. Moreover, LTPK is blocked by postsynaptic calcium chelator FIGURE 13 Examples of NMDA...

Box 4

There are two types of short-term plasticity exhibited at hippocampal Schaffer collateral synapses and elsewhere that are activity-dependent just as is LTP. These are paired-pulse facilitation (PPF) and post-tetanic potentiation (PTP). Paired-pulse facilitation is a form of short-term synaptic plasticity that is commonly held to be due to residual calcium augmenting neurotrans-mitter release presynaptically. When two single stimulus pulses are applied with interpulse intervals ranging from 20...

Forgetting

Given the continual turnover of the molecular constituents of our CNS, it's amazing that we can remember anything at all for any period of time. With this in mind, the emerging recognition of the error-proneness of human memory may come as no surprise. Daniel Schacter has delineated and categorized the flawed nature of human memory in his recent book The Seven Sins of Memory (25). Forgetting and memory lability come part and parcel with molecular turnover. Even an extremely low error rate as...

600 500 400 300 200 100

FIGURE 8 Experimental results for various aspects of the Morris water maze. (A) Average escape latency was assessed during training on the hidden platform task. Performance for mice (n 13) improved over the course of the training, indicating learning of the task and the location of the hidden platform. Animals were trained using ten blocks of four training trials, over a 5-day period. (B and C) Probe tests are used to assess whether the animal has used a selective spatial strategy in learning...

L

Lashley Maze Rat's Eye View, 60 Lashley, Karl, 30, 35, 52 Latent inhibition, conditioned taste aversion, 41 hippocampal refractory in shock alone control test, 50 Learning, 4 component of memory, 7 induction of memory, 257 modulatory factors, 23-24 suvival value, 9 LeDoux, Joseph, 47, 84b, 275-278b Lee, Hei-sung, 216 Leitges, Michael, 202-203 Leptin, 152, 153f Levenson, Jonathan, 125-127b Levy, Michael, 176-177 Ligand-gated ion channels, 95b Light-dark exploration task, 57 LIMK-1,328-329b...

Agingrelated Memory Decline

As most people over the age of 60 will attest, a decline in learning and memory is a part of the normal aging process (see reference 1 for a review). Most noticeable in humans is the decline in hippocampus-dependent forms of memory, the learning and remembering of new names, recent events, and even spatial information. For the most part, in normal individuals, these memory deficits are not debilitating, but they are quite noticeable because they are involved so directly in human conscious...

Williams Syndrome

The LIMK-1 pathway is one of the specific mechanisms whereby the rho system regulates cytoskeletal structure. LIMK-1 homozygous knockout mice, as might be expected, have alterations in actin microfilaments owing to derangements of actin turnover (27). They also manifest altered dendritic spine morphology at Schaffer-collateral synapses in the hippocampus. Specifically, they have fewer actin microfilaments than the normally actin-dense spines, and the dendritic spines in LIMK-1 knockout mice...

The Tg2576 Mouse

The Tg2576 strain is a mouse model for AD in which the transgene is the human 695 splice-variant of APP that contains the double mutation K670M, N671L driven by a hamster prion protein gene promoter (expression is predominantly in neurons). The brains of these animals contain about five times more transgenic mutant human APP than endogenous mouse APP. Transgenic APP expression appears to remain unchanged between 2 and 14 months of age. They exhibit about a fivefold increase in Ap40 and a 10- to...

The Ubiquitin System Plays A Role In Synaptic Plasticity And Memory In Aplysia

Decrease in the overall ratio of regulatory to catalytic subunits, promoting an excess of free, active catalytic subunits and a persistent increase in PKA activity. By this clever mechanism, a chain of events is set in motion whereby a biochemical effect is established in the cell that outlasts the initial, triggering elevation of the second messenger cAMP. The PKA will remain activated until compensatory resynthesis of new regulatory subunit occurs, or until the catalytic subunit is degraded....

Kv

The work of Jack Byrne's laboratory has been instrumental in the discovery of the modulation of this channel as a mechanism for presynaptic facilitation in Aplysia sensory neurons (9). Ikv is a voltage-sensitive potassium channel that opens in response to the membrane depolarization caused by the arrival of the action potential. After opening, the potassium current flowing through this channel contributes substantially to returning the membrane potential to its resting level. Therefore, in...

Ne

FIGURE 12 The dendritic tree and regulation of action potential propagation. (A) This photograph is of pyramidal neuron dendrites and a single axon fiber passing through them. Photo by Michael Hausser and Beverly Clark. (B) Two ways to regulate the likelihood of a back-propagating action potential reaching a given distal synapse are shown. One possibility is neurotransmitter (e.g., NE) regulation of local potassium channels determining the extent of action potential propagation (1). A second...

H

H Current, 159 H.M., 62, 84-86, 86f, 319, 323 H7, 219-220, 219f Habits, 16 Habituation, 12-13, 12f Hardy, John, 349 Hargreave's radiant heat apparatus, 56b Hawkins, Bob, 13, 243, 321b, 373 Hebb, Donald, 92 Hebbosome, 169-170b Hebb's Postulate, 92, 107, 183, 389 Hermissenda, 15-16b Hippocampal circuit, 93-94, 93f Hippocampal lesions, 24, 51, 75, 85 Hippocampal projections, 94 Hippocampal recordings in vivo, 274, 275-278b, 283 L-LTP experiment, 234 patch clamp recording, 98b, 128 population field...

References

A. (1988) Aging and the physiology of spatial memory. Neurobiol. Aging 9 563-568. 2. Barnes, C. A., Suster, M. S., Shen, J., and McNaughton, B. L. (1997). Multistability of cognitive maps in the hippocampus of old rats. Nature 388 272-275. 3. Barnes, C. A., Rao, G., and Houston, F. P. (2000). LTP induction threshold change in old rats at the perforant path granule cell synapse. Neurobiol. Aging 21 613-620. 4. Barnes, C. A., Rao, G., and Shen, J. (1997). Age-related decrease in the...

Modeling The Cterminal Autophosphorylation Sites On

How are the sites of phosphorylation on PKC rendered inaccessible to phosphatases We proposed a protected site model, whereby the conformation of PKC regulates accessibility of the phosphates to phos-phatase. In this model, in the unstimulated conformation, sites of PKC phosphorylation are protected through steric hindrance by the surrounding areas of the protein. Upon binding of activating ligands, a conforma-tional change occurs, making the phos-phorylation sites accessible at the surface of...

Biochemical Mechanisms for Long Term Information Storage at the Cellular Level

The Case for Altered Gene Expression in L-LTP II. Signaling Mechanisms A. A Core Signal Transduction Cascade Linking Calcium to the Transcription Factor CREB B. Modulatory Influences That Impinge Upon This Cascade C. Additional Transcription Factors Besides CREB That May Be Involved in L-LTP Induction E. mRNA Targeting and Transport F. Effects of the Gene Products on Synaptic Structure III. Summary

Nmda Receptorindependent

Although the vast majority of studies of LTP and its molecular mechanisms have investigated NMDA receptor-dependent processes, as mentioned previously there also are several types of NMDA receptor-independent LTP. We will not discuss the mechanisms for these types of LTP very much in this book for two reasons. First, there have not been many studies investigating the molecular basis of NMDA receptor-independent LTP, at least relative to its NMDA receptor-dependent counterpart. Second, in those...

T

Taste learning, 41 see also Neophobia, Conditioned Taste Aversion, TATA box, 241, 241f Tau, 341b, 346 Tauopathies, 346 TBL-1, 383 65, 72-77 Temporal integration in LTP, 130-131, 130f, 224b, 244 Tg2576 mouse model, 349f, Theta frequency firing pattern Theta Rhythm, 66, 66f, 103-104 Thioflavin S, 341b Through the Glass Darkly, 366 Time-dependent learning tasks, see Temporal information processing tissue Plasminogen Activator (t-PA), 248-249 Tonegawa, Susumu, 47, 240, 285 Trace conditioning,...

Ps1

Knockout Knockout Knockout Transgenic + - developmental defects, - - lethal Forebrain decreased hippocampal neurogenesis (104, 105) Memory and LTP deficits (106, 107) Hippocampal gliosis (108) Modest phenotype (109) No learning phenotype, accelerated plaque disposition when combined with APP V717F(66, 110) Tg2576 mice exhibit many behavioral and pathological features of AD including elevated production of Ap peptides, age-dependent accumulation of amyloid fibrils, and plaque formation with...

The Molecules Of

Recent studies have given a number of important insights into the molecular mechanisms underlying cerebellar LTD. Cerebellar LTD induction requires mGluR and AMPAR activation, and postsynaptic Ca2+ influx through voltage-gated Ca2+ channels (reviewed in reference 10). The mGluR activation produces DAG, which subsequently along with calcium activates PKC. This PKC activation is necessary for the induction of cerebellar LTD (60), as has been shown in a variety of inhibitor studies, and PKC...

Nonsyndromic Xlinked Mental Retardation

There are a variety of different forms of mental retardation that are not syndromic, or linked to a specific and consistent spectrum of clinical features other than cognitive impairment, and there have been a number of different genes identified as contributing to these nonsyndromic forms of mental retardation. Some of the interesting genes on the X chromosome that have been associated with mental retardation include the L1 neural cell adhesion molecule and three different genes involved in the...

Regulation Of Ras By Gaps And Gefs

Ras is a low-molecular-weight GTP-binding protein (G protein) classically studied as a target for particular receptor tyrosine kinases. Ras acts as a critical relay in signal transduction by cycling between an active conformational state when bound to GTP, and an inactive state when bound to GDP (see figure). The GTPase, or turn-off activity of ras is dependent on the opposing effects of two distinct classes of regulatory ras-binding molecules GAPs and GEFs (guanine nucleotide exchange...

Rubinsteintaybi Syndrome

Another mental retardation syndrome associated with the PKA ERK CREB pathway is Rubinstein-Taybi Syndrome (RTS). RTS patients have some facial abnormalities, broad big toes and thumbs, and mental retardation. The RTS gene has been mapped to chromosome 16 and identified as CREB Binding Protein (CBP). As described earlier, CBP is a transcriptional co-activator with CREB that obligatorily participates with phospho-CREB to regulate gene expression downstream of the CRE (20). CBP is a Histone Acetyl...

Chapter Summary

In this chapter, we explored several of the fundamentally important issues related to information storage in neurons. How is a persisting biochemical signal generated How is that signal transmitted to an effector system to alter neuronal function If there are multiple biochemical mechanisms for information storage, how might one mechanism transition into the next In addressing these critical issues, a number of specific molecular mechanisms were proposed in the context of E-LTP at...

Dendritic Protein Synthesis

Trauma Responses

In this final section we will begin to address issues related to the E-LTP to L-LTP transition. I include them in this chapter because they involve the generation of persisting signals, specifically the increased synthesis of proteins thus, these mechanisms fit well within the general theme of this chapter. Also, there are data to suggest that regulation of protein synthesis may be a downstream target of some of the specific persisting signals involved in E-LTP, such as persistently activated...

Control Experiments

Open Field Analysis and Elevated Plus Maze Performance Open field analysis is used to measure the level of spontaneous motor activity, exploratory behavior, and habituation of animals to an open area. Animals are placed in an open field chamber (e.g., 40 by 40 by 30 cm box) for 15 minutes in standard room-lighting conditions. Activity in the open field is typically monitored by light beams and photoreceptors on each side of the chamber and analyzed by a computer-operated optical animal...

Conscious Learningsubject To Conscious And Unconscious Recall

Human declarative learning is what we typically think of when we think of learning. This is the conscious acquisition of new facts, or the formation of memories for events that occur in our lives, that are available for subsequent recall at will. The extent to which you remember what you read in this book will depend upon the processes of conscious declarative learning. Of course, the extent to which you remember this book will also depend on a large number of other factors, such as motivation,...

Radiant Thinking Theory

In this chapter we will discuss the mechanisms unique to inducing and maintaining the long-lasting, late phase of LTP. This is an exciting, wide-open area of LTP research right now, one of those areas where it is clear that important work is underway but where the surface has just been scratched in terms of our understanding. L-LTP is defined in terms of an enduring, protein synthesis-dependent form of synap-tic potentiation in area CA1, as I will describe in more detail later. However, the...

Alternative Mechanisms For

It seems obvious that if there is an increase in synaptic strength, it must be the result of either an increase in neurotransmitter release or an increase in postsynaptic responsiveness. However, what if it's neither of these Are there alternative models that can explain synaptic potentiation that involve neither mechanism Two alternate possibilities have received some attention. They are the possibilities of diminished re-uptake of glutamate, leading to increased synaptic glutamate levels and...

Studying The Hippocampus

If you are interested in studying the roles of the hippocampus in the behaving animal, how do you even begin to go about it One approach is to remove the hippocampus or inactivate it and assess the cognitive and behavioral consequences of this experimental manipulation. These types of studies were the first to lead to an appreciation of the role of the hippocampus in memory consolidation (reviewed in reference 1). In fact, studies in a human patient, known as patient H.M., were breakthrough...

Ltp Can Include An Increased Ap Firing Component

Another caveat to keep in mind is that the preceding discussion deals only with mechanisms contributing to increases in synaptic strength. The increased EPSP is typically measured in field recording experiments as an increase in the initial slope of the EPSP (or EPSP magnitude), as was discussed in the previous chapter. A second component of LTP is referred to as EPSP-spike (E-S) potentiation. E-S potentia-tion was identified by Bliss and Lomo in the first published report of LTP (11) and is...

Unconscious Learning

In this section, we will explore several simple (i.e., nonassociative) forms of learning. Keep in mind that even those forms of learning that exhibit themselves in a fairly straightforward manner at the behavioral level involve elaborate underlying cellular and molecular machinery. In this section, we will emphasize that several forms of nonassociative learning are exhibited by animals, including habituation, dishabituation, and sensitization (see Figure 6). These forms of learning involve...

Modern Experimental Uses Of Rodent Behavioral Models

Having briefly described several of the basic rodent learning paradigms in common use, we now turn our attention to thinking about their application in cellular and molecular studies. By way of introduction to this topic, I think it is useful to step back and review the basics of experimental design. In the next section we will consider the basics of hypothesis testing. We then will proceed to considering how the fundamentals of experimental design are applied in the modern era in extending...

Angelman Syndrome

The use of traditional (i.e., non-inducible) knockout mouse models to try to study the signal transduction events involved in synaptic plasticity and memory has been widely and legitimately criticized because of the great confound of secondary effects of loss of the gene. In particular, developmental derangements can contribute to any observed phenotype, and there is a real concern that the effect of loss of the gene product is not an indication of the protein having any necessary role in an...

Signaling Mechanisms

Ponse Immunitaire Theileria Annulata

We now turn our attention to discussing the mechanisms by which L-LTP-associated changes in gene expression are achieved. How does the L-LTP-triggering calcium elevation at the synaptic spine get a signal to the nucleus In the following section, I will summarize a variety of studies investigating this question. Leading groups in this area are the laboratories of Dan Storm, Dick Tsien, Eric Kandel, Susumu Tonegawa, Alcino Silva, Tim Bliss, and Jocelyn Caboche the following summary draws...

Ltp Does Not Equal Memory

The strong hypothesis that LTP equals memory makes a number of predictions. We can frame these in the general form that we have been using throughout the book block, mimic, and measure. Thus, The block experiment agents that block LTP should block memory formation. A corollary of this is that agents that enhance LTP should enhance memory. The mimic experiment inducing LTP in the right place in the brain should cause a behavioral change indistinguishable from learned behavior. A variation of...

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FIGURE 5 Transcriptional regulation pathways controlling the expression of synaptic plasticity-associated genes. See text for discussion. occurs with L-LTP, these interesting findings support the idea that late waves of altered gene expression contribute to memory consolidation involving hip-pocampal neurons. Thus, we see that at least two (zif268 and krox 20) and probably several more transcription factor-encoding genes are up-regulated in L-LTP. Overall, these findings that transcription...

Monitoring Baseline Synaptic Transmission

Magnitude of the stimulus one delivers to the presynaptic fibers, differences from preparation to preparation (electrode placement, slice thickness, etc.) cause variability in the magnitude of the synaptic response elicited by a constant stimulus amplitude. One approach commonly to compare one preparation (or animal strain) to the next is to quantitate the EPSP relative to the amplitude of the fiber volley in that same hippocampal slice (see figure 5A). The rationale is that the fiber volley,...

Downs Syndrome

Mental retardation can arise not only from loss or derangement of the function of a gene product but also from aberrant overproduction of a gene product. One example of mental retardation in this category is Down's Syndrome. Down's Syndrome results not from a genetic mutation but from aberrant chromosome duplication, specifically duplication of one copy of chromosome 21. For this reason, Down's Syndrome is also referred to as Trisomy 21. Because of this unique mechanism, Down's Syndrome is not...

Of Mice And Rats

Rats have been the prototype animal for learning studies, although recently great effort has been expended to adapt these procedures to mice. This is because the recent advent of transgenic mouse technologies has generated substantial optimism concerning the development of murine models for human learning disorders and memory dysfunction, as well as optimism for their application to understanding the basic molecular mechanisms of memory itself. Moreover, the potential applicability of...

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FIGURE 9 Path tracking in the probe test. Representative probe trial of a mouse in the Morris water maze task. (A) The swim path trace shown here provides an excellent example of a selective search. This particular subject was trained with the platform located in the northeast quadrant. During the probe trial, this mouse spent 56 of the time in the correct quadrant and crossed the exact area where the platform had been nine times. Adult male 129S3 SvImJ mice (formerly 129 Sv-+p+Tyr-c+Mgf-slJ J...

Ltp Can Be Divided Into Phases

Pensamiento Irradiante

Contemporary models divide very long-lasting LTP (i.e., LTP lasting in the range of 5 to 6 hours) into at least three phases. LTP comprising all three phases can be induced with repeated trains of high-frequency stimulation in area CA1 (see Figure 7), and the phases are expressed FIGURE 5 Increased action potential firing over the course of TFS. (A) The TFS protocol and TFS-induced LTP in mouse hippocampal slices. (B) Electrode placement configuration for recording EPSP and population spikes...

The Chemistry of Perpetual Memory

Short-, Long-, and Ultralong-Term Forms of Learning II. Use of Invertebrate Preparations to Study Simple Forms of Learning III. Short-Term Facilitation in Aplysia is Mediated by Changes in the Levels of Intracellular Second Messengers Thus, Reaction Category 1 Altered Levels of Second Messengers IV. Intermediate-Term Facilitation in Aplysia Involves Altered Gene Expression and Persistent Protein Kinase Activation A Second Category of Reaction Thus, We Have Reaction Category 2 Generation of...

Eyeblink Conditioning

During classical associative learning, an animal is taught to associate a neutral conditioned stimulus (CS) with an aversive unconditioned stimulus (US). Classical conditioning of the eye-blink response in rabbits uses the association of a neutral stimulus such as tone or light with a nociceptive stimulus, such as an airpuff delivered to the eye or a periorbital shock. Re-presentation of the CS results in an eye-blink conditioned response (CR) in anticipation of the US. Trace eye-blink...

Central Pattern Generators

BOX 1, cont'd Central program for swimming in Tritonia. (A) Swimming movements as described previously. (B) Intracellular recordings from neurons in the Tritonia CNS. The top record represents a cell that drives the animal's downward (ventral) flexion the lower record shows the cell that drives the upward (dorsal) flexion. The numbers between records correspond to the numbers in A and show the types of recordings obtained during the corresponding phases of the swimming movement. From Willows...

Recording From Individual Neurons

Neurone Pyramidale

Most of the data under discussion in this chapter were generated using extracellular recording techniques, but a number of much more sophisticated electrophysiologic techniques have been used to great effect in studies of LTP. These types of techniques fall into two broad categories generally referred to as sharp electrode recording and patch clamp recording. The basic difference in the two techniques is that sharp electrode recording impales the neuron with the recording electrode, while patch...

Summary A General Chemical Model For Memory

Learning and memory have always intrigued those interested in the functioning of the brain. The mammalian CNS has an amazing capacity to store and recall diverse types of information, and learned responses shape to a great degree an animal's behavior. How are memories formed and stored Contemporary understanding of this issue highlights the importance of changes in synaptic strength (synaptic plasticity) as the means whereby the nervous system forms and stores memory. But by what means are...

The Biochemistry of LTP Induction

LTP Induction Component 1 Mechanisms Upstream of the NMDA Receptor That Directly Regulate NMDA Receptor Function A. The Structure of the NMDA Receptor B. Kinase Regulation of the NMDA Receptor C. Redox Regulation of the NMDA Receptor D. Polyamine Regulation of the NMDA Receptor III. LTP Induction Component 2 Mechanisms Upstream of the NMDA Receptor That Control Membrane Depolarization A. Dendritic Potassium Channels B. Voltage-Dependent Sodium Channels (and Calcium Channels ) IV. LTP...

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GABA, 95b, 104-106, 291-293b GABA receptor, 95b, 161 GABAergic function, 313 GABAergic interneurons, 94, 93f, 128-130, 129f Gage, Fred, 246b GAP-43, 220, 220f Gene expression, 234, 243f Genetically engineered animals, 266 caveats to use, 266-267b LTP and memory link, 269 Genomic Regulation in Memory Formation, 232 Gerendasy, Dan, 180 Getting, Peter, 375b increased release during LTP, 120 kinetics of release, 125-127b re-uptake of, 125-127b Glycine, 104 Gould, Elizabeth, 246b Graded acquisition...

Behavioral Assessments In Rodents

Conditioning Fear

One popular behavioral model system with which to study learning and memory is a robust learning paradigm that capitalizes on the capacity of mammals, including rodents, to associate environmental cues with a mild aversive stimulus. This type of learning, generally called fear conditioning, is an example of classical associative conditioning similar to Pavlovian conditioning. Some aspects of the neuronal circuitry underlying this behavior have been worked out and it is clear that the amygdala...

Mechanisms For The Generation Of The Actual Persisting Biochemical Signals

Coincidence Illustration

Thus far, we have been discussing the mechanisms for regulating postsynaptic calcium and its immediate effectors, mechanism that determine if an LTP-inducing level of calcium is reached. Point 6 transitions us into the mechanisms whereby this triggering level of calcium is converted into a persisting signal that maintains LTP. As described in the beginning of the chapter, the details of these mechanisms are dealt with in Chapter 7 for E-LTP and Chapter 8 for...

Mouse Models For Ad

Progress in understanding AD and developing new therapies for AD hinges upon the availability of suitable model systems for investigating the disease in the laboratory. In this vein, the application of transgenic animal technology to the pursuit of investigating AD appears to be a critically important endeavor. There are several considerations that factor into the critical role of genetic engineering in developing suitable laboratory models for AD. First, AD is an exclusively human disorder no...

Diagnosing Ad

Ads That Feature Attribute

At present there is no definitive method for pre-mortem diagnosis of AD. Accepted practice is for AD to be diagnosed postmortem by pathological examination of autopsy tissue. Histopathological analysis of post-mortem tissue uses criteria not appreciably different from those described by Alois Alzheimer himself in 1907 10 . The gross hallmarks are cortical atrophy, enlargement of the ventricles, and shrinkage of the hippocampus and surrounding areas of the medial temporal lobe. Microscopic...

Shortterm Facilitation In Aplysia Is Mediated By Changes In The Levels Of Intracellular Second Messengers

What happens when serotonin is applied to sensory neurons Serotonin binds to receptors in the neuron's cell surface membrane that are coupled to adenylyl cyclase and phospholipase C, which generate cAMP and DAG, respectively. When a sensory neuron sees a single pulse of serotonin, adenylyl cyclase and phos-pholipase C are activated, cAMP and DAG levels increase, and the activities of PKA and PKC are greatly enhanced. As long as serotonin is present, these enzymatic activities remain elevated....

BOX 1contd Central Pattern Generators

Leech Swim Central Pattern Generator

Again, this pattern of behavior is mediated by the highly coordinated firing of an elaborate network of neurons in the animal's nervous system. Much of the circuitry and cellular physiology of this central pattern generator was worked out in the late Peter Getting's laboratory. Why do I bring this up in the context of general theories of the chemistry of memory Because these are classic examples of hard-wired behavioral responses. They are seemingly immutable in the absence of injury to the...

Temporal Integration In Ltp Induction

At one level, it is a statement of the obvious to say that LTP induction depends on temporal integration. After all, the only thing that distinguishes the LTP induction protocols from baseline stimulation is that, during the LTP induction protocol, stimulation is delivered at a higher rate. It obviously is the case that if the only thing that is different is that the synapse is seeing activity at 100 pulses per second rather than once every 20 seconds, then LTP is being triggered by unique...

Types Of Receptors And Potential Sites Of Plasticity

Brain Slice Recording Chamber

And phospholipase A2 PLA2 , which liberates free arachidonic acid that can be converted into a wide variety of active metabolites. We will explore these systems and others in excruciating detail in Chapters 6-8. Finally, it is important to note that the targets of these various signaling pathways are as diverse as the genome itself. In terms of neuronal function, particularly important targets are the presynaptic proteins associated with neurotransmitter release, membrane K channels, Ca2...

Chapter Overview

Korrosion Elektrochemisch

The chapter will be broken down into three broad sections see Figure 1 . The first section will deal with two well-established targets of the triggering calcium for LTP CaMKII and PKC. In this section, I will focus principally on the known mechanisms for generation of persistently activated forms of these kinases, forms of the molecules that are capable of serving as molecular memory traces in LTP and memory in FIGURE 1 Chapter summary. This chapter deals with three primary issues related to...

Rodent Models Of Pain Plasticity

In humans, tissue injury results in persistently increased pain sensation to mildly noxious stimuli hyperalgesia and pain perception to normally non-noxious stimuli allodynia . These two forms of sensitization clearly fit within the definition of learning developed in the first chapter persisting behavioral modification in response to an environmental signal. However, in this case, one mechanism contributing to the altered behavior is persisting production of chemical signals locally at the...

Akap

Regulate likelihood of LTP induction This consideration also serves as an important caveat for interpreting results from NMDA receptor knockout mice. This apparently clean experimental manipulation, wherein the NMDA receptor is entirely lost, likely results in a large number of secondary effects on molecules normally associated with the NMDA receptor postsynaptically. In fact, experiments using various deletion mutants missing the cytoplasmic anchoring domains of the NMDA receptor have allowed...

Depotentiation And

When scientists began to think seriously about the possible involvement of LTP in memory in the animal, a theoretical conundrum arose. If synapses can be potentiated and this potentiation is very long-lasting, over time the synapses will be driven to their maximum synaptic strength. In this condition, there is no longer synaptic plasticity and no further capacity for that synapse to participate in synaptic-plasticity-dependent processes. Worse yet, over the lifetime of an animal, synapses will...

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Sequenz App Secretase

This is the human amino acid sequence. In keeping with our focus on rodent models, I also have included in parentheses the rat sequence, which differs only at the three indicated amino acids. Current work focuses on the 42-amino acid variant as a principal culprit in AD, as we will return to later. Ap42, being a fairly small peptide, can assume a number of different conformations in solution and even in protein crystals. One three-dimensional structure of an Ap peptide that has been determined...