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Dimitri M Kullmann

Publications and source records attributed to Dimitri M Kullmann.

28 records · Page 2Linked to original sources
PubMed2003

Epilepsy genetics.

Genetics have for a long time been suspected of playing an important role in idiopathic generalized epilepsy. The last decade has seen the discovery of several genes underlying epilepsy transmitted in a Mendelian fashion. Among these are genes causing recessive neurodevelopmental disorders complicated by seizures. In addition, several genes, mainly coding for ion channels, have been identified in rare families exhibiting a wide variety of idiopathic epilepsy phenotypes. The next decade will likely reveal whether these or related genes also act as susceptibility factors for sporadic epilepsy.

Epilepsy↗
PubMed2002

Variable K(+) channel subunit dysfunction in inherited mutations of KCNA1.

Mutations of KCNA1, which codes for the K(+) channel subunit hKv1.1, are associated with the human autosomal dominant disease episodic ataxia type 1 (EA1). Five recently described mutations are associated with a broad range of phenotypes: neuromyotonia alone or with seizures, EA1 with seizures, or very drug-resistant EA1. Here we investigated the consequences of each mutation for channel assembly, trafficking, gating and permeation. We related data obtained from co-expression of mutant and wild-type hKv1.1 to the results of expressing mutant-wild-type fusion proteins, and combined electrophysiological recordings in Xenopus oocytes with a pharmacological discrimination of the contribution of mutant and wild-type subunits to channels expressed at the membrane. We also applied confocal laser scanning microscopy to measure the level of expression of either wild-type or mutant subunits tagged with green fluorescent protein (GFP). R417stop truncates most of the C-terminus and is associated with severe drug-resistant EA1. Electrophysiological and pharmacological measurements indicated that the mutation impairs both tetramerisation of R417stop with wild-type subunits, and membrane targeting of heterotetramers. This conclusion was supported by confocal laser scanning imaging of enhanced GFP (EGFP)-tagged hKv1.1 subunits. Co-expression of R417stop with wild-type hKv1.2 subunits yielded similar results to co-expression with wild-type hKv1.1. Mutations associated with typical EA1 (V404I) or with neuromyotonia alone (P244H) significantly affected neither tetramerisation nor trafficking, and only altered channel kinetics. Two other mutations associated with a severe phenotype (T226R, A242P) yielded an intermediate result. The phenotypic variability of KCNA1 mutations is reflected in a wide range of disorders of channel assembly, trafficking and kinetics.

Animals↗
PubMed2002

Relative picrotoxin insensitivity distinguishes ionotropic GABA receptor-mediated IPSCs in hippocampal interneurons.

Inhibitory GABAergic signalling in the hippocampus plays an important role in synchronizing principal cells and regulating the excitability of this seizure-prone structure. Distinct mechanisms modulate release from GABAergic terminals in the hippocampus, depending on whether the postsynaptic partner is an interneuron or a principal cell. Here, we report that postsynaptic ionotropic GABA receptors in principal cells and interneurons also show a striking pharmacological difference. The broad-spectrum antagonist picrotoxin (PTX) was less potent at blocking IPSCs evoked in stratum radiatum interneurons than in pyramidal neurons in the CA1 region. GABA-evoked currents in membrane patches from interneurons showed a smaller mean unitary conductance than in patches from pyramidal neurons. Because retinal GABA(C) receptors show decreased picrotoxin sensitivity and conductance, we examined the effect of the GABA(C) receptor agonist cis-aminocrotonic acid (CACA). Although this agent evoked picrotoxin-resistant currents in interneurons, these were enhanced by the GABA(A) allosteric modulator pentobarbital. Moreover, both picrotoxin-resistant IPSCs and CACA-evoked currents were blocked by the GABA(A) receptor-selective antagonist bicuculline. The presence of relatively picrotoxin-resistant GABA(A) receptors in interneurons provides a potential target for agents to modulate the activity of sub-populations of hippocampal neurons.

Animals↗
PubMed2002

Neurological disorders caused by inherited ion-channel mutations.

Several neurological diseases-including neuromuscular disorders, movement disorders, migraine, and epilepsy-are caused by inherited mutations of ion channels. The list of these "channelopathies" is expanding rapidly, as is the phenotypic range associated with each channel. At present the best understood channelopathies are those that affect muscle-fibre excitability. These channelopathies produce a range of disorders which include: periodic paralysis, myotonias, malignant hyperthermia, and congenital myasthenic syndromes. By contrast, the mechanisms of diseases caused by mutations of ion channels that are expressed in neurons are less well understood. However, as for the muscle channelopathies, a striking feature is that many neuronal channelopathies cause paroxysmal symptoms. This review summarises the clinical features of the known neurological channelopathies, within the context of the functions of the individual ion channels.

Animals↗
PubMed2002

Functional characterization of compound heterozygosity for GlyRalpha1 mutations in the startle disease hyperekplexia.

The human disease hyperekplexia is characterized by excessive startle reactions to auditory and cutaneous stimuli. In its familial form, hyperekplexia has been associated with both dominant and recessive mutations of the GLRA1 gene encoding the glycine receptor alpha1 subunit (GlyRalpha1), which mediates inhibitory transmission in the spinal cord and brainstem. Here we have examined the functional consequences of two amino acid substitutions found in a compound heterozygous family, R252H and R392H, to investigate the mechanisms determining this inheritance pattern. When expressed in Xenopus laevis oocytes, both mutations were non-functional. Neither mutant affected the electrophysiological properties of wild type GlyRalpha1 when co-expressed. We introduced a green fluorescent protein tag to mutant subunits and found that both mutant proteins were detectable. Evidence that subcellular localization differed from wild type was significant for one of the mutants. Thus, an effective loss of functional GlyRalpha1-mediated current underlies hyperekplexia in this family, whereas a partial loss is asymptomatic.

Animals↗
PubMed2002

Glutamatergic modulation of GABAergic signaling among hippocampal interneurons: novel mechanisms regulating hippocampal excitability.

PURPOSE: Because interneurons play a central role in regulating the excitability of the hippocampal formation, it is important to understand the mechanisms that modulate gamma-aminobutyric acid (GABA)ergic signaling among them. This study addresses the modulation of GABA release from interneuron terminals by presynaptic glutamate receptors. METHODS: Whole-cell recordings were obtained from CA1 stratum radiatum interneurons in guinea pig hippocampal slices. Selective agonists and blockers of glutamate receptors were used to study modulation of GABAergic transmission by group III metabotropic receptors or kainate receptors. Antidromic action-potential initiation also was analyzed by stimulating the axons of interneurons. RESULTS: Agonists of group III metabotropic glutamate receptors attenuated monosynaptic GABAergic signals in interneurons, but not in pyramidal neurons, in agreement with anatomic evidence on the distribution of these receptors. Submicromolar kainate enhanced the frequency and amplitude of spontaneous GABAergic signals in interneurons. Kainate also depolarized the axons of hippocampal interneurons, and triggered spontaneous ectopic action potentials in axons. Synaptically released glutamate reproduced many of the effects of both agonists, implying that these receptors can sense the ambient glutamate concentration, and therefore indirectly respond to the excitatory traffic in the hippocampus. When the two classes of receptors were stimulated simultaneously, complex interactions were obtained. CONCLUSIONS: Group III metabotropic receptors and kainate receptors profoundly affect GABAergic signaling among interneurons of the hippocampus. Glutamatergic modulation of GABAergic signaling among interneurons represents a novel class of mechanisms that potentially plays a major role in determining the initiation, propagation, and termination of seizures.

Animals↗
PubMed2002

Do mossy fibers release GABA?

PURPOSE: Mossy fibers are the sole excitatory projection from dentate gyrus granule cells to the hippocampus, forming part of the trisynaptic hippocampal circuit. They undergo significant plasticity during epileptogenesis and have been implicated in seizure generation. Mossy fibers are a highly unusual projection in the mammalian brain; in addition to glutamate, they release adenosine, dynorphin, zinc, and possibly other peptides. Mossy fiber terminals also show intense immunoreactivity for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and immunoreactivity for GAD67. The purpose of this review is to present physiologic evidence of GABA release by mossy fibers and its modulation by epileptic activity. METHODS: We used hippocampal slices from 3- to 5-week-old guinea pigs and made whole-cell voltage clamp recordings from CA3 pyramidal cells. We placed stimulating electrodes in stratum granulosum and adjusted their position in order to recruit mossy fiber to CA3 projections. RESULTS: We have shown that electrical stimuli that recruit dentate granule cells elicit monosynaptic GABAA receptor-mediated synaptic signals in CA3 pyramidal neurons. These inhibitory signals satisfy the criteria that distinguish mossy fiber-CA3 synapses: high sensitivity to metabotropic glutamate-receptor agonists, facilitation during repetitive stimulation, and N-methyl-D-aspartate (NMDA) receptor-independent long-term potentiation. CONCLUSIONS: We have thus provided compelling evidence that there is a mossy fiber GABAergic signal. The physiologic role of this mossy fiber GABAergic signal is uncertain, but may be of developmental importance. Other evidence suggests that this GABAergic signal is transiently upregulated after seizures. This could have an inhibitory or disinhibitory effect, and further work is needed to elucidate its actual role.

Animals↗
PubMed2002

The neuronal channelopathies.

This review addresses the molecular and cellular mechanisms of diseases caused by inherited mutations of ion channels in neurones. Among important recent advances is the elucidation of several dominantly inherited epilepsies caused by mutations of both voltage-gated and ligand-gated ion channels. The neuronal channelopathies show evidence of phenotypic convergence; notably, episodic ataxia can be caused by mutations of either calcium or potassium channels. The channelopathies also show evidence of phenotypic divergence; for instance, different mutations of the same calcium channel gene are associated with familial hemiplegic migraine, episodic or progressive ataxia, coma and epilepsy. Future developments are likely to include the discovery of other ion channel genes associated with inherited and sporadic CNS disorders. The full range of manifestations of inherited ion channel mutations remains to be established.

Animals↗
PubMedDate not supplied

Another migraine gene.

Explore the source record for details and available documents.

Chromosomes, Human, Pair 19↗