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PubMed1996

Hippocampal long- and short-term potentiation is modulated by adrenalectomy and corticosterone.

The effect of acute corticosterone (CORT) treatment on elaboration of long-term potentiation (LTP) and short-term potentiation (STP) in intact and adrenalectomized rats was investigated. Both forms of synaptic plasticity were evaluated as fractional increases in population spike amplitude in dentate gyrus granule cells following brief, high-frequency stimulation of the medial perforant pathway in vivo. LTP was distinguished from STP by the magnitude and time course of population spike facilitation. Adrenalectomy resulted in profound reduction of LTP extent, without any significant effect upon STP. Replacement of glucocorticoid by a single injection of CORT to previously adrenalectomized rats restored LTP to control levels. When CORT was applied to intact subjects, it slightly, but significantly, impaired LTP development. No effect of CORT on STP induction and time course was found. Taken together, these results show that the modulation of synaptic efficiency in hippocampal dentate gyrus by circulating glucocorticoid depends on the form of plasticity examined. LTP was found to be more susceptible to the impairment induced by both high and low levels of glucocorticoid than STP.

Adrenalectomy↗
PubMed1993

In vitro MR microscopy of the hippocampus in Alzheimer's disease.

We used MR microscopy at 7 tesla to identify the anatomy of the degenerating hippocampus in Alzheimer's disease (AD), which we then correlated with the histopathologic findings in the same specimens. The specimens studied were resected postmortem from 13 patients with confirmed AD and from nine age-matched controls. We imaged the specimens in the coronal plane using either three-dimensional Fourier encoding or single-slice Carr, Purcell, Meiboom, Gill (CPMG) spin echo sequences. On all specimens imaged with the CPMG pulse sequence, we calculated the T2 relaxation times for subfields within the hippocampus. Histologic sections were taken from each specimen and compared with the corresponding MR image. Using histologic boundaries, we quantified the number of neuritic plaques and neurofibrillary tangles in each hippocampal subfield. We measured the area, morphometric characteristics, and width of identifiable signal variant regions on each image and compared these measurements with the histopathologic findings. The mean cross-sectional area of the hippocampus in AD was decreased by 31% compared with the control group. This atrophy was highly correlated with tangle counts within the hippocampus, but not with plaque counts. The width of the gray matter in hippocampal area CA1, as identified by MR, correlated with the total area of the hippocampus. An age-related decrease in the size of a low-signal region that corresponds histologically to input projections comprising part of the perforant pathway was identified. Measurements of the T2 relaxation times of hippocampal subfields showed little regional variability and were not accurate indicators of disease presence or severity (p > 0.05).

Aged↗
PubMed2003

[Amyloid-beta peptide metabolism and Alzheimer's disease].

The deposition of amyloid-beta peptide (Abeta) causes the long-term pathological cascade of Alzheimer's disease (AD). Neprilysin is a rate-limiting peptidase, which participates in Abeta degradation in brain. As demonstrated by reverse genetics, the disruption of neprilysin gene causes an elevation in endogenous Abeta levels in the mouse brain in a gene-dose-dependent manner. Therefore, a reduction of neprilysin activity will contribute to Abeta deposition and thus to AD development. Neprilysin is localized at presynapses and on axons, and its expression levels are decreased at the terminal zones and on axons of the lateral perforant pathway and the mossy fibers with aging in mice, suggesting that local concentrations of Abeta are likely to be elevated at the sites, which play crucial roles on certain forms of learning and memory and are highly vulnerable to AD. Overexpression of neprilysin decreased both extracellular and intracellular Abeta levels in primary cortical neurons. These results indicate that up-regulation of neprilysin activity would be a relevant strategy for therapy and prevention through reduction of the Abeta levels. Recently, we have found that a certain neuropeptide regulates the expression of neprilysin in primary neurons. Since a number of receptors for neuropeptides are G-protein-coupled receptors, we would control brain Abetalevels pharmacologically by the manipulation of neprilysin activity.

Aging↗
PubMed2004

The repulsive guidance molecule RGMa is involved in the formation of afferent connections in the dentate gyrus.

In the developing dentate gyrus, afferent fiber projections terminate in distinct laminas. This relies on an accurately regulated spatiotemporal network of guidance molecules. Here, we have analyzed the functional role of the glycosylphosphatidylinositol (GPI)-anchored repulsive guidance molecule RGMa. In situ hybridization in embryonic and postnatal brain showed expression of RGMa in the cornu ammonis and hilus of the hippocampus. In the dentate gyrus, RGM immunostaining was confined to the inner molecular layer, whereas the outer molecular layers targeted by entorhinal fibers remained free. To test the repulsive capacity of RGMa, different setups were used: the stripe and explant outgrowth assays with recombinant RGMa, and entorhino-hippocampal cocultures incubated either with a neutralizing RGMa antibody (Ab) or with the GPI anchor-digesting drug phosphatidylinositol-specific phospholipase C. Entorhinal axons were clearly repelled by RGMa in the stripe and outgrowth assays. After disrupting the RGMa function, the specific laminar termination pattern in entorhino-hippocampal cocultures was lost, and entorhinal axons entered inappropriate hippocampal areas. Our data indicate an important role of RGMa for the layer-specific termination of the perforant pathway as a repulsive signal that compels entorhinal fibers to stay in their correct target zone.

Afferent Pathways↗
PubMed2004

Role of hippocampal CA3 mu-opioid receptors in spatial learning and memory.

The dorsal CA3 region of the hippocampus is unique in its connectivity, sensitivity to neurotoxic lesions, and its ability to encode and retrieve episodic memories. Computational models of the CA3 region predict that blocking mossy-fiber and/or perforant path activity to CA3 would cause impairments in learning and recall of spatial memory, respectively. Because the CA3 region contains micro-opioid receptors and receives inputs from the mossy-fiber and lateral perforant pathways, both of which contain and release opioid peptides, we tested the hypothesis that inactivating micro-opioid receptors in the CA3 region would cause spatial learning and memory impairments and retrieval deficits. In this study, male Sprague Dawley rats were trained in a Morris water maze after a single bilateral intrahippocampal injection of either saline or the selective and irreversible micro-opioid receptor antagonist beta-funaltrexamine (beta-FNA) into area CA3. We found that micro-opioid receptor binding decreased 24 hr after beta-FNA injection and returned to control levels 11 d after injection. Injections of beta-FNA into the CA3 region, but not into the ventricles, caused a significant impairment in the acquisition of spatial learning without causing sensory or motor deficits. New learning was not affected once micro-opioid receptor levels replenished (>11 d after injection). In pretrained animals, beta-FNA significantly impaired spatial memory retrieval and new (reversal) learning. These data are consistent with theoretical models of CA3 function and suggest that CA3 micro-opioid receptors play an important role in the acquisition and retrieval of spatial memory.

Animals↗
PubMed1998

Tiagabine: a new therapeutic option for people with intellectual disability and partial epilepsy.

Tiagabine exerts its antiepileptic drug (AED) activity by selectively inhibiting the uptake of gamma-aminobutyric acid (GABA) onto the transporter molecules, and thus, increasing extracellular concentrations of GABA in the brain. The absorption and elimination of tiagabine follow linear pharmacokinetics. Tiagabine is metabolized by hepatic cytochrome P450 enzymes and enzyme-inducing AEDs increase tiagabine clearance by 50-65%. Tiagabine has shown no clinically important interactions with other drugs, including oral contraceptives. In the perforant pathway stimulation model of status epilepticus, tiagabine reduced the seizure number and severity, and also prevented the loss of pyramidal cells in the hippocampus as well as alleviated impairment of the spatial memory impairment associated with hippocampal damage. Tiagabine has both antiepileptogenic and anticonvulsant effects in the kindling model of epilepsy. Based on the data from the short- and long-term add-on studies, tiagabine is effective adjunctive therapy for all partial seizure types in adolescents and adults. Conversion to tiagabine monotherapy has been also possible in substantial amount of patients with partial seizures in three trials. Tiagabine is generally well-tolerated. The most common adverse events in controlled studies involve the central nervous system; for example, dizziness, asthenia, nervousness, tremor, depressed mood and emotional lability. Special safety analyses with formal neuropsychological testing suggest that tiagabine does not adversely affect cognition or mood. Tiagabine represents an important new therapeutic option for patients with treatment-refractory partial seizures. The role of tiagabine in the management of partial epilepsy of patients with intellectual disability is especially emphasized since tiagabine has a low side-effect profile in the cognitive area.

Adult↗
PubMedDate not supplied

Egr3/Pilot, a zinc finger transcription factor, is rapidly regulated by activity in brain neurons and colocalizes with Egr1/zif268.

Programs of gene activation may underlie long-term adaptive cellular responses to extracellular ligands. We have used a differential cDNA cloning strategy to identify genes that are strongly induced by excitatory stimuli in the adult rat hippocampus. Here, we report the rat cDNA sequence of a zinc-finger transcription factor, Egr3/Pilot, and characterize its regulated mRNA expression in brain. Egr3 mRNA is rapidly and transiently induced in neurons of the hippocampus and cortex by electroconvulsive seizure. mRNA levels peak 2 hr after the seizure and remain elevated for as long as 8 hr. Egr3 mRNA is also rapidly induced in granule cells of the dentate gyrus by synaptic NMDA receptor activation elicited by patterned stimulation of the perforant pathway and by drugs that alter dopamine neurotransmission in the striatum. Basal levels of Egr3 mRNA in the cortex appear to be driven by natural synaptic activity because monocular deprivation rapidly decreases Egr3 mRNA in the deafferented visual cortex. Aspects of the protein structure, sequence-specific DNA binding, transcriptional activity, and regulation of Egr3 are highly similar to another zinc-finger transcription factor, Egr1/zif268. Moreover, we demonstrate colocalization of Egr3 and zif268 mRNAs in neurons of normal and stimulated cortex. Our studies suggest that interactions between these coregulated transcription factors may be important in defining long-term, neuroplastic responses.

Amino Acid Sequence↗
PubMedDate not supplied

[The development of the slow potentiation of the population spike of a long-term nonstimulating input in rats in a state of anesthetic sleep].

Changes in synaptic efficacy of the medial perforant pathway were studied after the long-term deprivation of the afferent inputs in hippocampus of rats under chloral hydrate or urethane anesthesia. Evoked field potential population spikes and population excitatory postsynaptic potentials were recorded in the dentate gyrus. The long-term deprivation obtained by cessation of stimulation of the tested input for up to 4 hours resulted in an enhancement (up to 190%, p < 0.01) of the population spike amplitude.

Action Potentials↗
PubMed2000

Altered synaptic transmission in the hippocampus of the castrated male mouse is reversed by testosterone replacement.

PURPOSE: To determine the effect of castration on hippocampal function, we have investigated synaptic transmission in the castrated male mouse in vivo. We also examined whether administering testosterone can reverse the changes. MATERIALS AND METHODS: Male 12 weeks-old C57BL/6J mice were divided into three experimental groups; sham-castration (Control), the castration group (Cast), and the castration plus testosterone propionate group (Cast+TP). Field excitatory postsynaptic potentials (fEPSP) were evoked in the CA1 area of the hippocampus by stimulating the commissural fibers of the contralateral hippocampus. Field EPSPs were evoked in the granular cells of the dentate gyrus (DG) by stimulating the ipsilateral perforant path fibers. RESULTS: Laminar analysis of the fEPSPs in the hippocampal CA1 pyramidal cell layer did not differ significantly between the three experimental groups. However, paired pulse facilitation (PPF) of the fEPSP with short inter-stimulus intervals (30 to 100 msec) was significantly suppressed in Cast group. This suppression was reversed by testosterone injection (Cast+TP). Longterm potentiation (LTP) in the CA1 pyramidal neurons by high frequency stimulation (HFS) did not differ significantly between the three experimental groups, whereas potentiation evoked by primed burst stimulation (PBS) was much weaker in the Cast group compared with the Control group. Testosterone injection restored the PBS-induced potentiation to the control level. Synaptic transmission between perforant pathway and the granule cells in the dentate gyrus (DG) did not differ significantly among the three experimental groups. CONCLUSIONS: Suppression of PPF and impairment of the potentiation by PBS in CA1 hippocampal neurons was observed in castrated male mice and these changes were reversed by testosterone injection. These findings suggest that altered synaptic transmission in the castrated male mouse is caused by disturbance of inhibitory neuronal networks that are influenced by testosterone.

Animals↗
PubMedDate not supplied

Hippocampal synaptic plasticity: effects of neonatal stress in freely moving adult male rats.

The present study examines the effects of neonatal isolation on hippocampal LTP in adult male rats. Changes in dentate granule cell population measures, i.e., EPSP slope and population spike amplitude (PSA), evoked by tetanization of the medial perforant pathway were used to assess the effects of neonatal isolation on LTP over a period of 96 h. Following tetanization significant group differences were obtained for input/output (I/O) response measures of EPSP slope and PSA, with isolated males showing consistently higher values than in the other two groups. Comparisons made at 1 h post-tetanization (establishment of LTP) indicated that isolated males showed significantly greater enhancement than any other group. At 96 h (maintenance of LTP), however, neonatally isolated males showed significantly greater enhancement than either non-isolated siblings or unhandled controls. Additionally, isolation resulted in prolonging the duration of enhancement obtained from males. Thus, males show different enhancement profiles with respect to both the magnitude and duration of LTP and neonatal isolation alters these profiles in profound manner.

Animals↗
PubMed2003

The glycine transporter type 1 inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior.

Glycine acts as a necessary coagonist for glutamate at the NMDA receptor (NMDAR) complex by binding to the strychnine-insensitive glycine-B binding site on the NR1 subunit. The fact that glycine is normally found in the brain and spinal cord at concentrations that exceed those required to saturate this site has led to the speculation that glycine normally saturates NMDAR-containing synapses in vivo. However, additional lines of evidence suggest that synaptic glycine may be efficiently regulated in synaptic areas by the glycine transporter type 1 (GlyT1). The recent description of a potent and selective GlyT1 inhibitor (N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine [NFPS]) provides a tool for evaluation of the hypothesis that inhibition of GlyT1 may increase synaptic glycine and thereby potentiate NMDAR function in vivo. In the present study, we found that (+)-NFPS demonstrated >10-fold greater activity in an in vitro functional glycine reuptake assay relative to the racemic compound. In vivo, (+/-)-NFPS significantly enhanced long-term potentiation in the hippocampal dentate gyrus induced by high-frequency electrical stimulation of the afferent perforant pathway. Furthermore, (+)-NFPS induced a pattern of c-Fos immunoreactivity comparable with the atypical antipsychotic clozapine and enhanced prepulse inhibition of the acoustic startle response in DBA/2J mice, a strain with low basal levels of prepulse inhibition. Collectively, these data suggest that selective inhibition of GlyT1 can enhance NMDAR-sensitive activity in vivo and also support the idea that GlyT1 may represent a novel target for developing therapeutics to treat disorders associated with NMDAR hypofunction.

Amino Acid Transport Systems, Neutral↗
PubMed2005

[Periodontal-endodontal interactions].

The periodontal ligament and the root canals system have a common developmental, anatomical and functional link. Those include the apical foramina, accessory canals and dental tubules whereas the pathological pathways perforation and vertical fractures. Similar microflora- bacteria, virus and yeast also have documented at the both nisus. This article describes the influence of the periodontium on the pulp and vise versa. The pulp is highly survivable and posses high ability to sustain the disease and treatment and periodontal disease and periodontal treatment exhibit small effect on the pulp. However, pulp necrosis is a risk factor to damage the periodontal ligament of the teeth.

Dental Pulp Cavity↗
PubMed1986

Dynorphin- and enkephalin-like immunoreactivity is altered in limbic-basal ganglia regions of rat brain after repeated electroconvulsive shock.

In an attempt to determine whether the opioid peptides derived from prodynorphin participate in the effects of electroconvulsive shock (ECS), we used radioimmunoassay and immunocytochemistry to measure dynorphin-like immunoreactivity (DN-LI) in various rat brain regions after repeated ECS treatments. Ten daily ECSs caused a significant increase in dynorphin A (1-8)-LI in most limbic-basal ganglia structures, including hypothalamus (50%), striatum (30%), and septum (30%). No significant change was found in the frontal cortex or the neurointermediate lobe of the pituitary. In contrast, 10 ECS treatments depleted DN-LI in hippocampal mossy fibers by 64%. A detailed time-course study revealed that a single shock caused a small but significant increase in hippocampal DN-LI, whereas three consecutive shocks depleted DN-LI by 30%. The maximal decrease in DN-LI was reached after six daily ECSs. The level of DN-LI in the hippocampus partly recovered, but remained lower than the control value 4, 7, and 14 d after the cessation of six daily ECSs (50, 77, and 83% of control value, respectively). In contrast with the ECS-induced depletion of hippocampal dynorphin, 10 daily ECSs caused a significant increase (40%) in (Met5)-enkephalin-LI in the hippocampus, as well as in other limbic-basal ganglia structures. Immunocytochemistry revealed that enkephalin-LI was increased in the perforant pathway, which is presynaptic to the dynorphin-containing mossy fiber pathway in the hippocampus. These observations suggest that different mechanisms may regulate these two opioid peptide systems in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Mechanisms of behaviorally-elicited and electrically-elicited long-term potentiation.

Electrically-elicited LTP in the hippocampal formation need not depend for either elicitation or its maintenance, upon any region of the brain outside the hippocampal formation. Behaviorally-elicited LTP certainly must depend for its elicitation upon input from other brain regions, specially the perforant pathway from the entorhinal cortex showa potentiation. Certainly there is variation in the evidence that spine shape change occurs in response to behavioral situations. Lee et al and Chang and Greenough have reported increased synaptic density, indicating the formation of new synapsee in subfield CA1 of the hippocampus following the induction of LTP. Synapses may form in responses to behaviorally-induced neural activity. Synapse formation is also compatible with other physiological changes reported to be associated with LTP induction such as increased neurotransmitter release and increased receptor numbers. Thus it remain perhaps the most likely basis for LTP and one of the most likely candidates for involvement in long-term memory in general.

Animals↗
PubMed1986

Long-term enhancement of hippocampal synaptic transmission and the acquisition of spatial information.

The hypothesis that memories are stored as a specific distribution of strengths in a population of modifiable synapses was examined by the bilateral induction of long-term enhancement in synapses of the main afferent fiber system to the hippocampal formation in rats. Brief, high-frequency activation of the perforant pathway in chronically prepared animals resulted in a persistent increase in the field EPSP and population spike, measured extracellularly in fascia dentata. This treatment resulted in a profound and persistent deficit in the acquisition of new spatial information in a task requiring spatial "reference" memory, and disruption of recently acquired spatial information. Well-established spatial memory was completely unaffected, however, as was the acquisition of spatial information into short-term "working" memory. These results support the hypothesis that, during the formation of "cognitive maps," spatial information must be temporarily stored at modifiable synapses at the input stage to the hippocampal formation, but that this information is not needed once the representation of the environment is well established. Spatial working memory, in a familiar environment, appears not to depend on the distribution of synaptic strengths in this system at all.

Animals↗
PubMed1986

Parallel antagonism of synaptic transmission and kainate/quisqualate responses in the hippocampus by piperazine-2,3-dicarboxylic acid analogs.

A new series of potent antagonists of excitatory neurotransmission in the rat hippocampus has been identified. These derivatives of piperazine-2,3-dicarboxylate (PzDA) include the most potent acidic amino acid antagonists yet described for Schaffer collateral-commissural EPSPs. These antagonists also effectively block excitatory synaptic responses recorded in the lateral and medial perforant pathways and in the mossy fiber pathway. The PzDA derivatives also block focal depolarizations produced by kainate, quisqualate, and N-methyl-D-aspartate. N-methyl-D-aspartate responses are more susceptible to inhibition by PzDA derivatives, although the spectrum of antagonism of N-methyl-D-aspartate and synaptic responses by PzDA derivatives is not parallel. However, the antagonism of kainate and quisqualate responses by PzDA derivatives shows the same rank order of potency as synaptic responses. These data indicate that synaptic receptors in the hippocampus have a pharmacologic profile similar to that of kainate or quisqualate receptors.

Animals↗
PubMed1986

Anatomical evidence for direct projections from the entorhinal area to the entire cortical mantle in the rat.

The entorhinal area is the most highly differentiated cortical field of the hippocampal formation from an anatomical point of view, and is best known as the origin of the perforant pathway, a massive association projection to the molecular layer of the dentate gyrus and Ammon's horn. This pathway is important as the first link in the so-called "trisynaptic circuit," which is thought to form the basic unit of information processing in the hippocampal formation and has been implicated in the elaboration of short-term memory and the more permanent storage of selected events in other parts of the cortical mantle. We have reexamined the efferent projections of the lateral entorhinal area with a sensitive new method that utilizes the anterograde axonal transport of a lectin, Phaseolus vulgaris leukoagglutinin (PHA-L), that is not internalized by fibers of passage, and displays labeled axons with the clarity of Golgi impregnations. The results of 5 experiments with injections confined entirely to the lateral entorhinal area suggest that this area sends fibers to innervate the entire cortical mantle, as well as to a longitudinal zone extending the length of the striatum (nucleus accumbens and medial caudoputamen) and the basolateral complex of the amygdala. In an additional series of experiments, injections of the fluorescent retrograde tracer fast blue that were centered in medial prefrontal, somatosensory, auditory, and motor areas of the cortex invariably labeled many neurons in layer IV of the lateral entorhinal area, as well as in other layers, depending on the site of injection. Finally, the results of double retrograde tracer experiments indicated that the 2 densest projections from the lateral entorhinal area--to the medial prefrontal region and to the dentate gyrus and Ammon's horn--arise from essentially separate populations of neurons. These findings serve to clarify the neural mechanisms underlying the role of the hippocampal formation in learning and memory, as well as in locomotor activity associated with goal-oriented behavior.

Animals↗