Biomedical subjects

C Nitsch

Publications and source records attributed to C Nitsch.

At least 19 recordsLinked to original sources

PubMed2005

GABA(B) receptor expression and cellular localization in gerbil hippocampus after transient global ischemia.

Using in situ hybridization, the expression of the GABA receptor subtype B subunit 1 (GABA(B) R1) and subunit 2 (GABA(B) R2) following transient global ischemia in the gerbil hippocampus was investigated. In sham-operated animals, mRNAs of both subunits were mainly detected in hippocampal pyramidal cells and interneurons with lower expression levels of the GABA(B) R2 in the CA1 field. Four days after transient cerebral ischemia, neuronal message decreased in conjunction with neuronal death and both receptor subunits disappeared from the pyramidal cell layer. However, GABA(B) R1 and GABA(B) R2 were still expressed in a few cells. In situ hybridization of the GABA synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) remained unchanged after the ischemic insult. Double-labeling experiments revealed that in the postischemic hippocampus GABA(B) R1 and GABA(B) R2 were not present in GFAP-reactive astrocytes, but that the surviving parvalbumin-containing interneurons possessed GABA(B) R1 and GABA(B) R2 mRNA.

Animals↗

PubMed2001

Ischemia-induced degeneration of CA1 pyramidal cells decreases seizure severity in a subgroup of epileptic gerbils and affects parvalbumin immunoreactivity of CA1 interneurons.

Mongolian gerbils are epilepsy-prone animals. In adult gerbils two major groups can be differentiated according to their seizure behavior: Highly seizure-sensitive gerbils exhibit facial and forelimb clonus or generalized tonic-clonic seizures from the first test on, while kindled-like gerbils are seizure free for the first three to six consecutive tests, later develop forelimb myoclonus, and eventually progress to generalized tonic-clonic seizures. In the hippocampus, seizure history of the individual animal is mirrored in the intensity in which GABAergic neurons are immunostained for the calcium-binding protein parvalbumin: they lose parvalbumin with increasing seizure incidence. In a first step to clarify the influence of hippocampal projection neurons on spontaneous seizure behavior and related parvalbumin expression, we induced degeneration of the CA1 pyramidal cells by transient forebrain ischemia. This results in a decreased seizure sensitivity in highly seizure-sensitive gerbils. The kindling-like process, however, is not permanently blocked by the ischemic nerve cell loss, suggesting that an intact CA1 field is not a prerequisite for the development of seizure behavior. The seizure-induced loss of parvalbumin from the ischemia-resistant interneurons recovers after ischemia. Thus, changes in parvalbumin content brought about by repeated seizures are not permanent but can rather be modulated by novel stimuli.

Animals↗

PubMed2000

[Psychological descriptors of excessive use of analgesic medication].

INTRODUCTION: Patients suffering from migraine and tension-type-headache are at risk of misusing analgesics and therefore developing chronic drug-induced headache. The present study compares migraine patients with and without abuse to identify psychological descriptors promoting drug abuse. METHODS: We examined 21 in-patients with migraine and drug-abuse and 21 out-patients with migraine and no drug-abuse who were comparable regarding age and diverse pain variables (intensity, frequency, duration, etc. ). Psychometric questionnaires measured the constructs "pain-", "depression", "self-efficacy" and "pain-coping". Using a standardized interview we investigated the external (environment) and internal (mental factors) conditions of all patients during medication intake. RESULTS: Migraineurs who misused medications showed significantly greater disability, greater helplessness and anxiety due to pain and a tendency towards more marked general depression than non-abusers. The extent of the helpless and depressive coping with pain was best suited for distinguishing the patients with and without drug abuse, followed by the fact that those with abuse receive drugs from several doctors at the same time and demand that the drugs free them of all complaints. CONCLUSIONS: These findings suggest that migraine patients with drug abuse often take analgesics not according to their headache, but rather depending on certain other factors.

English Abstract↗

PubMed2000

Species-specific expression of parvalbumin in the entorhinal cortex of the Mongolian gerbil: dependence on local activity but not extrinsic afferents.

Mongolian gerbils are genetically predisposed to develop epileptic seizures in limbic structures. A species-specific property of the Mongolian gerbil is the expression of the calcium-binding protein parvalbumin in the perforant path where it is predominantly concentrated in nerve terminals. To test the hypothesis that this atypical expression of parvalbumin is induced by seizure-correlated hyperactivity in the entorhinohippocampal loop, we investigated whether it is dependent on extrinsic afferents to the entorhinal cortex. We cultivated organotypic slice cultures of neonate gerbil entorhinal cortex, isolated from all regions it is normally connected with in vivo. In these cultures, parvalbumin-expressing neurons demonstrated their characteristic features like in vivo. Blockade of spontaneous local activity with the sodium-channel blocker tetrodotoxin, however, considerably reduced the number of parvalbumin-expressing neurons in culture. These results indicate that spontaneous local activity, but not activity mediated by extrinsic afferents, is an essential factor for the expression of parvalbumin in the entorhinal cortex of the Mongolian gerbil.

Afferent Pathways↗

PubMed1998

Composition of ibotenic acid-induced calcifications in rat substantia nigra.

Agonists of the excitatory neurotransmitter glutamate have neurotoxic properties and are, therefore, frequently used to place locally circumscript brain lesions. In certain vulnerable brain areas, especially the substantia nigra and globus pallidus, the ensuing neurodegeneration is accompanied by the formation of calcium deposits. In the present study, we investigated the structure and chemical composition of calcium deposits formed in rat substantia nigra upon local application of ibotenic acid. Using scanning and transmission electron microscopy in combination with X-ray analysis and analysis of the electron diffraction patterns, we demonstrate that the inorganic components of the calcifications consist of calcium and phosphate. The calcium phosphate is deposited in a polycrystalline manner in degenerating neurons and in a matrix surrounding the degenerated complexes. New matrix is continuously added around the enlarging calcium deposits. Content of inorganic material is always higher in the center of the deposits than in the margin, but in every case the diffraction pattern reveals that the calcium phosphates are present in the form of hydroxyapatite. Thus, organic and inorganic components of the calcifications are subject to a continuous process of growth and maturation. The ibotenic acid-induced calcium deposits in rat substantia nigra provide a reliable model system to study the pathogenesis of non-arteriosclerotic calcifications.

Animals↗

PubMed1998

Seizure patterns of Mongolian gerbils subjected to a prolonged weekly test schedule: evidence for a kindling-like phenomenon in the adult population.

PURPOSE: Mongolian gerbils (Meriones unguiculatus) seize in response to sensory stimulation and forced exploratory behavior, but the incidence and severity of their seizures are variable. We wished to characterize the seizure pattern of gerbils from our breeding colony. METHODS: Ninety-three gerbils aged 1-16 months were tested for a mean of 24 consecutive weeks and assigned to a category according to their seizure pattern. Frequency distribution histograms of the mean scores assigned every 5 weeks were plotted for each category. Mean age, number of seizures, onset of the first facial and forelimb myoclonus, and of the first generalized tonic-clonic seizure (GTCS) were compared among categories. We performed correlation analysis between onset of seizures and animal age. RESULTS: From the 93 tested, no seizure-resistant gerbils could be isolated. Four major categories were distinguished. Category 1, highly seizure-sensitive gerbils (39%), exhibited seizures from the first few weeks of test on. Category 2, consisting of approximately 37%, were seizure-free for the first three to six consecutive tests, later developing facial and forelimb myoclonus and eventually GTCS. Because such progressive development of seizures was similar to that occurring upon electrical kindling, the gerbils were classified as kindled-like (KL). Among KL gerbils, older individuals were significantly more refractory to seizures. In category 3, gerbils (10%) exhibited inconsistent seizure behavior. Category 4 consisted of significantly younger animals (11%) with rapid progress to generalized seizures. CONCLUSIONS: Seizures of progressive severity can be induced in adult gerbils with a prolonged test regimen. As a consequence, the number of regularly seizing gerbils in a colony can be increased. Prolonged tests starting at a defined age may help characterize seizure development better in this genetic model of limbic epilepsy.

Age Factors↗

PubMed1997

XX-agonadism in a fetus with multiple dysraphic lesions: a new syndrome.

We report on a 19-week-old fetus with a 46,XX karyotype, normal female external genitalia, complete gonadal agenesis, large encephalocele, spina bifida, and omphalocele. We postulate a new syndrome. Hitherto no consistent malformation patterns have been observed in agonadism patients. True agonadism, including even the unusual finding of an XX gonosomal status, is obviously not as rare as suggested.

Abnormalities, Multiple↗

PubMed1997

Parvalbumin disappears from GABAergic CA1 neurons of the gerbil hippocampus with seizure onset while its presence persists in the perforant path.

Mongolian gerbils are epilepsy prone animals, a trait observable at the behavioural level during the 2nd month of life. As a unique species difference, gerbils express the calcium-binding protein parvalbumin (PV) in the perforant path from the entorhinal cortex to the hippocampus. In this study, we determined the time of appearance of PV in the layer II neurons of the entorhinal cortex and the perforant path terminals in gerbils between post-natal days 30 and 50. Signs of low grade seizures were observed in few animals from P40 onward. PV stain in the entorhinal cortex and perforant path terminals was already detectable at P30, well before the onset of behavioural seizures and did not change with age. It is suggested that the presence of PV in this pathway may be related to the generation early in life of an epileptogenic focus in the limbic forebrain. Altered inhibitory hippocampal circuits have also been suggested as a cause of seizures in the gerbil. Therefore, we quantitated hippocampal GABA-immunoreactive neurons and the PV-immunoreactive subpopulation. A group of gerbils with a high density of stained pyramidal interneurons in CA1 and one lacking PV-stained perikarya could be distinguished at P40 and P50. The density of GABA-immunoreactive nerve cells however, remained the same in both groups and through the ages studied. Thus, perikaryal PV is lost from intact GABAergic nerve cells at the same time as behavioural seizures are observed. The loss of PV from GABAergic neurons may affect their functional properties and be instrumental for the maintainance of behavioural seizures.

Age of Onset↗

PubMed1997

Endogenous serine protease inhibitor modulates epileptic activity and hippocampal long-term potentiation.

Protease nexin-1 (PN-1), a member of the serpin superfamily, controls the activity of extracellular serine proteases and is expressed in the brain. Mutant mice overexpressing PN-1 in brain under the control of the Thy-1 promoter (Thy 1/PN-1) or lacking PN-1 (PN-1-/-) were found to develop epileptic activity in vivo and in vitro. Theta burst-induced long-term potentiation (LTP) and NMDA receptor-mediated synaptic transmission in the CA1 field of hippocampal slices were augmented in Thy 1/PN-1 mice and reduced in PN-1-/- mice. Compensatory changes in GABA-mediated inhibition in Thy 1/PN-1 mice suggest that altered brain PN-1 levels lead to an imbalance between excitatory and inhibitory synaptic transmission.

Amyloid beta-Protein Precursor↗

PubMed1997

Loss of perikaryal parvalbumin immunoreactivity from surviving GABAergic neurons in the CA1 field of epileptic gerbils.

The Mongolian gerbil (Meriones unguiculatus) is known as a genetic model of epilepsy. Seizure behavior ranges from subtle events like arrest of motor activity and facial spasms to grand mal seizures followed by automatisms. Exploratory behavior in a stressful situation represents the most effective environment for provoking seizures in gerbils. Modifications of the inhibitory hippocampal circuits have been suggested as a cause of seizure susceptibility in the gerbil. This study presents a quantitative analysis of the hippocampal parvalbumin (PV)-immunoreactive and gamma-aminobutyric acid (GABA)-immunoreactive neurons in gerbils whose seizure sensitivity had been scored. PV is a cytosolic calcium-binding protein synthesized by a subpopulation of GABAergic neurons and thought to be responsible for the fast spiking capability of this subset of neurons. We show that the number of PV-immunoreactive neurons in the CA1 field of the gerbil hippocampus decreases in repeatedly seizing animals as compared to non-seizing controls. The lowest density of PV-immunoreactive neurons was observed 1 hour after the last generalized seizure. No changes in the density of GABA-immunoreactive neurons in field CA1 paralleled the obvious loss of perikaryal PV-immunoreactivity. The CA1 field represents the final output region to extrahippocampal brain areas, and its recruitment or not into seizure activity is crucial for the spreading of hippocampal discharges to the adjacent neocortex. A reduction of such a calcium-buffering system in the soma and dendrites may affect the spike characteristics of PV-containing GABAergic neurons and may alter their response to glutamatergic transmission. A reduced inhibitory control of pyramidal cells may ensue, facilitating neuronal excitability as a result.

Animals↗

PubMed1997

Apoptosis and expression of inducible nitric oxide synthase are mutually exclusive in renal mesangial cells.

Nitric oxide (NO) is a multipurpose messenger molecule, important for blood vessel relaxation, neuronal communication, and antimicrobial activities. The generation of NO from L-arginine is catalyzed by NO synthase (NOS). An inducible form of NOS, iNOS, was first characterized in macrophages and then in many other tissues and cells, including renal mesangial cells. Mesangial cells play a crucial role in the regulation of the glomerular filtration rate as well as in the pathophysiology of certain forms of glomerulonephritis in which mesangial cells and macrophages produce NO in high amounts. Because reports have associated NO production with apoptotic cell death in macrophages and we recently demonstrated NO-mediated apoptosis in mesangial cells, we searched for the relationship between in situ iNOS induction and apoptosis by iNOS immunocytochemistry and terminal desoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. RAW 264.7 macrophages exhibited homogeneous iNOS expression and apoptotic nuclei in the iNOS-containing cells upon stimulation with interferon-gamma and lipopolysaccharide. In contrast, stimulated rat mesangial cells stained heterogeneously for iNOS, depending on cell passage and iNOS-stimulating pathway. Mesangial cells expressing iNOS did not display signs of apoptosis and, vice versa, cells showing characteristic features of apoptosis did not stain for iNOS. Thus, our study suggests that mesangial cells react to stimulation by interleukin-1 and/or cAMP-elevating compounds with mutually exclusive responses, either by expression of iNOS or by undergoing programmed cell death.

Animals↗

PubMed1996

Excitotoxic brain lesion modifies binding to a USF binding site acting as a negative regulatory element in the Protease nexin-1 promoter.

The expression of the serine protease inhibitor Protease nexin-1 (PN-1) is upregulated in glial cells following different types of lesion in the nervous system. A strong negative regulatory element has been shown by the missing nucleoside technique to be a CACGTG site (E-box) in the proximal part of the PN-1 promoter. The factor binding to this site is specifically recognized by antibodies directed against the human upstream stimulatory factor (USF). Point mutations in the E-box binding site which abolish USF binding in vitro increase the transcriptional activity of the PN-1 promoter. Cotransfection of a PN-1 promoter/reporter construct together with an expression vector for human USF1 confirms the negative regulatory function of this site. Finally, we show that the binding to this USF site changed after ibotenic acid-induced lesion of the caudate putamen in the rat brain.

Amyloid beta-Protein Precursor↗

PubMed1995

Synaptic reorganisation in the rat striatum after dopaminergic deafferentation: an ultrastructural study using glutamate decarboxylase immunocytochemistry.

The ultrastructure of GABAergic and non-GABAergic synapses in the adult rat neostriatum was examined 6-8 months after unilateral removal of the nigrostriatal dopaminergic pathway by 6-hydroxydopamine injection into the medial forebrain bundle. GABAergic profiles were identified by preembedding glutamate decarboxylase (GAD) immunocytochemistry performed on parasagittal vibratome sections. In three representative fields of the striatum, the nature and number of boutons and their postsynaptic partners were determined and the differences between the striata ipsi- and contralateral to the lesion analyzed. The percentage of GAD-immunoreactive boutons was increased from 23% on the intact side to 28% on the lesioned side. In addition, the GABAergic boutons underwent significantly more multiple contacts with several independent postsynaptic profiles, preferentially with dendritic spines. This could reflect a lesion-induced sprouting of local GABAergic axon terminals. On the other hand, although the vast majority of GABAergic boutons underwent synaptic contacts with dendrites (77% vs. 80%), the number of boutons per dendrite or per dendritic circumference remained unchanged. Thus, the higher frequency of GABAergic boutons may simply reflect the loss of the dopaminergic nerve endings, without a heterosynaptic replacement by GABAergic boutons. The deafferentation also induced structural changes of the postsynaptic profiles. Some dendritic spines had a shortened neck; others were completely integrated in the dendrite which now contained a spine apparatus and was contacted by boutons with the features of axospinous synapses. The spine retraction resulted in a quantitative decrease in the number of spines. Analysis of the synaptic curvature revealed that only spines with a flat contact zone were lost. Concurrently, the number of dendrites was increased, of the GAD-containing in particular, suggesting that the denrites of GABAergic interneurons tend to elongate and/or arborize. Taken together, the results of the present study show that the dopaminergic denervation caused a remodeling of the postsynaptic neurons. The relative increase of the number of GABAergic boutons and their synaptic contacts suggests that an altered wiring of the intrinsic GABAergic system contributes to the changes in the striatal output activity.

Animals↗

PubMed1995

Distribution of parvalbumin-containing interneurons in the hippocampus of the gerbil--a qualitative and quantitative statistical analysis.

In the gerbil (Meriones unguiculatus) hippocampal formation, the calcium-binding protein parvalbumin (PV) shows a unique species-specific distribution: it is present in the perforant path from the entorhinal cortex to the stratum molecular of the dentate are and cornu ammonis. A possible relation of this to the seizure-sensitivity of gerbils has been suggested. In addition, as in other species, PV is contained in a subpopulation of GABAergic nerve cells of the gerbil hippocampus. The characteristics of these PV-containing neurons are here described. Distribution and shape of the PV-positive neurons in general agreed with the features described for rat hippocampus with two notable exceptions: in CA2 PV-containing perikarya were densely crowded and gave rise to an intense immunoreactive plexus around the pyramidal cells and, in CA1, the number of stained neurons was variable, often much lower than in rats and occasionally not a single PV-positive neuron was present. In parasagittal brain sections of the lateralities 1.0, 1.6 and 2.2 mm from the midline, obtained from 27 male gerbils, the number of PV-containing neurons was determined. The data set obtained in CA3 and dentate area resembled unimodal distributions, while in CA1 a bimodal frequency distribution was present. Since parametric and non-parametric correlation tests rely on a unimodal distribution of the data set, they gave falsely significant values in CA1. The bimodal distribution suggests that, with respect to the PV-containing interneurons in CA1, two different populations of gerbils were included in our sample, those with many positive neurons and those with only a few. Since the nerve terminal staining is preserved also in those gerbils with only a few positive perikarya in CA1, it seems possible that an unknown factor influenced PV expression and storage in the soma. Sex, age, seasonal or circadian rhythm or quality of immunocytochemical staining did not influence the outcome of the quantitative analysis. However, a relation of the expression of the high affinity calcium buffering PV in interneurons and the individual seizure sensitivity of the gerbil is considered.

Age Factors↗

PubMed1994

Re-expression of glia-derived nexin/protease nexin 1 depends on mode of lesion-induction or terminal degeneration: observations after excitotoxin or 6-hydroxydopamine lesions of rat substantia nigra.

The serine protease inhibitor and neurite outgrowth promoter glia derived nexin (GDN) is expressed in the rat CNS during embryogenesis and persists in the olfactory system of the adult where receptor neurons are replaced throughout life. We investigated whether GDN-immunoreactivity also appears in the adult at sites of synaptic rearrangement following nerve cell death and anterograde terminal degeneration in experimental models for Parkinson's disease. Rat substantia nigra was unilaterally lesioned by stereotaxic application of different toxins: 6-hydroxydopamine, which selectively destroys dopaminergic neurons, the excitotoxic glutamate analog ibotenic acid, or the glutamate receptor agonists N-methyl-D-aspartate and quisqualate, which cause circumscript lesions of the whole substantia nigra. Nerve cell death and astroglial reactivity were monitored by parallel cresyl staining and immunocytochemistry for glial fibrillary acidic protein, at survival times ranging from 2 to 100 days. Sustained de novo synthesis of GDN occurred in the dopamine depleted caudate putamen following excitotoxin or 6-hydroxydopamine induced degeneration of the substantia nigra and of the nigrostriatal pathway provided that the lesions were nearly complete. This is consistent with compensatory changes occurring in deafferented caudate putamen and suggests a permissive role of GDN in neuronal plasticity. In the substantia nigra astroglia exhibited GDN-immunoreactivity following excitotoxin injection but not after application of 6-hydroxydopamine. Thus differences in action mechanisms of neurotoxins may have distinct consequences on the astrocyte mediated response of the same affected brain region.

Amyloid beta-Protein Precursor↗

PubMed1994

The neurite growth promoting protease nexin 1 in glial cells of the olfactory bulb of the gerbil: an ultrastructural study.

The glia-derived serine protease inhibitor and neurite outgrowth promoter protease nexin-1 (PN-1) is expressed in Schwann cell precursors and astroblasts during embryogenesis. In the adult nervous system, PN-1 persists in the Schwann cells and olfactory glia only. Light-microscopic immunohistochemistry has revealed the presence of PN-1 in the olfactory mucosa and in the nerve fiber layer of the olfactory bulb. The present electron-microscopic study of the gerbil olfactory bulb confirms the occurrence of PN-1 in ensheathing cells of the olfactory nerve fiber layer, a special type of glia which envelopes olfactory axons. In addition, PN-1 is contained in typical astrocytes of the nerve fiber layer and of the glomerular layer. It is inferred that synthesis of PN-1 in the olfactory bulbs is maintained throughout adulthood because its neurite outgrowth promoting action is required for the continuous renewal of olfactory receptor neurons.

Amyloid beta-Protein Precursor↗

PubMed1994

Evidence for the colocalization of parvalbumin and glutamate, but not GABA, in the perforant path of the gerbil hippocampal formation: a combined immunocytochemical and microquantitative analysis.

Gerbils (Meriones unguiculatus) are known for their seizure sensitivity, which is dependent on an intact perforant path from the entorhinal cortex to the hippocampus. In contrast with other species, the perforant path in gerbils contains parvalbumin, a cytosolic high-affinity calcium-binding protein. Parvalbumin is known to be present in a subpopulation of GABA-containing neurons and is thought to be responsible for their physiological characteristics of fast spiking activity and lack of spike adaptation. Therefore, the question arose of whether this projection in gerbils is GABAergic or glutamatergic as in other species. In a first approach to this question, the effect of lesioning the origin of the perforant path, the entorhinal cortex, on levels of GABA and glutamate was determined by enzymatic-luminometric assay in single layers of the dentate gyrus of lyophilized brain sections. Parallel sections were cryofixed using an acidified acetone-formaldehyde mixture at -20 degrees C for 48 h, and subsequently stained for parvalbumin immunocytochemistry. Seven days after ablation of the entorhinal cortex, parvalbumin staining was undetectable in the termination zone of the perforant path, the outer two-thirds of the stratum moleculare. In parallel, glutamate content was reduced to 80% of controls (and of the unoperated contralateral side) but unchanged in the inner third of the stratum moleculare and in stratum granulare. GABA content was not significantly altered by the lesion. From these results, we conclude that in the gerbil as in other species, the perforant path contains glutamate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

The glia-derived protease nexin 1 persists for over 1 year in rat brain areas selectively lesioned by transient global ischaemia.

The re-expression of the developmentally regulated serine protease inhibitor glia-derived nexin (GDN) was investigated 1 year after transient global ischaemia induced by the four-vessel occlusion technique in rats. The CA1 sector of the hippocampus was severely shrunken due to the absence of pyramidal cells, but still clearly discernible due to the continued presence of the parvalbumin-containing GABAergic neurons. In this partially neuron-depleted hippocampus, GDN immunoreactivity was found in reactive astrocytes containing glial fibrillary acidic protein. GDN-positive astrocytes were also found in other lesioned areas, the reticular thalamic nucleus and the cerebellar cortex. Thus, the re-expression of GDN in the adult excitotoxically lesioned brain described previously in the gerbil model of ischaemia persists. The continued presence of the protease inhibitor might disturb the proteolytic balance and lead to the deposition of pathological breakdown products of proteins, e.g. beta-amyloid.

Amyloid beta-Protein Precursor↗