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G Richter-Levin

Publications and source records attributed to G Richter-Levin.

At least 19 recordsLinked to original sources
PubMed2003

Simultaneous induction of long-term potentiation in the hippocampus and the amygdala by entorhinal cortex activation: mechanistic and temporal profiles.

The medial temporal lobe, including the entorhinal cortex, the amygdala and the hippocampus, has an important role in learning and memory, and its circuits exhibit synaptic plasticity (long-term potentiation [LTP]). The entorhinal cortex is positioned to exert a potent influence on the amygdala and the hippocampus given its extensive monosynaptic projections to both areas. We therefore studied the effects of activation of the entorhinal cortex with simultaneous recording of LTP in the hippocampus and amygdala in the anesthetized rat. theta Burst stimulation of the lateral entorhinal cortex induced LTP simultaneously in the basal amygdaloid nucleus and in the dentate gyrus. However, the mechanisms involved in the induction of LTP in the two areas differed. The N-methyl-D-aspartate receptor antagonist 3-[(+/-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid delivered 1 h before LTP induction (10 mg/kg, i.p.), blocked LTP in the dentate gyrus but not in the amygdala. In addition we found that the basal amygdala as well as the dentate gyrus sustained late-phase LTP (10 h) which may participate in memory encoding and/or modulation processes. Overall, the results suggest a coordinating role for the entorhinal cortex by simultaneously modulating activity and plasticity in these structures, albeit through different mechanisms. Interactive encoding of this sort is believed to endow memories with a different, more integrative, quality than when either pathway is activated alone.

Amygdala↗
PubMed2003

LTP but not seizure is associated with up-regulation of AKAP-150.

We have used differential display to profile and compare the mRNAs expressed in the hippocampus of freely moving animals after the induction of long-term potentiation (LTP) at the perforant path-dentate gyrus synapse with control rats receiving low-frequency stimulation. We have combined this with in situ hybridization and have identified A-kinase anchoring protein of 150 kDa (AKAP-150) as a gene selectively up-regulated during the maintenance phase of LTP. AKAP-150 mRNA has a biphasic modulation in the dentate gyrus following the induction of LTP. The expression of AKAP-150 was 29% lower than stimulated controls 1 h after the induction of LTP. Its expression was enhanced 3 (50%), 6 (239%) and 12 h (210%) after induction, returning to control levels by 24 h postinduction. The NMDA receptor antagonist CPP blocked the tetanus-induced modulation of AKAP-150 expression. Interestingly, strong generalized stimulation produced by electroconvulsive shock did not increase the expression of AKAP-150. This implies that the AKAP-150 harbours a novel property of selective responsiveness to the stimulation patterns that trigger NMDA-dependent LTP in vivo. Its selective up-regulation during LTP and its identified functions as a scaffold for protein kinase A, protein kinase C, calmodulin, calcineurin and ionotropic glutamate receptors suggest that AKAP-150 encodes is an important effector protein in the expression of late LTP.

A Kinase Anchor Proteins↗
PubMed2002

Local circuit plasticity in the rat dentate gyrus: characterization and aging-related impairment.

We have used frequency-dependent inhibition, a form of short-term plasticity mediated by the activation of inhibitory interneurons, to characterize in vivo alterations in local circuit activity and plasticity in the dentate gyrus of the anesthetized rat. The application of the GABA-A receptor blocker, bicuculline, induced a transient reduction in frequency-dependent inhibition, indicating that this form of local circuit activity is GABA-mediated. Delivering theta burst stimulation to the perforant pathway of the hippocampus induced long-term potentiation of the population excitatory post-synaptic potential, reflecting the potentiation of the perforant path-dentate gyrus granule cell synapses. Concomitantly, theta burst stimulation caused a lasting reduction in frequency-dependent inhibition. In aged rats, long-term potentiation could be induced to the same level as in young rats, but while in young rats frequency-dependent inhibition was concomitantly reduced, frequency-dependent inhibition in the old rats did not show this form of plasticity. Our results indicate that theta burst stimulation induces a form of local circuit plasticity independently of its known capacity to induce synaptic plasticity, and that this form of local circuit plasticity is compromised in aging. Based on these results we propose a potential role for plasticity at the level of the local circuit in learning and memory.

Aging↗
PubMed2001

A gradient of plasticity in the amygdala revealed by cortical and subcortical stimulation, in vivo.

Projections to the amygdala from various cortical and subcortical areas terminate in different nuclei. In the present study we examined long-term potentiation of synaptic transmission in the lateral or the basal amygdaloid nuclei by theta burst stimulation of thalamic vs. cortical sensory projections in the anesthetized rat. Although both the medial geniculate nucleus and the dorsal perirhinal cortex have direct projections to lateral nucleus, only the thalamic stimulation induced long-term potentiation of field potentials recorded in the lateral nucleus. In contrast, cortical (ventral perirhinal cortex) but not thalamic stimulation induced long-term potentiation in the basal nucleus. Since the thalamic pathway is believed to process simple/unimodal stimulus features, and the perirhinal cortex complex/polymodal sensory representations, the dissociation of long-term potentiation in lateral and basal nuclei suggests that the basal nucleus may serve as an amygdaloid sensory interface for complex stimulus information similar to the role of the lateral nucleus in relation to relatively simple representations. Thus plasticity of simple and complex representations may involve different amygdala inputs and circuits.

Amygdala↗
PubMed2001

Acute and repeated swim stress effects on peripheral benzodiazepine receptors in the rat hippocampus, adrenal, and kidney.

Peripheral benzodiazepine receptor (PBR) density has been found to be sensitive to stress. We set out to compare the influences of acute and repeated swim stress on behavior and PBR density. Following acute and repeated swim stress, rats were tested in an elevated plus-maze and an open-field test for anxiety levels, and tissues were collected from the adrenal gland, kidney, and hippocampus for measurements of PBR density. The acute rather than the repeated stress led to robust alterations in PBR density. The largest reduction in hippocampal and adrenal gland PBR density was found one hour after acute stress. In the hippocampus, acute stress caused a biphasic change in PBR density: a robust reduction in PBR density one hour after the acute stress and a distinct elevation in PBR density at 24 hours, while 72 hours after stress the elevation in PBR density appeared to be reduced.

Adrenal Glands↗
PubMed2001

Differential activation of hippocampus and amygdala following spatial learning under stress.

We examined the activation of memory-related processes in the hippocampus and the amygdala following spatial learning under stress, in the rat. Animals were trained in a water maze in a massed spatial task under two stress conditions (cold and warm water). In the dorsal CA1, training was accompanied by increased phosphorylation of ERK2 only in animals that have acquired the task (irrespective of whether they were trained in cold or warm water). In the amygdala, significant activation of ERK2 was found only in animals that learned the task well under high levels of stress. Hence, the results suggest that the amygdala and the hippocampus are differentially activated following spatial learning, depending on the level of stress involved.

Amygdala↗
PubMed2001

Is LTP in the hippocampus a useful model for learning-related alterations in gene expression?

It is well established that the formation of long-term memory requires de novo protein synthesis. Altered gene expression is therefore critical in the signal transduction cascade activated by the learning experience. Long-term potentiation (LTP) is a mnemonic model in which particular patterns of activation of incoming excitatory fibers (representing the learning experience) may induce long-lasting enhancement of the communication between the involved pre- and post-synapses (representing the memory). Therefore, cellular and molecular mechanisms of LTP have been extensively studied under the assumption that their understanding will contribute to our comprehension of the mechanisms underlying memory formation. In recent years, however, this analogy has been challenged by reports of inconsistency between LTP and memory. Here we assess LTP in the hippocampus as a model system to study spatial memory-related alterations in gene expression. We focus on three molecular families that are likely to play a role in synaptic plasticity: (1) synaptic communication related proteins; (2) signal transduction machinery; and (3) growth factors. Reviewing first the literature on LTP and then behavioral research we found both consistent and inconsistent findings regarding the LTP/memory linkage. The importance of restricting the discussion to both a learning phase and a brain (sub)structure, as well as of incorporating more physiological LTP stimulation protocols, is discussed. We conclude that while LTP is indeed limited as a model of memory, a careful use of it as a model system of synaptic plasticity is fruitful and productive in screening out candidate memory-related genes.

Animals↗
PubMed2000

LTP in the rat basal amygdala induced by perirhinal cortex stimulation in vivo.

The present study examined the effects of ventral perirhinal cortex (vPRC) stimulation on evoked field potentials (EPs) in the basal amygdala (BN), using extracellular recording techniques. Single pulse stimulation of the vPRC reliably evoked a negative field potential in the BN that was missing in the lateral nucleus. Paired-pulses delivered to the vPRC induced a short-lasting facilitation at intervals between 15 and 120 ms. Application of brief theta burst stimulation to the vPRC produced an enduring long-term potentiation (LTP) that reached 150% of control values. The induction of LTP was not accompanied by a decrease in paired-pulse facilitation. These results suggest that emotional learning involving complex stimulus representations may be mediated by cortico-amygdalar projections amenable to LTP.

Amygdala↗
PubMed2000

Re-structuring of synapses 24 hours after induction of long-term potentiation in the dentate gyrus of the rat hippocampus in vivo.

In male rats, long-term potentiation was induced unilaterally in the dentate gyrus, either by high frequency (200Hz) or theta rhythm stimulation. Structural synaptic changes were examined 24h after induction using quantitative electron microscopy. A disector technique was employed in order to estimate the density of synapses (using 70-80-nm sections) and of granule cell nuclei (using 2-microm sections) in the middle, and inner molecular layer in both hemispheres. Synaptic height and total lateral areas of synaptic active zones per unit tissue volume were assessed via assumption-free stereological techniques coupled with image analysis. The results obtained indicated that both synaptic density and number (corrected per neuron) of axo-spinous, but not axo-dendritic, synapses were approximately 40% higher in the middle, but not inner molecular layer of the potentiated hemisphere compared to the contralateral (control hemisphere). No significant inter-hemispheric difference was found in the volume densities of lateral areas of active zones. These data suggest that 24h after long-term potentiation induction, active zones of existing axo-spinous synapses either split forming separate contacts, or decrease in size while new synapses are formed.

Animals↗
PubMed1999

Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat.

Explicit memory may depend on the hippocampus, whereas the amygdala may be part of an emotional memory system. Priming stimulation of the basolateral group of the amygdala (BLA) resulted in an enhanced long-term potentiation (LTP) in the dentate gyrus (DG) to perforant path (PP) stimulation 30, 90, 150, and 180 min after high-frequency stimulation (HFS). Exposure of rats to a behavioral stress is reported to inhibit DG LTP. Because the amygdala is thought to mediate emotional responses, we examined the apparent discrepancy between the effects of behavioral stress induced 1 hr before HFS to the PP and of amygdala priming on hippocampal plasticity by stimulating the BLA 1 hr before HFS to the PP. The two delayed protocols inhibited the expression of LTP to PP stimulation, whereas priming the BLA immediately before HFS to the PP enhanced DG LTP. Moreover, exposure to the behavioral stress blocked the enhancing effects of BLA priming on LTP. We propose that the activation of the BLA (either by behavioral stress or by direct electrical stimulation) has a biphasic effect on hippocampal plasticity: an immediate excitatory effect and a longer-lasting inhibitory effect.

Amygdala↗
PubMed1999

Priming stimulation in the basolateral amygdala modulates synaptic plasticity in the rat dentate gyrus.

We investigated the effects of basolateral amygdala (BLA) priming on long-term potentiation (LTP) in the dentate gyrus (DG). In the control animals, the induction of high-frequency stimulation (HFS) to the perforant path (PP) resulted in hippocampal LTP at all the time intervals tested. A priming stimulation to the BLA prior to the application of HFS to the PP resulted in the enhancement of the excitatory post-synaptic potential (EPSP)-LTP and population spike (PS)-LTP in the DG from 90-min post-HFS onwards. These findings suggest that the amygdala has a potential role in the modulation of some aspects of memory that are mediated by the hippocampus.

Action Potentials↗
PubMed1999

Frequency-dependent inhibition in the dentate gyrus is attenuated by the NMDA receptor blocker MK-801 at doses that do not yet affect long-term potentiation.

The dual impairment of both long-term potentiation (LTP) in the dentate gyrus and spatial memory by N-methyl-D-aspartate (NMDA) blockers such as 2-aminophosphonovaleric acid (APV) or dizocilpine (MK-801) is considered supportive evidence for the hypothesis that LTP-like mechanisms are involved in spatial memory. However, several studies suggest that, at doses that affect aspects of behavior, LTP is not yet blocked. One possible explanation may be that the blockade of NMDA receptors affect processes other than LTP, which are required for learning. In the present study, we assessed in vivo the effects of the NMDA receptor antagonist MK-801 on LTP and on frequency-dependent inhibition, which has previously been shown to reflect activity of GABAergic interneurons in the rat dentate gyrus. We report here that NMDA receptors are instrumental in frequency-dependent inhibition. Furthermore, frequency-dependent inhibition was found to be more sensitive than LTP to the NMDA antagonist MK-801. Our findings indicate that, in addition to the blockade of LTP, the application of NMDA antagonists affects local circuit activity in the dentate gyrus. The results direct attention to the potential role of interneuronal activity in general and of frequency-dependent inhibition in particular in dentate gyrus related behaviors.

Animals↗
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

Acute and long-term behavioral correlates of underwater trauma--potential relevance to stress and post-stress syndromes.

As a consequence of a brief but significantly extreme stressor, an individual will experience a stress response, which may sometimes develop into Acute Stress Disorder (ASD) or Post-Traumatic Stress Disorder (PTSD). Though a rat model for ASD and PTSD is not expected to encompass the richness and complexity of the disorders in humans, it will enable the study of the common underlying mechanisms that generate the disorders, the study of pre-trauma etiological aspects of the disorders and the screening of drugs with potential relevance to the treatment of the disorders. One well-documented aspect of PTSD is the enhancing influence of contextual elements on the appearance of symptoms of the post-stress trauma. To exploit this effect, we have chosen to assess the effects of an underwater trauma in the Morris water maze since the effects of such trauma on memory and attention can be later evaluated in the context of the trauma. At both 1 h and 3 weeks after the trauma, significant behavioral deficits were observed in the water maze. The effects of the underwater trauma on the performance of rats in the water maze were context specific. Underwater trauma in a different (out-of-context) water container had no effects on the ability of rats to perform a spatial memory task in the water maze. An elevated level of anxiety was found in the plus maze test, independently of whether the trauma was performed in the water maze or in a different (out-of-context) water container. The results indicate that a within-context underwater trauma has both acute and lasting behavioral consequences which can be assessed using a spatial memory test in the context of the trauma. The results are discussed in relation to their relevance to stress and PTSD.

Analysis of Variance↗
PubMed1998

Hippocampal plasticity involves extensive gene induction and multiple cellular mechanisms.

Long-term plasticity of the central nervous system (CNS) involves induction of a set of genes whose identity is incompletely characterized. To identify candidate plasticity-related genes (CPGs), we conducted an exhaustive screen for genes that undergo induction or downregulation in the hippocampus dentate gyrus (DG) following animal treatment with the potent glutamate analog, kainate. The screen yielded 362 upregulated CPGs and 41 downregulated transcripts (dCPGs). Of these, 66 CPGs and 5 dCPGs are known genes that encode for a variety of signal transduction proteins, transcription factors, and structural proteins. Seven novel CPGs predict the following putative functions: cpg2--a dystrophin-like cytoskeletal protein; cpg4--a heat-shock protein: cpg16--a protein kinase; cpg20--a transcription factor; cpg21--a dual-specificity MAP-kinase phosphatase; and cpg30 and cpg38--two new seven-transmembrane domain receptors. Experiments performed in vitro and with cultured hippocampal cells confirmed the ability of the cpg-21 product to inactivate the MAP-kinase. To test relevance to neural plasticity, 66 CPGs were tested for induction by stimuli producing long-term potentiation (LTP). Approximately one-fourth of the genes examined were upregulated by LTP. These results indicate that an extensive genetic response is induced in mammalian brain after glutamate receptor activation, and imply that a significant proportion of this activity is coinduced by LTP. Based on the identified CPGs, it is conceivable that multiple cellular mechanisms underlie long-term plasticity of the nervous system.

Amino Acid Sequence↗
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↗