Search PubMed⌕ Search

Biomedical subjects

Eric R Kandel

Publications and source records attributed to Eric R Kandel.

70 records · Page 4Linked to original sources
PubMed2003

Activity-dependent presynaptic facilitation and hebbian LTP are both required and interact during classical conditioning in Aplysia.

Using a simplified preparation of the Aplysia siphon-withdrawal reflex, we previously found that associative plasticity at synapses between sensory neurons and motor neurons contributes importantly to classical conditioning of the reflex. We have now tested the roles in that plasticity of two associative cellular mechanisms: activity-dependent enhancement of presynaptic facilitation and postsynaptically induced long-term potentiation. By perturbing molecular signaling pathways in individual neurons, we have provided the most direct evidence to date that each of these mechanisms contributes to behavioral learning. In addition, our results suggest that the two mechanisms are not independent but rather interact through retrograde signaling.

Action Potentials↗
PubMed2003

Characterization of Caenorhabditis elegans homologs of the Down syndrome candidate gene DYRK1A.

The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits. Increased expression of the dual-specificity protein kinase DYRK1A kinase (DYRK1A) appears to play a significant role in the neuropathology of Down syndrome. To shed light on the cellular role of DYRK1A and related genes we identified three DYRK/minibrain-like genes in the genome sequence of Caenorhabditis elegans, termed mbk-1, mbk-2, and hpk-1. We found these genes to be widely expressed and to localize to distinct subcellular compartments. We isolated deletion alleles in all three genes and show that loss of mbk-1, the gene most closely related to DYRK1A, causes no obvious defects, while another gene, mbk-2, is essential for viability. The overexpression of DYRK1A in Down syndrome led us to examine the effects of overexpression of its C. elegans ortholog mbk-1. We found that animals containing additional copies of the mbk-1 gene display behavioral defects in chemotaxis toward volatile chemoattractants and that the extent of these defects correlates with mbk-1 gene dosage. Using tissue-specific and inducible promoters, we show that additional copies of mbk-1 can impair olfaction cell-autonomously in mature, fully differentiated neurons and that this impairment is reversible. Our results suggest that increased gene dosage of human DYRK1A in trisomy 21 may disrupt the function of fully differentiated neurons and that this disruption is reversible.

Animals↗
PubMed2003

A parallel between radical reductionism in science and in art.

Neural science represents an important bridge between the natural sciences concerned with the nature of the physical world and the humanities concerned with the nature of human existence. We try to illustrate this bridging function in two ways. One, we show that many neural scientists study the brain to address humanistically important questions about the mind first raised by classical philosophy. Second, in certain instances the humanities and neural sciences use common methodologies to achieve their respective goals.

Animals↗
PubMed2003

CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects.

The treatment of memory disorders, such as the gradual weakening of memory with age, the ravages of Alzheimer's disease and the cognitive deficits in various forms of mental retardation, may greatly benefit from a better understanding of the molecular and cellular mechanisms of memory formation. There is increasing interest in the possibility of pharmacologically enhancing learning and memory even in the absence of specific anatomically evident pathology. Substantial evidence in experimental systems ranging from molluscs to humans indicates that the cAMP response element binding protein (CREB) is a core component of the molecular switch that converts short- to long-term memory. Recent studies have greatly strengthened and refined our understanding of the role of CREB in learning and memory in mammals, in addition to providing greater insight into the molecular mechanisms of CREB regulation and function. This involvement of CREB and the upstream signalling pathways leading to its activation in learning-associated plasticity makes them attractive targets for drugs aimed at improving memory function, in both diseased and healthy individuals. However, CREB and its close relatives cAMP response element modulator and activating transcription factor-1 are ubiquitous proteins with several critical functions. This creates hurdles that the authors believe may limit the usefulness of CREB per se as a target for the development of memory-enhancing drugs, and focus on components of the upstream signalling pathways or on specific downstream targets will be required.

Amino Acid Sequence↗
PubMed2002

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

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

Amygdala↗
PubMed2002

Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure.

Excitatory and inhibitory inputs converge on single neurons and are integrated into a coherent output. Although much is known about short-term integration, little is known about how neurons sum opposing signals for long-term synaptic plasticity and memory storage. In Aplysia, we find that when a sensory neuron simultaneously receives inputs from the facilitatory transmitter 5-HT at one set of synapses and the inhibitory transmitter FMRFamide at another, long-term facilitation is blocked and synapse-specific long-term depression dominates. Chromatin immunoprecipitation assays show that 5-HT induces the downstream gene C/EBP by activating CREB1, which recruits CBP for histone acetylation, whereas FMRFa leads to CREB1 displacement by CREB2 and recruitment of HDAC5 to deacetylate histones. When the two transmitters are applied together, facilitation is blocked because CREB2 and HDAC5 displace CREB1-CBP, thereby deacetylating histones.

Acetylation↗
PubMed2002

Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory.

CREB is critical for long-lasting synaptic and behavioral plasticity in invertebrates. Its role in the mammalian hippocampus is less clear. We have interfered with CREB family transcription factors in region CA1 of the dorsal hippocampus. This impairs learning in the Morris water maze, which specifically requires the dorsal hippocampus, but not context conditioning, which does not. The deficit is specific to long-term memory, as shown in an object recognition task. Several forms of late-phase LTP are normal, but forskolin-induced and dopamine-regulated potentiation are disrupted. These experiments represent the first targeting of the dorsal hippocampus in genetically modified mice and confirm a role for CREB in hippocampus-dependent learning. Nevertheless, they suggest that some experimental forms of plasticity bypass the requirement for CREB.

Activating Transcription Factor 1↗
PubMed2002

Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala.

Auditory information critical for fear conditioning, a model of emotional learning, is conveyed to the lateral nucleus of the amygdala via two routes: directly from the medial geniculate nucleus and indirectly from the auditory cortex. Here we show in the cortico-amygdala pathway that learned fear occludes electrically induced long-term potentiation (LTP). Quantal analysis of the expression of LTP in this pathway reveals a significant presynaptic component reflected in an increase in probability of transmitter release. Conditioned fear also is accompanied by the enhancement in transmitter release at this cortico-amygdala synapse. These results indicate that the synaptic projections from the auditory cortex to the lateral amygdala are modified during the acquisition and expression of fear to auditory stimulation, thus further strengthening the proposed link between LTP in the auditory pathways to the amygdala and learned fear.

Amygdala↗
PubMed2002

Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture.

Restricted and regulated expression in mice of VP16-CREB, a constitutively active form of CREB, in hippocampal CA1 neurons lowers the threshold for eliciting a persistent late phase of long-term potentiation (L-LTP) in the Schaffer collateral pathway. This L-LTP has unusual properties in that its induction is not dependent on transcription. Pharmacological and two-pathway experiments suggest a model in which VP16-CREB activates the transcription of CRE-driven genes and leads to a cell-wide distribution of proteins that prime the synapses for subsequent synapse-specific capture of L-LTP by a weak stimulus. Our analysis indicates that synaptic capture of CRE-driven gene products may be sufficient for consolidation of LTP and provides insight into the molecular mechanisms of synaptic tagging and synapse-specific potentiation.

Animals↗
PubMed2002

Novel mechanism for gonadotropin-releasing hormone neuronal migration involving Gas6/Ark signaling to p38 mitogen-activated protein kinase.

Gonadotropin-releasing hormone (GnRH) is the central regulator of the reproductive axis. Normal sexual maturation depends on the migration of GnRH neurons from the olfactory placode to the hypothalamus during development. Previously, we showed restricted expression of the membrane receptor adhesion-related kinase (Ark) in immortalized cell lines derived from migratory but not postmigratory GnRH neurons. In addition, Ark and GnRH transcripts were detected along the GnRH neuron migratory route in the E13 mouse cribriform plate. In the present study, we examined the role of Ark and its ligand, Gas6 (encoded by growth arrest-specific gene 6), in GnRH neuron migration. Gas6 stimulated lamellipodial extension, membrane ruffling, and chemotaxis of immortalized NLT GnRH neuronal cells via the Ark receptor. Gas6/Ark signaling promoted activation of the Rho family GTPase Rac, and adenoviral-mediated expression of dominant negative N17Rac abolished Gas6/Ark-induced actin cytoskeletal reorganization and migration of GnRH neuronal cells. In addition, p38 MAPK was activated downstream of Ark and Rac, and inhibition of p38 MAPK with either SB203580 or adenoviral dominant negative p38alpha also blocked Gas6/Ark-mediated migration. Finally, downstream of Rac and p38 mitogen-activated protein kinase (MAPK), Gas6/Ark signaling promoted activation of MAPK-activated protein kinase 2 and induced phosphorylation of HSP25, a known regulator of cortical actin remodeling. The data are the first to demonstrate a migratory signaling pathway downstream of Ark/Axl family receptors and suggest a previously unidentified role for p38 MAPK in neuronal migration. Furthermore, these studies support a potential role for Ark in the regulation of GnRH neuronal migration.

Animals↗
PubMedDate not supplied

Age-related enhancement of a protein synthesis-dependent late phase of LTP induced by low frequency paired-pulse stimulation in hippocampus.

Protein synthesis-dependent late phase of LTP (L-LTP) is typically induced by repeated high-frequency stimulation (HFS). This form of L-LTP is reduced in the aged animal and is positively correlated with age-related memory loss. Here we report a novel form of protein synthesis-dependent late phase of LTP in the CA1 region of hippocampus induced by a brief 1-Hz paired-pulse stimulation (PP-1 Hz, 1 min). In contrast to L-LTP induced by HFS, the late phase of PP-1 Hz LTP does not exist in young adult animals. Rather, it emerges and becomes enhanced in an age-related way. Thus, in 1.5- to 2-mo-old mice, a brief PP-1 Hz stimulation induces only a short lasting LTP, decaying to baseline in about 90 min. By contrast, PP-1 Hz stimulation induces an enduring and protein synthesis dependent LTP in 12- to 18-mo-old mice. The PP-1 Hz-induced L-LTP is dependent on NMDA receptor activation, requires voltage-dependent calcium channels, and is modulated by dopamine D1/D5 receptors. Because memory ability declines with aging, the age-related enhancement of L-LTP induced by PP-1 Hz stimulation indicates that this form of L-LTP appears to be inversely correlated with memory ability.

Aging↗
PubMedDate not supplied

Chronically increased Gsalpha signaling disrupts associative and spatial learning.

The cAMP/PKA pathway plays a critical role in learning and memory systems in animals ranging from mice to Drosophila to Aplysia. Studies of olfactory learning in Drosophila suggest that altered expression of either positive or negative regulators of the cAMP/PKA signaling pathway beyond a certain optimum range may be deleterious. Here we provide genetic evidence of the behavioral and physiological effects of increased signaling through the cAMP/PKA pathway in mice. We have generated transgenic mice in which the expression of a constitutively active form of Gsalpha (Gsalpha* Q227L), the G protein that stimulates adenylyl cyclase activity, is driven in neurons within the forebrain by the promoter from the CaMKIIalpha gene. Despite significantly increased adenylyl cyclase activity, Gsalpha* transgenic mice exhibit PKA-dependent decreases in levels of cAMP due to a compensatory up-regulation in phosphodiesterase activity. Interestingly, Gsalpha* transgenic mice also exhibit enhanced basal synaptic transmission. Consistent with a role for the cAMP/PKA pathway in learning and memory, Gsalpha* transgenic mice show impairments in spatial learning in the Morris water maze and in contextual and cued fear conditioning tasks. The learning deficits observed in these transgenic mice suggest that associative and spatial learning requires regulated Gsalpha protein signaling, much as does olfactory learning in Drosophila.

Adenylyl Cyclases↗
PubMedDate not supplied

Using an aplysia two-hybrid system to examine the interactions between transcription factors involved in long-term facilitation in the nervous system of aplysia.

Interactions between ApCREB1a, ApCREB2, and ApC/EBP have been studied using conventional methods such as the yeast two-hybrid system. However, it is unclear whether these memory-related transcription factors actually interact in the native environment in neurons. To clarify this question, we have developed an Aplysia two-hybrid system and found, consistent with previous studies that ApCREB2 interacts with ApCREB1a and ApC/EBP, and that ApC/EBP forms homodimers. We have also found that ApCREB1a and ApC/EBP do not interact. Therefore, our study shows that formerly described interactions between the proteins actually occur in the Aplysia neurons and that interactions between these transcription factors are specific.

Animals↗
PubMedDate not supplied

Altered hippocampal transcript profile accompanies an age-related spatial memory deficit in mice.

We have carried out a global survey of age-related changes in mRNA levels in the C57BL/6NIA mouse hippocampus and found a difference in the hippocampal gene expression profile between 2-month-old young mice and 15-month-old middle-aged mice correlated with an age-related cognitive deficit in hippocampal-based explicit memory formation. Middle-aged mice displayed a mild but specific deficit in spatial memory in the Morris water maze. By using Affymetrix GeneChip microarrays, we found a distinct pattern of age-related change, consisting mostly of gene overexpression in the middle-aged mice, suggesting that the induction of negative regulators in the middle-aged hippocampus could be involved in impairment of learning. Interestingly, we report changes in transcript levels for genes that could affect synaptic plasticity. Those changes could be involved in the memory deficits we observed in the 15-month-old mice. In agreement with previous reports, we also found altered expression in genes related to inflammation, protein processing, and oxidative stress.

Aging↗
PubMedDate not supplied

Selective modulation of some forms of schaffer collateral-CA1 synaptic plasticity in mice with a disruption of the CPEB-1 gene.

CPEB-1 is a sequence-specific RNA binding protein that stimulates the polyadenylation-induced translation of mRNAs containing the cytoplasmic polyadenylation element (CPE). Although CPEB-1 was identified originally in Xenopus oocytes, it has also been found at postsynaptic sites of hippocampal neurons where, in response to N-methyl-D-aspartate receptor activation, it is thought to induce the polyadenylation and translation of alphaCaMKII and perhaps other CPE-containing mRNAs. Because some forms of synaptic modification appear to be influenced by local (synaptic) protein synthesis, we examined long-term potentiation (LTP) in CPEB-1 knockout mice. Although the basal synaptic transmission of Schaffer collateral-CA1 neurons was not affected in the knockout mice, we found that there was a modest deficit in LTP evoked by a single train of 100 Hz stimulation, but a greater deficit in LTP evoked by one train of theta-burst stimulation. In contrast, LTP evoked by either four trains of 100 Hz stimulation or five trains of theta-burst stimulation were not or were only modestly affected, respectively. The deficit in LTP evoked by single stimulation in knockout mice appeared several minutes after tetanic stimulation. Long-term depression (LTD) evoked by 1 Hz stimulation was moderately facilitated; however, a stronger and more enduring form of LTD induced by paired-pulse 1 Hz stimulation was unaffected. These data suggest that CPEB-1 contributes in the translational control of mRNAs that is critical only for some selected forms of LTP and LTD.

Action Potentials↗