Biomedical subjects

A Ylinen

Publications and source records attributed to A Ylinen.

At least 37 records · Page 2Linked to original sources

PubMed1996

Failure of carbamazepine to prevent behavioural and histopathological sequels of experimentally induced status epilepticus.

Sustained electrical stimulation of the perforant pathway was used to induce long-lasting hippocampal seizures in conscious rats. One hour prior to stimulation, rats were given i.p. injections of either saline or a commonly used antiepileptic drug, carbamazepine (5H-dibenz[b, f]azepine-5-carboxamide; CBZ; 20 mg/kg). When tested 2 weeks later in a water maze, both the saline- and the carbamazepine-pretreated rats showed similarly a severe impairment in spatial learning compared to non-stimulated controls. Histological evaluation revealed that the pyramidal cell damage was (P < 0.05) milder in the carbamazepine-pretreated group in the CA1, but not the CA3c subfield. However, the number of somatostatin-immunoreactive neurons in both stimulated groups was reduced equally. Thus, at the dose of 20 mg/kg, which is a usual anticonvulsive dose in humans, carbamazepine seems to offer only partial protection against pyramidal cell damage, but no protection against the hilar somatostatin-immunoreactive neuron loss or the spatial learning deficit after perforant pathway stimulation in rats. The result clearly differs from that obtained either with a GABA (gamma-aminobutyric acid)-enhancing drug and a novel antiepileptic, vigabatrin (4-amino-hex-5-enoic acid) or with a competitive NMDA (N-methyl-D-aspartate) receptor antagonist, CGP 39551 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid carboxyethylester) in the same test situation.

Animals↗

PubMed1995

Morphometric and electrical properties of reconstructed hippocampal CA3 neurons recorded in vivo.

CA3 pyramidal neurons were stained with biocytin during intracellular recording in rat hippocampus in vivo and reconstructed using a computer-based system. The in vivo CA3 neurons were characterized primarily according to their proximity to the hilus and secondarily with respect to the septotemporal location. Neurons measured in CA3a (n = 4), in CA3b (n = 4), and in posterior/ventral locations (n = 3) had the greatest dendritic lengths (19.8, 19.1, and 26.8 mm on average, respectively). Cells closer to the hilus showed much shorter dendritic lengths, averaging 10.4 mm for CA3c neurons (n = 4) and 11.6 mm for zone 3 neurons (n = 2). Half of the cells showed more than one major apical dendrite, and dendritic trees were highly variable even within CA3 subregions. The mean electronic length for these cell groups averaged between 0.30 lambda (CA3c) and 0.45 lambda (posterior/ventral), assuming a constant specific-membrane resistivity of 60 K omega-cm2. These CA3 neurons form a database of reconstructed neurons for further morphometric and electrical modelling studies. The large degree of variability between individual CA3 neurons indicates that both dendritic and electrical properties should be specifically calculated for each cell rather than assuming a "typical" morphology.

Animals↗

PubMed1995

The effects of NMDA receptor antagonists at anticonvulsive doses on the performance of rats in the water maze task.

In the present study we investigated the effects of two competitive NMDA receptor antagonists, CGP 37849 (DL-(E)-2-amino-4-methyl-phosphono-3-pentonoic acid) and CGP 39551 (carboxyethyl ester of CGP 37849) as well as MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenz(a,d)cycloheptene-5,10-imine hydrogen maleate), a non-competitive antagonist, administered systemically before training, on the acquisition of a water maze task used to assess spatial learning and memory in rats. The competitive NMDA receptor antagonists dose dependently impaired water maze acquisition (increased escape distance), but did not significantly affect swimming speed in rats. MK-801 induced clear behavioral effects and impaired the acquisition of the water maze task. However, as training advanced drug-treated rats did show a decrease in distance swam per trial before encountering the platform in the water pool. This suggests that drug treatments did not abolish learning. When the anticonvulsive properties of the drugs were determined, MK-801 did not show any protection in the maximal electroshock (MES) test at doses already impairing the acquisition of the water maze task while the two competitive NMDA receptor antagonists protected the rats against seizures at doses not impairing acquisition. This result suggests a wider therapeutic range for CGP 39551 and especially for CGP 37849 than for MK-801 in the treatment of epilepsy.

2-Amino-5-phosphonovalerate↗

PubMed1995

Intracellular correlates of hippocampal theta rhythm in identified pyramidal cells, granule cells, and basket cells.

The cellular-synaptic generation of rhythmic slow activity (RSA or theta) in the hippocampus has been investigated by intracellular recording from principal cells and basket cells in anesthetized rats. In addition, the voltage-, coherence-, and phase versus depth profiles were examined by simultaneously recording field activity at 16 sites in the intact rat, during urethane anesthesia, and after bilateral entorhinal cortex lesion. In the extracellular experiments the large peak of theta at the hippocampal fissure was attenuated by urethane anesthesia and abolished by entorhinal cortex lesion. The phase versus depth profiles were similar during urethane anesthesia and following entorhinal cortex lesion but distinctly different in the intact, awake rat. These observations suggest that dendritic currents underlying theta in the awake rat may not be revealed under urethane anesthesia. The frequency of theta-related membrane potential oscillation was voltage-independent in pyramidal neurons, granule cells, and basket cells. On the other hand, the phase and amplitude of intracellular theta were voltage-dependent in all three cell types with an almost complete phase reversal at chloride equilibrium potential in pyramidal cells and basket cells. At strong depolarization levels (less than 30 mV) pyramidal cells emitted calcium spike oscillations, phase-locked to theta. Basket cells possessed the most regular membrane oscillations of the three cell types. All neurons of this study were verified by intracellular injection of biocytin. The observations provide direct evidence that theta-related rhythmic hyper-polarization of principal cells is brought about by the rhythmically discharging basket neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

PubMed1995

Effects of NMDA receptor modulation on hippocampal type 2 theta activity in rats.

1. The present study was designed to investigate whether pharmacological modulation of N-methyl-D-aspartate (NMDA) receptor function could modify hippocampal type 2 theta activity in the dentate gyrus of rats. 2. The effects of pre-recording administration of d-cycloserine (DCS: 1.0, 3.0 and 9.0 mg/kg, i.p.), a partial agonist at the NMDA receptor associated glycine site, and MK-801 (0.1 mg/kg, i.p.), a noncompetitive NMDA receptor antagonist, were examined in freely moving rats. 3. Using adult Wistar rats, which had recording electrodes implanted unilaterally into the hilus of dentate gyrus, we recorded five 4 sec epochs of awake-immobility-related hippocampal EEG activity bands (1-20 Hz) 40 min after d-cycloserine and 2 hr after administration of MK-801. 4. In the off-line analysis, the spectral power and the frequency at the maximal theta power were calculated. 5. D-cycloserine (1.0-9.0 mg/kg) did not affect the frequency at the maximal theta power. However, the dose of 3.0 mg/kg, though not the 1.0 or 9.0 mg/kg doses, significantly increased the spectral power of the hippocampal immobility-related EEG activity. 6. In line with the previous findings, 0.1 mg/kg MK-801 decreased both the frequency at the maximal theta power as well as the spectral power of hippocampal type 2 EEG activity. 7. The present data show a clear relationship between NMDA receptors and hippocampal type 2 theta activity and suggest that the pharmacological modulation of the receptor function, using appropriate doses of glycine binding site agonist, d-cycloserine, may be a possible means to positively modulate the immobility-related hippocampal EEG activity.

Animals↗

PubMed1995

Long-term efficacy and cognitive effects of vigabatrin.

Vigabatrin is effective as add-on therapy in about 50% of patients with partial epilepsy refractory to drugs. Furthermore, at least half of the original responders maintain the response over several years. As monotherapy, both vigabatrin and carbamazepine seem to be successful in a similar proportion of newly diagnosed patients with epilepsy, but carbamazepine monotherapy fails more often due to side-effects and vigabatrin more often due to lack of efficacy. However, vigabatrin monotherapy seems to be extremely well tolerated, particularly in relation to cognitive function.

Anticonvulsants↗

PubMed1995

Hippocampal CA1 interneurons: an in vivo intracellular labeling study.

Fast spiking interneurons in the CA1 area of the dorsal hippocampus were recorded from and filled with biocytin in anesthetized rats. The full extent of their dendrites and axonal arborizations as well as their calcium binding protein content were examined. Based on the spatial extent of axon collaterals, local circuit cells (basket and O-LM neurons) and long-range cells (bistratified, trilaminar, and backprojection neurons) could be distinguished. Basket cells were immunoreactive for parvalbumin and their axon collaterals were confined to the pyramidal layer. A single basket cell contacted more than 1500 pyramidal neurons and 60 other parvalbumin-positive interneurons. Commissural stimulation directly discharged basket cells, followed by an early and late IPSPs, indicating interneuronal inhibition of basket cells. The dendrites of another local circuit neuron (O-LM) were confined to stratum oriens and it had a small but high-density axonal terminal field in stratum lacunosum-moleculare. The fastest firing cell of all interneurons was a calbindin-immunoreactive bistratified neuron with axonal targets in stratum oriens and radiatum. Two neurons with their cell bodies in the alveus innervated the CA3 region (backprojection cells), in addition to rich axon collaterals in the CA1 region. The trilaminar interneuron had axon collaterals in strata radiatum, oriens and pyramidale with its dendrites confined to stratum oriens. Commissural stimulation evoked an early EPSP-IPSP-late depolarizing potential sequence in this cell. All interneurons formed symmetric synapses with their targets at the electron microscopic level. These findings indicate that interneurons with distinct axonal targets have differential functions in shaping the physiological patterns of the CA1 network.

Animals↗

PubMed1995

Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms.

Sharp wave bursts, induced by a cooperative discharge of CA3 pyramidal cells, are the most synchronous physiological pattern in the hippocampus. In conjunction with sharp wave bursts, CA1 pyramidal cells display a high-frequency (200 Hz) network oscillation (ripple). In the present study extracellular field and unit activity was recorded simultaneously from 16 closely spaces sites in the awake rat and the intracellular activity of CA1 pyramidal cells during the network oscillation was studied under anesthesia. Current source density analysis of the high-frequency oscillation revealed circumscribed sinks and sources in the vicinity of the pyramidal layer. Single pyramidal cells discharged at a low frequency but were phase locked to the negative peak of the locally derived field oscillation. Approximately 10% of the simultaneously recorded pyramidal cells fired during a given oscillatory event. Putative interneurons increased their discharge rates during the field ripples severalfold and often maintained a 200 Hz frequency during the oscillatory event. Under urethane and ketamine anesthesia the frequency of ripples was slower (100-120 Hz) than in the awake rat (180-200 Hz). Halothane anesthesia prevented the occurrence of high-frequency field oscillations in the CA1 region. Both the amplitude (1-4 mV) and phase of the intracellular ripple, but not its frequency, were voltage dependent. The amplitude of intracellular ripple was smallest between -70 and -80 mV. The phase of intracellular oscillation relative to the extracellular ripple reversed when the membrane was hyperpolarized more than -80 mV. A histologically verified CA1 basket cell increased its firing rate during the network oscillation and discharged at the frequency of the extracellular ripple. These findings indicate that the intracellularly recorded fast oscillatory rhythm is not solely dependent on membrane currents intrinsic to the CA1 pyramidal cells but it is a network driven phenomenon dependent upon the participation of inhibitory interneurons. We hypothesize that fast field oscillation (200 Hz) in the CA1 region reflects summed IPSPs in pyramidal cells as a result of high-frequency barrage of interneurons. The sharp wave associated synchronous discharge of pyramidal cells in the millisecond range can exert a powerful influence on retrohippocampal targets and may facilitate the transfer of transiently stored memory traces from the hippocampus to the entorhinal cortex.

Anesthesia↗

PubMed1994

Inhibitory CA1-CA3-hilar region feedback in the hippocampus.

The organization of the hippocampus is generally thought of as a series of cell groups that form a unidirectionally excited chain, regulated by localized inhibitory circuits. With the use of in vivo intracellular labeling, histochemical, and extracellular tracing methods, a longitudinally widespread, inhibitory feedback in rat brain from the CA1 area to the CA3 and hilar regions was observed. This long-range, cross-regional inhibition may allow precise synchronization of population activity by timing the occurrence of action potentials in the principal cells and may contribute to the coordinated induction of synaptic plasticity in distributed networks.

Animals↗

PubMed1994

The hippocampal CA3 network: an in vivo intracellular labeling study.

The intrahippocampal distribution of axon collaterals of individual CA3 pyramidal cells was investigated in the rat. Pyramidal cells in the CA3 region of the hippocampus were physiologically characterized and filled with biocytin in anesthetized animals. Their axonal trees were reconstructed with the aid of a drawing tube. Single CA3 pyramidal cells arborized most extensively in the CA1 region, covering approximately two-thirds of the longitudinal axis of the hippocampus. The total length of axon collaterals in the CA3 region was less than in CA1 and the axon branches tended to cluster in narrow bands (200-800 microns), usually several hundred microns anterior or posterior to the cell body. The majority of the recurrent collaterals of a given neuron remained in the same subfield (CA3a, b, or c) as the parent cell. CA3a neurons innervated predominantly the basal dendrites, whereas neurons located proximal to the hilus (CA3c) terminated predominantly on the apical dendrites of both CA1 and CA3 cells. Two cells, with horizontal dendrites and numerous thorny excrescences at the CA3c-hilus transitional zone, were also labeled and projected to both CA3 and CA1 regions. All CA3 neurons projected some collaterals to the hilar region. Proximal (CA3c) neurons had numerous collaterals in the hilus proper. One CA3c pyramidal cell in the dorsal hippocampus sent an axon collaterals to the inner third of the molecular layer. CA3c pyramidal cells in the ventral hippocampus had extensive projections to the inner third of the dentate molecular layer, as well as numerous collaterals in the hilus, CA3, and CA1 areas, and several axon collaterals penetrated the subiculum. The total projected axon length of a single neuron ranged from 150 to 300 mm. On the basis of the projected axon length and bouton density (mean interbouton distance: 4.7 microns), we estimate that a single CA3 pyramidal cell can make synapses with 30,000-60,000 neurons in the ipsilateral hippocampus. The concentrated distribution of the axon collaterals ("patches") indicates that subpopulations of neurons may receive disproportionately denser innervation, whereas innervation in the rest of the target zones is rather sparse. These observations offer new insights into the physiological organization of the CA3 pyramidal cell network.

Animals↗

PubMed1994

Long-term study with gabapentin in patients with drug-resistant epileptic seizures.

OBJECTIVE: To study the efficacy and safety of gabapentin in long-term treatment. DESIGN: A 4-year follow-up study of 25 patients with visits at 3-month intervals. SETTING: The patients were followed up in the outpatient unit of the University Hospital of Kuopio (Finland). PATIENTS: We treated 25 patients with drug-resistant complex partial seizures and secondarily generalized seizures in an open-label long-term study, using gabapentin as an additional means of therapy after a 3-month double-blind, placebo-controlled phase. Thirteen patients showed no benefit from gabapentin; the study medication was discontinued after 4 to 6 months of treatment. Of the 12 patients who responded enough to continue treatment, five were withdrawn due to different reasons, one because of loss of response. MAIN OUTCOME MEASURES: The number of patients receiving the study drug in the follow-up and reduction of seizure frequency from baseline level as analyzed by the Wilcoxon test. RESULTS: Seven patients received gabapentin therapy for more than 4 years. The median follow-up time was 54 months. There was a significant reduction in seizure frequency throughout the follow-up period. Five of seven patients had a greater than 50% seizure frequency reduction at 4 years, representing 20% of the 25 patients who entered the study. CONCLUSIONS: Gabapentin possesses good efficacy in long-term treatment of patients with partial and secondarily generalized epileptic seizures. It is safe to use, and it is fairly well tolerated even in long-term treatment.

Acetates↗

PubMed1993

Preservation of hippocampal NMDA receptors may be crucial for spatial learning after epileptic seizures in rats.

Sustained electrical stimulation of the perforant pathway (PP) was used to induce hippocampal seizures in conscious rats. About 4.5 h prior to stimulation, animals were given i.p. injections of either saline or CGP 39551 (10 mg/kg), a competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. When tested 2 weeks later in water maze, the saline pretreated rats showed a severe impairment in spatial learning whereas the animals treated with CGP 39551 had the same escape latencies as the non-stimulated controls. Histological evaluation of cellular degeneration revealed that the number of somatostatin-immunoreactive (SOM-IR) neurons in both stimulated groups was reduced almost equally, but in the CGP 39551 treated animals pyramidal cell damage was partly protected. However, in contrast to the placebo group, NMDA-sensitive [3H]glutamate binding in strata radiatum and oriens of the CA1 area was not significantly reduced in the CGP 39551 group. Thus, the present results suggest that the CGP 39551 treatment was able to protect against the delayed phase of the excitotoxic cell damage, and that the preservation of NMDA receptors partly accounts for the good learning ability of the CGP 39551 pretreated, PP-stimulated rats.

2-Amino-5-phosphonovalerate↗

PubMed1993

Long-term antiepileptic efficacy of vigabatrin in drug-refractory epilepsy in mentally retarded patients. A 5-year follow-up study.

The long-term clinical, neurophysiologic, and psychological effects of add-on vigabatrin treatment were evaluated in a group of 36 mentally handicapped patients with drug-refractory epilepsy. After an initial 3-month follow-up period, 15 (42%) of 36 patients had at least a 50% decrease in seizure frequency compared with baseline. After a 2-year follow-up period, nine (25%) of 36 patients retained the initially observed antiepileptic effects of vigabatrin, and after 5 years, eight (22%) of 36 patients did so. Five (33%) of the 15 patients who initially exhibited a favorable antiepileptic response to vigabatrin lost that response during a 5-year follow-up. Partial-onset seizures represented the seizure type best controlled by vigabatrin. Side effects were mostly mild, and plasma levels of other antiepileptic medication remained unchanged. No impairment of psychological performance was observed during vigabatrin treatment compared with baseline. Also, no clear change was observed in the background or epileptiform activity in the electroencephalogram during the study. Our findings suggest that vigabatrin as an add-on therapeutic effectively controls seizures in a subpopulation of patients with severe epilepsy. In addition, the antiepileptic response, if achieved, is long lasting in about half of the patients.

Adult↗

PubMed1993

Long-term alterations in NMDA-sensitive L-[3H]glutamate binding in the rat hippocampus following fimbria-fornix lesioning.

Subcortical deafferentation of the rat hippocampus has been suggested to offer a model for developing limbic epilepsy. In the present study, the long-term effect of fimbria-fornix lesioning on the density and distribution of hippocampal N-methyl-D-aspartate (NMDA)-sensitive L-[3H]glutamate binding was studied using quantitative autoradiography. Compared to controls of the same age, the fimbria-fornix-lesioned (FFL) rats showed 1 year after lesioning a uniform, 20-33% increase in NMDA receptor density throughout the hippocampus, which was statistically significant in the stratum radiatum of the CA1 area (P = 0.001 and P < 0.05) and in the inner and outer halves of the dentate molecular layer (P < 0.05 for both). The increased receptor density in the FFL rats may reflect a long-term process of regeneration within the hippocampal formation, which could partly account for the maintenance or development of epileptogenity. The control animals, which were over 1 year old, showed lower binding density than young animals in all areas measured, thus suggesting a decrease in NMDA receptor binding during normal aging.

Animals↗

PubMed1993

Biochemical and morphological changes in the rat hippocampus following transection of the fimbria-fornix.

According to electrophysiological studies, the subcortically denervated hippocampus has been suggested as a model for limbic epilepsy. We investigated a) whether fimbrial lesioning leads to any biochemical or morphological changes in the rat hippocampus, b) if these changes give any explanation to the previously indicated hyperexcitability, and c) if the changes are in line with the findings in other experimental models and human epilepsy. The fimbria-fornix transection was done by aspiration. Four months later, spontaneous EEG activities were recorded, and the hippocampal formation was processed for histology. In addition, a separate group of lesioned rats was used for hippocampal amino acid analysis. Hyperexcitable functioning of the hippocampus was seen as frequent and rhythmic spiking activity in 25% of the fimbria-fornix-lesioned rats, although the rest of them had spikes occasionally. The amino acids analysis revealed a notable decrease in the concentration of GABA but no significant changes in the amount of excitatory amino acids. This suggests impaired GABAergic functioning but does not exclude possible abnormalities in the release of both excitatory and inhibitory amino acids. The number of somatostatin-immunoreactive (SOM-IR) neurons, a subpopulation of GABAergic neurons, was decreased in all the areas of the hippocampus (CA3 > CA1 > hilus), but this was statistically significant only in the CA3 area. Interestingly, it is the region from which interictal spiking activity in the subcortically denervated rat presumable originates. Immunostaining for synaptophysin showed a dense band of granules in the inner molecular layer of the dentate gyrus, indicating probable synaptic reorganization of associational afferents.

Acetylcholinesterase↗

PubMed1993

NMDA-sensitive [3H]glutamate binding in the epileptic rat hippocampus: an autoradiographic study.

Sustained stimulation of the perforant pathway (PP) offers a model for studying seizure-induced pathology of the hippocampal formation. Using quantitative autoradiography, NMDA-sensitive glutamate binding was evaluated in the rat hippocampus three weeks after PP-stimulation. Decreased receptor binding (38-44%) was found together with pyramidal cell damage and gliosis in the CA1 area, ipsilateral to the stimulation (p < or = 0.001). In the dentate gyrus, however, a 20% increase in receptor density was observed bilaterally within the molecular layer (significant within the outer molecular layer of the contralateral side, on the suprapyramidal location; p < or = 0.05). These results are similar to those found in epileptic patients and suggest a prominent role for NMDA receptors in epilepsy.

Animals↗

PubMed1992

Pattern of neuronal death in the rat hippocampus after status epilepticus. Relationship to calcium binding protein content and ischemic vulnerability.

The pattern of hippocampal cell death has been studied following hippocampal seizure activity and status epilepticus induced by 110-min stimulation of the perforant pathway in awake rats. The order of vulnerability of principal cells in the different hippocampal subfields--as determined by silver impregnation--was found to be very similar to the pattern found in ischemia; i.e., dentate hilus greater than CA1, subiculum greater than CA3c greater than CA3a,b greater than dentate granule cells. The hilar somatostatin-containing cells were the most vulnerable cell type, whereas all other subpopulations of nonprincipal neurons--visualized by immunocytochemistry for the calcium binding proteins parvalbumin and calbindin--were remarkably resistant. Pyramidal cells in the CA3 region containing neither of the examined calcium binding proteins were more resistant to overexcitation than CA1 pyramidal cells, most of which do contain calbindin. This indicates that no simple relationship exists between vulnerability in status epilepticus and neuronal calcium binding protein content, and that local and/or systemic hypoxia during status epilepticus may be responsible for the ischemic pattern of cell death.

Animals↗

PubMed1992

Hippocampal mobility-related theta activity is not diminished by vigabatrin, a GABAmimetic antiepileptic drug, in normal rats.

Lesions causing loss of hippocampal theta activity have been shown to result in spatial memory deficits in rats. On the other hand, hippocampal theta activity is thought to be associated only with motor activity, and its role in learning/memory is not clear. Vigabatrin, an inhibitor of GABA-tranasminase, causes elevation of brain GABA levels. Previously, we have found that subchronic administration of vigabatrin did not impair spatial learning/memory in a water maze task. This experiment was carried out to further examine the hippocampal effects of vigabatrin by studying whether vigabatrin at antiepileptic doses affects mobility-related hippocampal EEG. Administration of vigabatrin (100 mg/kg or 500 mg/kg, IP) to nonepileptic rats caused no significant changes in mobility-related rhythmic theta activity, and the relative spectral power of theta frequency had a slight increasing tendency. These results suggest that the vigabatrin-induced enhanced GABAergic inhibition does not disturb normal mobility-related hippocampal theta activity.

Aminocaproates↗