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T V Bliss

Publications and source records attributed to T V Bliss.

At least 19 recordsLinked to original sources
PubMed2001

A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories.

The induction of long-term potentiation (LTP) in the dentate gyrus of the hippocampus is associated with a rapid and robust transcription of the immediate early gene Zif268. We used a mutant mouse with a targeted disruption of Zif268 to ask whether this gene, which encodes a zinc finger transcription factor, is required for the maintenance of late LTP and for the expression of long-term memory. We show that whereas mutant mice exhibit early LTP in the dentate gyrus, late LTP is absent when measured 24 and 48 hours after tetanus in the freely moving animal. In both spatial and non-spatial learning tasks, short-term memory remained intact, whereas performance was impaired in tests requiring long-term memory. Thus, Zif268 is essential for the transition from short- to long-term synaptic plasticity and for the expression of long-term memories.

Anesthetics↗
PubMed2000

Protein phosphatase-1 regulation in the induction of long-term potentiation: heterogeneous molecular mechanisms.

Protein phosphatase inhibitor-1 (I-1) has been proposed as a regulatory element in the signal transduction cascade that couples postsynaptic calcium influx to long-term changes in synaptic strength. We have evaluated this model using mice lacking I-1. Recordings made in slices prepared from mutant animals and also in anesthetized mutant animals indicated that long-term potentiation (LTP) is deficient at perforant path-dentate granule cell synapses. In vitro, this deficit was restricted to synapses of the lateral perforant path. LTP at Schaffer collateral-CA1 pyramidal cell synapses remained normal. Thus, protein phosphatase-1-mediated regulation of NMDA receptor-dependent synaptic plasticity involves heterogeneous molecular mechanisms, in both different dendritic subregions and different neuronal subtypes. Examination of the performance of I-1 mutants in spatial learning tests indicated that intact LTP at lateral perforant path-granule cell synapses is either redundant or is not involved in this form of learning.

Animals↗
PubMed2000

ERKI/II regulation by the muscarinic acetylcholine receptors in neurons.

Muscarinic acetylcholine receptors (mAChRs) are known to be involved in learning and memory, but the molecular basis of their involvement is not well understood. The availability of new and specific biochemical tools has revealed a crucial role for the mitogen-activated protein kinase (MAPK) family in learning and memory. Here, we examine the link between mAChRs and MAPK in neurons. Using the MAPK kinase (MEK)-specific inhibitor PD98059, we first demonstrate a necessary role for active ERKI/II in long-term potentiation in vivo. Using phospho-specific antibodies that recognize the activated form of ERKI/II, we find that the level of ERKI/II activation in brain is regulated by mAChRs. Carbachol, a muscarinic agonist, induces prolonged activation of ERKI/II, without effect on the related kinase SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal protein kinase) in primary cortical cultures. ERKI/II activation is Src-dependent and partially phosphoinositide-3 kinase- and Ca(2+)-dependent but is PKC-independent. M1-M4 mAChR subtypes expressed in COS-7 cells can all induce ERKI/II activation using a signal transduction pathway similar to that operating in neurons. The nature of the signal transduction suggests that ERKI/II can serve as a convergence site for mAChR activation and other neurotransmitter receptors.

Animals↗
PubMed1999

Molecular mechanisms of long-term potentiation in the insular cortex in vivo.

We have investigated molecular mechanisms of synaptic plasticity in the pathway between two forebrain structures important for taste learning, the basolateral amygdala (BLA) and the insular cortex. We report here that in vivo long-term potentiation (LTP) induced by BLA stimulation requires functional NMDA receptors and is modulated by muscarinic acetylcholine receptors. In addition, LTP results in the activation of cortical extracellular regulated kinase 1/2 (ERK1/2) and is blocked by inhibitors of ERK1/2 activation. Previous findings demonstrated the involvement of the same molecular mechanisms in the same cortical area during novel taste learning. The results demonstrate that both synaptic and behavioral plasticity share common molecular mechanisms in the insular cortex.

Amygdala↗
PubMed1999

Photolytically released nitric oxide produces a delayed but persistent suppression of LTP in area CA1 of the rat hippocampal slice.

1. We have used flash photolysis of a caged form of nitric oxide (NO), potassium pentachloronitrosylruthenate (K2Ru(NO)Cl5), to apply known concentrations of NO, with a high degree of temporal resolution, to hippocampal slices prepared from juvenile male rats maintained in an interface recording chamber. 2. Photolytically released NO (1-4.5 microM) from bath applied caged NO reduced the magnitude of long-term potentiation (LTP) in a concentration-dependent manner. This effect was abolished in the presence of the NO scavenger haemoglobin. NO had no effect on pre-established LTP. 3. Exposure to photolytically released NO had no effect on normal fast synaptic transmission, but did result in depression of N-methyl-D-aspartate (NMDA) receptor-mediated transmission recorded using extracellular electrodes. The onset of NO-induced depression was relatively slow, taking >40 s to manifest itself, and several minutes to achieve maximum depression (t approximately 70 s). NO-induced depression persisted for more than 2 h after photolysis. The time courses of the action of NO on NMDA receptor-mediated responses and its action on the induction of LTP were similar. 4. These results suggest that released NO may play a role in determining the subsequent threshold for the induction of LTP at Schaffer-commissural synapses through a reduction in the efficacy of NMDA receptor function when repeated conditioning trains are used.

Animals↗
PubMed1999

Single synaptic events evoke NMDA receptor-mediated release of calcium from internal stores in hippocampal dendritic spines.

We have used confocal microscopy to monitor synaptically evoked Ca2+ transients in the dendritic spines of hippocampal pyramidal cells. Individual spines respond to single afferent stimuli (<0.1 Hz) with Ca2+ transients or failures, reflecting the probability of transmitter release at the activated synapse. Both AMPA and NMDA glutamate receptor antagonists block the synaptically evoked Ca2+ transients; the block by AMPA antagonists is relieved by low Mg2+. The Ca2+ transients are mainly due to the release of calcium from internal stores, since they are abolished by antagonists of calcium-induced calcium release (CICR); CICR antagonists, however, do not depress spine Ca2+ transients generated by backpropagating action potentials. These results have implications for synaptic plasticity, since they show that synaptic stimulation can activate NMDA receptors, evoking substantial Ca2+ release from the internal stores in spines without inducing long-term potentiation (LTP) or depression (LTD).

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1999

Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice.

We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.

Aging↗
PubMed1998

Dissociation between genes activated in long-term potentiation and in spatial learning in the rat.

We have compared changes in mRNA of three genes, zif268, raf B, and syntaxin 1 B, following the unilateral induction of long-term potentiation (LTP) in rats previously trained in a water maze, and in behaviourally naive animals. mRNA of all three genes was enhanced in the potentiated dentate gyrus of naive animals 3 h after the induction of LTP. Training did not affect expression of mRNA for zif268 or for syntaxin 1 B. Expression of raf B was enhanced by training, and in trained animals the LTP-associated increase in expression of raf B was occluded. These results suggest that LTP and spatial training engage a common pathway utilizing an increase in mRNA for raf B, and demonstrate a dissociation between LTP and spatial learning with respect to expression of zif268 and syntaxin 1B.

Animals↗
PubMed1998

Behavioural, physiological and morphological analysis of a line of apolipoprotein E knockout mouse.

Using apolipoprotein E knockout mice derived from the Maeda source [Piedrahita J. A. et al. (1992) Proc. natn. Acad Sci. US.A. 89, 4471 4475], we have studied the influence of apolipoprotein E gene deletion on normal CNS function by neurological tests and water maze learning, hippocampal ultrastructure assessed by quantitative immunocytochemistry and electron microscopy, CNS plasticity, i.e. hippocampal long-term potentiation and amygdaloid kindling, and CNS repair, i.e. synaptic recovery in the hippocampus following deafferentation. In each study there was little difference between the apolipoprotein E knockout mice and wild-type controls of similar age and genetic background. Apolipoprotein E knockout mice aged eight months demonstrated accurate spatial learning and normal neurological function. Synaptophysin and microtubule-associated protein 2 immunohistochemistry and electron microscopic analysis of these animals revealed that the hippocampal synaptic and dendritic densities were similar between genotypes. The induction and maintenance of kindled seizures and hippocampal long-term potentiation were indistinguishable between groups. Finally, unilateral entorhinal cortex lesions produced a marked loss of hippocampal synaptophysin immunoreactivity in both groups and a marked up-regulation of apolipoprotein E in the wild-type group. Both apolipoprotein E knockout and wild-type groups showed immunohistochemical evidence of reactive synaptogenesis, although the apolipoprotein E knockout group may have initially shown greater synaptic loss. It is suggested that either apolipoprotein E is of no importance in the maintenance of synaptic integrity and in processes of CNS plasticity and repair, or more likely, alternative (apolipo)proteins may compensate for the loss of apolipoprotein E in the knockout animals.

Animals↗
PubMed1997

Activation of NMDA receptors is necessary for the induction of associative long-term potentiation in area CA1 of the rat hippocampal slice.

1. It is commonly assumed that the role of the strongly activated heterosynaptic input during the induction of associative long-term potentiation (LTP) is to relieve the magnesium blockade of NMDA receptors located at the weakly stimulated synapses and thereby allow the weak input to undergo potentiation. We tested this assumption by using a caged form of the NMDA receptor antagonist, D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) to block the activation of NMDA receptors at the weak input in a conditioning protocol for the induction of associative LTP in area CA1 of the rat hippocampal slice. 2. The effect of releasing D-AP5 by flash photolysis of 100 microM caged D-AP5 (N-[1-(2-nitrophenyl)ethoxycarbonyl]-D-AP5) on pharmacologically isolated NMDA receptor-mediated field EPSPs was examined in area CA1. The slope of the EPSP was reduced by 71% within 50 ms of the initiation of the photolytic reaction when the concentration of released D-AP5 had reached 2.0-2.5 microM and was reduced by 95% within 1 min (10 microM D-AP5 released). 3. Associative LTP was induced by pairing a strong tetanus to one input with a weak tetanus (subthreshold for homosynaptic LTP) to a second input. The strong tetanus preceded the weak by 50 ms. Rapid application of D-AP5, by flash photolysis of caged D-AP5, coincident with the last shock of the strong tetanus, resulted in the blockade of NMDA receptor activation during the period of the weak tetanus. Associative LTP was blocked by photolysis of caged D-AP5 but was normally expressed in experiments using caged L-AP5. 4. We conclude that activation of NMDA receptors at the weakly activated input is an essential requirement for synaptically induced associative LTP.

2-Amino-5-phosphonovalerate↗
PubMed1997

Induction and duration of long-term potentiation in the hippocampus of the freely moving mouse.

We describe a simple method, using readily available minaturised components, for inducing and monitoring long-term potentiation (LTP) at perforant path-granule cell synapses in the dentate gyrus of the freely moving mouse. Tetanic stimulation induced LTP of the field EPSP and the population spike which persisted for more than 24 h but was not present 10 days after the tetanus. The potentiation of the population spike was proportionately greater than the potentiation of the EPSP (E-S potentiation). Induction of LTP was blocked by intraperitoneal injections of the N-methyl-D-aspartate (NMDA) receptor antagonist, 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP).

Animals↗
PubMed1997

Reduction in spine density associated with long-term potentiation in the dentate gyrus suggests a spine fusion-and-branching model of potentiation.

Approximately 2,700 dendritic spines in Golgi-impregnated hippocampal granule cells were quantified via image analysis 24 h after the unilateral induction of long-term potentiation in seven rats. Stereological corrections were made using a tilting disector and analytical unfolding technique. In the potentiated hemisphere the mean spine density along dendrites was reduced by approximately 20%. The relative frequency of shorter, thicker spines was increased in potentiated tissue. Physiological consequences of two morphological changes leading to a reduction in spine density (retraction or fusion of spines) were examined using a compartmental model of a simplified granule cell. The model was constructed in the NEURON modeling environment and included a realistic population of 60 dendritic spines (with dual-component synapses and active Ca(2+)-dependent mechanisms). Simulations demonstrated that potentiation of postsynaptic responses was compatible with fusion (with branching) of a proportion of spines with their neighbors but was not compatible with retraction of spines. This result held over wide variations of model parameters as long as dendritic membranes were assumed to be excitable.

Animals↗
PubMed1997

Ultrastructural synaptic correlates of spatial learning in rat hippocampus.

Memory formation is believed to alter neural circuitry at the synaptic level. Although the hippocampus is known to play an important role in spatial learning, no experimental data exist on the synaptic correlates of this process at the ultrastructural level. Here, we have employed quantitative electron microscopy in order to compare the density, size and spatial arrangement of synapses in the dentate gyrus, and in area CA1, of spatially trained (water maze, invisible platform) versus control (visible platform) rats. No training-associated changes of hippocampal volume were found using a stereological estimaion (disector) of the volume density of dentate granule, or CA1 pyramidal cells. Nor were changes found in either density, or sizes of synapses (spinous or dendritic), in CA1 or dentate gyrus. However, analysis of synaptic spatial distribution showed a training-associated increase in the frequency of shorter distances (i.e. clustering) between synaptic active zones in CA1, but not dentate, thus indicating alterations in local neural circuitry. This finding indicates subtle changes in synaptic organization in area CA1 of the hippocampus following a learning experience, suggesting that spatial memory formation in mammalian hippocampus may involve topographical changes in local circuitry without synapse formation de novo.

Animals↗
PubMed1996

Enhanced tyrosine phosphorylation of the 2B subunit of the N-methyl-D-aspartate receptor in long-term potentiation.

Both serine/threonine and tyrosine phosphorylation of receptor proteins have been implicated in the process of long-term potentiation (LTP), but there has been no direct demonstration of a change in receptor phosphorylation after LTP induction. We show that, after induction of LTP in the dentate gyrus of anesthetized adult rats, there is an increase in the tyrosine phosphorylation of the 2B subunit of the N-methyl-D-aspartate (NMDA) receptor (NR2B), as well as several other unidentified proteins. Tyrosine phosphorylation of NR2B was measured in two ways: binding of antiphosphotyrosine antibodies (PY20) to glycoprotein(s) of 180 kDa (GP180) purified on Con A-Sepharose and binding of anti-NR2B antibodies to tyrosine-phosphorylated proteins purified on PY20-agarose. Three hours after LTP induction, anti-NR2B binding to tyrosine phosphorylated proteins, expressed as a ratio of tetanized to control dentate (Tet/Con), was 2.21 +/- 0.50 and PY20 binding to GP180 was 1.68 +/- 0.16. This increase in the number of tyrosine phosphorylated NR2B subunits occurred without a change in the total number of NR2B subunits. When the induction of LTP was blocked by pretreatment of the animal with the NMDA receptor antagonist MK801, the increase in PY20 binding to GP180 was also blocked (Tet/Con = 1.09 +/- 0.26). The increased PY20 binding to GP180 was also apparent 15 min after LTP induction (Tet/Con = 1.41 +/- 0.16) but not detectable 5 min after LTP induction (Tet/Con = 1.01 +/- 0.19). These results suggest that tyrosine phosphorylation of the NMDA receptor contributes to the maintenance of LTP.

Amino Acid Sequence↗