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M Qü

Publications and source records attributed to M Qü.

15 recordsLinked to original sources
PubMed1999

Current-source-density profiles associated with sharp waves in human epileptic neocortical tissue.

In human neocortical slices obtained during epilepsy surgery, sharp waves have been described to appear spontaneously, the shape of which met all criteria of epileptiform field potentials. In the present investigation, the current sinks and sources underlying these potentials were analysed. The cortical tissue used in the present study was a small portion of the tissue blocks excised for treatment of pharmacoresistant focal epilepsy. The tissue came from the temporal (n = 26), frontal (n = 1) and parietal (n = 1) lobes. Slices of 500 microm thickness were cut in the frontal plane perpendicular to the pial surface. Field potentials were recorded using a linear array of eight wire electrodes (diameter: 33 microm) with interelectrode distances of 300 microm. To scan a slice for sharp field potentials, this array was placed perpendicular to the pial surface at the midsection of each preparation, and consecutively at the respective midsections of the resulting halves of the slice. Each of these locations was termed a recording line. Depending on the appearance of spontaneous potentials, recording lines and slices were classified as either spontaneous or non-spontaneous. With both spontaneous and zero Mg(2+)-induced interictal discharges, in spontaneous slices, current sinks were preferentially located in layers II and III. In non-spontaneous slices, current sinks associated with interictal potentials could be found throughout all cortical laminae. With zero Mg(2+)-induced ictal activity, in spontaneous slices, the initial sinks were preferentially located in cortical laminae II and IIIa, and were shifted to lower ones after additional application of bicuculline. In non-spontaneous slices, no ictal-type discharges could be induced with omission of Mg2+ from the superfusate. Only addition of bicuculline elicited ictal-type activity, and sinks associated with this were preferentially located in layers II and IIIa. The results suggest that the supragranular layers, especially layer II, change qualitatively in functional organization in slices showing spontaneous discharges. We think that this special feature represents the function of the upper layers and can be blocked by bicuculline. This interpretation is supported by the observation that ictal discharges normally started in the upper layers in spontaneous and non-spontaneous slices, except for spontaneous slices with bicuculline, where the zone initiating discharges was translocated to deeper layers.

Adolescent↗
PubMed1998

Bihemispheric reduction of GABAA receptor binding following focal cortical photothrombotic lesions in the rat brain.

Focal brain lesions may lead to neuronal dysfunctions in remote (exofocal) brain regions. In the present study, focal lesions were induced in the hindlimb representation area of the parietal cerebral cortex in rats using the technique of photothrombosis. Photothrombosis occurs after illumination of the brain through the intact skull following intravenous injection of the photosensitive dye Rose Bengal. This resulted in cortical lesions with a diameter of about 2 mm. Quantitative receptor autoradiography was used to study alterations in the density of [3H]muscimol binding sites to GABAA receptors seven days after lesion induction. A reduced GABAA receptor binding (-13 to -27% of the control value) was found in layers II and III of remote exofocal regions in the ipsi- and contralateral cortex. The reduction was consistently more intense in the ipsilateral cortical areas than in those of the contralateral hemisphere. Using extracellular recordings, significant correlations between GABAA receptor binding and paired pulse inhibition could be demonstrated. The present investigation demonstrates that focal brain lesions cause a widespread, functionally effective down-regulation of GABAA receptors. These postlesional changes may result from lesion-induced alterations in cortical connectivity.

Animals↗
PubMed1998

Long-term cellular dysfunction after focal cerebral ischemia: in vitro analyses.

The long-term (< or = six months) functional consequences of permanent middle cerebral artery occlusion were studied with in vitro extra- and intracellular recording techniques in adult mouse neocortical slices. After survival times of one to three days, 28 days and six months, intracellular recordings from layers II/III pyramidal cells in the vicinity of the infarct did not reveal any statistically significant changes in the intrinsic membrane properties when compared to age-matched control animals. However, a pronounced hyperexcitability could be observed upon orthodromic synaptic stimulation in neocortical slices obtained from mice 28 days after induction of ischemia. Low-intensity electrical stimulation of the afferents elicited particularly in this group epileptiform extracellular field potential responses and intracellular excitatory postsynaptic potentials, that were longer in duration as compared to the controls. When the N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potential was pharmacologically isolated in a bathing solution containing 0.1 mM Mg2+ and 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione, the synaptic responses were longer and larger in the ischemic cortex as compared to the controls. Higher stimulus intensities evoked in normal medium a biphasic inhibitory postsynaptic potential, that contained in the 28 days post-ischemia group a prominent amino-phosphonovaleric acid-sensitive component, indicating a strong concurrent activation of a N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potential. This pronounced co-activation could only be observed in the 28 days ischemic group, and neither after one to three days or six months post-ischemia nor in the controls. The quantitative analysis of the efficiency of stimulus- evoked inhibitory postsynaptic potentials recorded in amino-phosphono-valeric acid revealed a reduction of GABA-mediated inhibition in ischemic cortex. Although this reduction in intracortical inhibition may already contribute to an augmentation of N-methyl-D-aspartate receptor-mediated excitation, our results do also indicate that the function of N-methyl-D-aspartate receptors is transiently enhanced in the ischemic cortex. This transient hyperexcitability does not only cause cellular dysfunction in the vicinity of the infarct, but may also contribute to neuronal damage due to excitotoxicity.

Animals↗
PubMed1998

Long-term changes of ionotropic glutamate and GABA receptors after unilateral permanent focal cerebral ischemia in the mouse brain.

Long-term hyperexcitability was found after unilateral, permanent middle cerebral artery occlusion in exofocal neocortical areas of the adult mouse [Mittmann et al. (1998) Neuroscience 85, 15-27]. The aim of the present study was to test the hypothesis in an identical paradigm of ischemia. whether alterations in the densities of both excitatory and inhibitory amino acid receptors may underlie these pathophysiological changes. Alterations in densities of [3H]dizocilpine, [3H]D,L-amino-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, [3H]kainate and [3H]muscimol binding sites were demonstrated with quantitative in vitro receptor autoradiography. All binding sites were severely reduced in the core of the ischemic lesion. A completely different reaction was found in the exofocal, histologically inconspicuous parts of the somatosensory cortex and the more remote neocortical areas of both hemispheres. The [3H]muscimol binding sites were significantly reduced four weeks after ischemia in the motor cortex, hindlimb representation area and exofocal parts of the primary and secondary somatosensory cortices of both hemispheres. The focus of the reduction in [3H]muscimol binding sites was found in lower layer V and upper layer VI. Contrastingly, the densities of [3H]dizocilpine binding sites were found to be increased in these areas, whereas those of [3H]D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and [3H]kainate binding sites did not show significant changes. The [3H]dizocilpine binding site density increased predominantly in layers III and IV. All binding sites were also reduced in the retrogradely reacting, gliotic part of the ipsilateral ventroposterior thalamic nucleus, whereas the [3H]D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding sites were increased in the surround of the ipsilateral nucleus and no changes in binding sites were seen in the whole contralateral nucleus. We conclude that permanent local ischemia leads to a long-term and widespread impairment of the normal balance between binding sites of excitatory and inhibitory neurotransmitter receptors in neocortical areas far away from the focus of the post-ischemic tissue damage. The imbalance comprises an up-regulation of the [3H]dizocilpine binding sites in the ion channels of N-methyl-D-aspartate receptors and a down-regulation of [3H]muscimol binding sites of the GABA(A) receptors in the ipsi- and contralateral neocortex. These changes at the receptor level explain the previously observed hyperexcitability with the appearance of epileptiform field potentials and the long duration of excitatory postsynaptic potentials four weeks after ischemia.

Animals↗
PubMed1998

Characterization of neuronal migration disorders in neocortical structures: extracellular in vitro recordings.

The majority of patients showing neuronal migration disorders in cortical structures suffer from pharmaco-resistant epilepsy. In order to study the molecular and cellular mechanisms underlying this pronounced hyperexcitability, we used an animal model of focal cortical dysplasia demonstrating structural malformations which resemble the human pathology of microgyria. Neocortical slices prepared from adult rats, which at the day of birth received a cortical freeze lesion, were analysed in vitro with an array of eight extracellular recording electrodes to investigate the pattern and pharmacology of propagating epileptiform activity in microgyric cortex. In cortical slices exhibiting neuronal migration disorders, orthodromic synaptic stimulation elicited late recurrent activity and early epileptiform responses that spread with 0.06 m/s over > or = 3.5 mm across the cortex. Application of a N-methyl-D-aspartate (NMDA) antagonist blocked the late recurrent activity, but not the propagation of the early epileptiform responses. The latter were blocked by an (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonist, indicating that the spread of this activity was predominantly mediated by activation of AMPA receptors. A very similar response pattern could be observed in neocortical slices obtained from untreated age-matched control rats, when the slice was partially disinhibited by bath-application of 5 microM bicuculline methiodide. Stimulus-evoked epileptiform signals recorded in disinhibited slices propagated with 0.08 m/s across the cortex and showed the same sensitivity to ionotropic glutamate antagonists as in dysplastic cortex. Our results indicate that widespread structural and/or functional modifications of the AMPA receptor and possibly also of the gamma-amino-butyric acid type A receptor contribute to the pronounced hyperexcitability in dysplastic cortex.

Animals↗
PubMed1998

Characterization of neuronal migration disorders in neocortical structures: quantitative receptor autoradiography of ionotropic glutamate, GABA(A) and GABA(B) receptors.

Epileptiform activity was previously described [Luhmann et al. (1998) Eur. J. Neurosci., 10, 3085-3094] in the neocortex of the adult rat following freeze lesioning of the newborn neocortex. After a survival time of 3 months, a small area of dysplastic cortex surrounded by histologically normal (exofocal) neocortex was observed. The dysplastic cortex is characterized by the formation of a small sulcus and a three- to four-layered architecture. Two questions are addressed here: (i) is the hyperexcitability associated with changes in binding to major excitatory and inhibitory transmitter receptors in the dysplastic cortex?; and (ii) do such changes also occur in the exofocal cortex? Alterations in binding to glutamatergic N-methyl-D-aspartate (NMDA), (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate and GABA(A) and GABA(B) (gamma-aminobutyric acid) receptors are demonstrated with quantitative in vitro receptor autoradiography by using the ligands [3H]MK-801, [3H]AMPA, [3H]kainate, [3H]muscimol and [3H]baclofen, respectively. In the dysplastic cortex, the binding to NMDA, AMPA and kainate receptors is significantly increased, whereas the binding to GABA(A) and GABA(B) receptors is reduced. Exofocal areas of the lesioned hemisphere show an imbalance between excitatory and inhibitory receptor binding with an up-regulation of the binding to AMPA and kainate, and a down-regulation to GABA(A) receptors. The binding to GABA(B) and NMDA receptors is not significantly changed in the exofocal areas. The imbalance between excitatory and inhibitory receptors may cause the hyperexcitability, as previously found in the identical experimental model, and may also induce epileptiform activity in the human cortex with migration disorders.

Animals↗
PubMed1998

Characterization of neuronal migration disorders in neocortical structures. II. Intracellular in vitro recordings.

Neuronal migration disorders (NMD) are involved in a variety of different developmental disturbances and in therapy-resistant epilepsy. The cellular mechanisms underlying the pronounced hyperexcitability in dysplastic cortex are not well understood and demand further clinical and experimental analyses. We used a focal freeze-lesion model in cerebral cortex of newborn rats to study the functional consequences of NMD. Intracellular recordings from supragranular regular spiking cells in cortical slices from adult sham-operated rats revealed normal passive and active intrinsic membrane properties and normal stimulus-evoked excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs, respectively). Regular spiking neurons recorded in rat dysplastic cortex showed on average a significantly smaller action potential amplitude, a slower spike rise, and a less steep primary frequency-current relationship. Stimulus-elicited EPSPs in NMD-affected cortex consisted of multiphasic burst discharges, which coincided with extracellular field potentials and lasted 150-800 ms. These epileptiform responses could be recorded at membrane potentials between -50 and -110 mV and were blocked by -2-amino-5-phosphonovaleric acid (APV), indicating the involvement of N-methyl--aspartate (NMDA) receptors. Isolated NMDA-mediated and APV-sensitive EPSPs could be recorded at membrane potentials negative to -70 mV, suggesting that NMDA receptors are activated at relatively negative membrane potentials. In comparison with the controls, polysynaptic IPSPs mediated by the gamma-aminobutyric acid (GABA) type A and B receptor were either absent or reduced in peak conductance in microgyric cortex by 27% (P < 0.05) and 17%, respectively. However, monosynaptic IPSPs recorded in the presence of ionotropic glutamate receptor antagonists revealed a similar efficacy in NMD and control cortex, indicating that GABAergic neurons in microgyric cortex get a weaker excitatory input. Our data indicate that the expression of epileptiform activity in NMD-affected cortex rather results from an imbalance between excitatory and inhibitory synaptic transmission than from alterations in the intrinsic membrane properties. This imbalance is caused by an increase in NMDA-receptor-mediated excitation in pyramidal neurons and a concurrent decrease of glutamatergic input onto inhibitory interneurons.

2-Amino-5-phosphonovalerate↗
PubMed1996

Structural asymmetries in the human forebrain and the forebrain of non-human primates and rats.

Possible asymmetries of the following structures were studied: volumes of total human hemispheres, cortex and white matter volumes in post-mortem- (unknown handedness) and living brains (male right-handers); volumes of the rat primary visual cortex, its mon- and binocular subfields, its layer iv and the density of myelinated fibres in layer iv; transmitter receptor densities (NMDA, AMPA, kainate and GABAA receptors) in sensorimotor regions of the rat cortex; volume of the motor cortex and the 3D-extent of the central sulcus in the post-mortem- (unknown handedness) and living human brain (male right-handers); petalia of the hemispheres in human (male right- and left-handers) and chimpanzee brains. Histological, MRI and receptor autoradiographic techniques were used. With the notable exceptions of the transmitter receptors and the total primary visual cortex in rats and the hemispheres in chimpanzees, which do not show any significant directional asymmetry, all other parameters studied are asymmetrically distributed between the right- and left hemispheres. The regional distribution pattern and the degree of asymmetry of frontal and occipital petalia in living human brains differ between right- and left-handers.

Animals↗
PubMed1996

Neuronal hyperexcitability and reduction of GABAA-receptor expression in the surround of cerebral photothrombosis.

Changes of neuronal excitability and gamma-aminobutyric acid (GABAA)-receptor expression were studied in the surround of photothrombotic infarcts, which were produced in the sensorimotor cortex of the rat by using the rose bengal technique. In a first series of experiments, multiunit recordings were performed on anesthetized animals 2-3 mm lateral from the lesion. Mean discharge frequency was considerably higher in recordings from lesioned animals (> 100 Hz in the first postlesional week) compared with control animals (mean, 15 Hz). These alterations were already present after 1 day but were most pronounced 3 to 7 days after lesion induction. Thereafter the hyperexcitability declined again, although it remained visible up to 4 months. In a second series of experiments, the GABAA-receptor expression was studied autoradiographically. This revealed a reduction of GABAA receptors in widespread brain areas ipsilateral to the lesion. The reduction was most pronounced in the first days after lesion induction and declined with longer intervals. It is concluded that cortical infarction due to photothrombosis leads to a long-lasting and widespread reduction of GABAA-receptor expression in the surround of the lesion, which is associated with an increased neuronal excitability. Such alterations may be responsible for epileptic seizures that can be observed in some patients after stroke and may contribute to neurologic deficits after stroke.

Animals↗
PubMed1995

Plasticity and neurotransmitter receptor changes in Alzheimer's disease and experimental cortical infarcts.

According to recently published data, the propagation of the typical neurofibrillary changes in Alzheimer's disease follows gradually and systematically the main pathways of fiber connections between different cortical areas. The functional deficits show a parallel development. Memory deficits as the first symptom of Alzheimer's disease can be explained by the initial lesion of the entorhinal-hippocampal connection. The next symptom is the impairment of emotional behaviour, which is caused by lesions in the hippocampus and the other parts of the limbic cortex. The following gnostic and praxic alterations can be explained by lesions in the association areas of the neocortex. Finally also motor disturbances become apparent, caused by lesions in the motor cortex. The tissue alterations in Alzheimer's disease represent a systemically spreading lesion in the cortex based on the destruction of synapses and finally of whole neurons, and on the impairment of normal neurotransmission. Since neurotransmission depends on transmitters and their receptors, the densities of transmitter receptors in the hippocampus, parietal association and premotor cortices in Alzheimer's disease were measured with quantitative receptor autoradiography. The degree of receptor changes in these regions decreases with the direction of the propagation of neurofibrillary changes from the hippocampus to the premotor cortex. With the exception of the GABAA receptor, the receptors in the hippocampus are reduced by approximately 70%. The reduction in the parietal association cortex amounts to only 30%. An upregulation of muscarinic M1 receptors was seen in the premotor cortex. The latter result is surprising in the context of a lesion model, but is in agreement with earlier immunohistochemical data about muscarinic receptors in the frontal cortex of Alzheimer patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗
PubMed1995

Mapping of human and macaque sensorimotor areas by integrating architectonic, transmitter receptor, MRI and PET data.

The human and macaque sensorimotor cortex was subdivided into numerous areas by a correlative analysis based on cytoarchitectonics, myeloarchitecture and the distribution of transmitter receptors. Receptor densities and laminar distribution patterns differ not only between motor and somatosensory regions, but also between different areas within these regions of the cortex. Changes in receptor distribution often match architectonically defined borders. Receptor findings provide new criteria for a more detailed mapping in the human brain which cannot be achieved by cytoarchitectonic analysis alone. Morphological data on these areas were integrated with functional data from positron emission tomography (PET) on the basis of a recently developed computerised brain atlas. The central sulcus marks the border between (1) the agranular motor cortex with a generally low density of glutamatergic, muscarinic, GABAergic and serotoninergic receptors, and (2) the granular somatosensory cortex with higher densities of these receptors. Rostral to the primary motor cortex, 2 isocortical areas are found on the mesial cortex which probably represent the functionally defined supplementary motor areas (SMA) SMA-proper (caudally) and pre-SMA (rostrally). Below SMA-proper the areas 24d (macaque) and the caudal cingulate motor area cmc (human) are located in the cingulate sulcus. Both regions correspond to the 'posterior cingulate motor areas' of recent PET studies and to the posterior part of the agranular cingulate cortex of architectonic studies. Below pre-SMA the area 24c (macaque) and the rostral cingulate motor area cmr (human) are located in the cingulate sulcus; they correspond to the 'anterior cingulate motor areas' of recent PET observations and to the anterior part of the agranular cingulate cortex of architectonic studies. Homologous sensorimotor areas can be defined in both species on the basis of common architectonic features.

Animals↗
PubMed1994

Aging of nucleolar organizer region in rat basal forebrain neurons related to learning and memory.

The nucleolar organizer of rat basal forebrain neurons was studied with histochemical and morphometrical techniques, in order to analyze quantitatively the morphological correlate of activity as it changes during learning and aging of the brain. The learning abilities of adult (2 months) and senile (30 months) rats were tested with a conditioned response learning paradigm. Four groups of rats were defined: one group consisted of untrained adults, a second group consisted of trained adults, and the senile rats were subdivided into one group, which was able to learn and another group which was not able to perform the test. Frozen sections through the basal nucleus were silver stained to visualize the nucleolar organizer and the area of its profile was measured. The data showed that the nucleolar organizer in both the trained adult and the senile rats who were able to learn, was much larger than that in the untrained adults and the senile rats who were not able to learn. In the latter groups the nucleolar organizers were of equal size. An additional finding was, that the senile rats who could not be trained, showed a lower neuronal density in the basal nucleus compared with that of the trainable senile and adult rats. The changes in the size of the nucleolar organizer are interpreted as a morphological sign of learning-induced increases in transcription and synthesis of ribosomal RNA.

Aging↗
PubMed1993

Regional distribution and heterogeneity of alpha-adrenoceptors in the rat and human central nervous system.

The regional and laminar distributions of alpha 1- and alpha 2-adrenoceptors and their subtypes were studied in Area 17, Area 18 and the hippocampus of the human brain and in 34 cortical and subcortical areas of the rat brain. Quantitative in vitro receptor autoradiography was used for monitoring the distribution patterns and receptor densities. Human brain: Considerable regional and laminar heterogeneities were found with higher alpha 2-receptor densities compared with alpha 1-receptors in Area 17. Inverse relations between both adrenoceptor types were demonstrated in Area 18 and the hippocampus. alpha 1-Adrenoceptors were most densely located in the superficial and deepest layers of the neocortex, whereas alpha 2-adrenoceptors showed the highest densities in layers III-V. alpha 1-Adrenoceptors (alpha 1, alpha 1A and alpha 1B) reached the highest densities in the dentate gyrus, alpha 2-receptors in the CA1 region (alpha 2(h)) and the dentate gyrus (alpha 2 and alpha 2A) of the hippocampus. Rat brain: The regional and laminar distributions of adrenoceptors in the hippocampus differed considerably from the human conditions. The primary motor cortex showed the highest alpha 1-adrenoceptor density (with the alpha 1B-adrenoceptor as predominating subtype) in the neocortex, whereas the alpha 2-adrenoceptor (with the alpha 2A-adrenoceptor as predominating subtype) reached the highest density in temporal neocortex. By far the highest alpha 1-adrenoceptor densities (with the alpha 1B-adrenoceptor as predominating subtype) were observed in the thalamic nuclei. The alpha 2-adrenoceptors were found with highest densities in the amygdala and locus coeruleus; the predominating subtype was here the alpha 2A-adrenoceptor. These results indicate considerable interspecies differences in the distribution of alpha-adrenoceptors between the rat and human hippocampus and a differentiation of noradrenaline-mediated effects by the heterogeneous regional distribution of alpha-adrenoceptor types.

Adrenergic alpha-Agonists↗
PubMed1991

Quantitative autoradiography of 11 different transmitter binding sites in the basal forebrain region of the rat--evidence of heterogeneity in distribution patterns.

The distribution of 12 different binding sites for acetylcholine, L-glutamate, GABA, 5-hydroxytryptamine, dopamine and noradrenaline was measured with quantitative receptor autoradiography in four regions of the rat basal forebrain (medial septal nucleus including vertical and horizontal limbs of the diagonal band of Broca, magnocellular preoptic nucleus, substantia innominata and basal nucleus of Meynert, ventral pallidum). L-Glutamate binding sites represent the largest portion of the analysed receptors in all regions, followed by muscarinic2, 5-hydroxytryptamine1 and GABAA receptors. Muscarinic1, dopamine1, dopamine2 and 5-hydroxytryptamine2 receptors and alpha 1-, alpha 1A- and alpha 1B-adrenoceptors represent the minor receptor populations. The largest portion of the dopamine receptors is represented by the dopamine1 subtype, and the alpha 1B subtype dominates the alpha 1-adrenoceptor group. A heterogeneity of the distribution patterns of the different receptors throughout the basal forebrain regions is found. A comparison of the patterns shows that alpha 1-adrenoceptors have a similar regional distribution to that of the muscarinic2 receptors, but both receptor types have reciprocal distributions compared with the 5-hydroxytryptamine1 receptors. The results indicate that one transmitter may exert different effects in the basal forebrain regions depending on the densities of the respective receptor subtypes. Moreover, similar or reciprocal distribution patterns of some, but not all, analysed receptors point to a non-random association (co-distribution) of the different transmitter systems in the basal forebrain regions.

Animals↗