Mutational analysis of spike-wave epilepsy phenotypes.
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Biomedical subjects
J L Noebels
Publications and source records attributed to J L Noebels.
Altered hippocampal network excitability in the hypernoradrenergic mutant mouse tottering.
A latent, gene-linked alteration of hippocampal network excitability in tg/tg mutant mice was unmasked in vitro by convulsant-activated synchronous neuronal discharges. Exposure to elevated extracellular potassium ions or 4-aminopyridine, but not picrotoxin, revealed an abnormally prolonged network discharge duration in the mutant CA3 pyramidal cell region. In both phenotypes, noradrenaline, and a selective beta-noradrenergic receptor agonist, isoproterenol, reversibly accelerated the frequency of the discharges. These findings identify an intrinsic alteration in the excitability of an isolated neuronal network in a model of inherited generalized spike-wave epilepsy, and further implicate noradrenergic mechanisms in the temporal modulation of hippocampal synchronization and epileptogenesis.
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Stargazer: a new neurological mutant on chromosome 15 in the mouse with prolonged cortical seizures.
We report here the initial description of the inheritance pattern, linkage mapping, and electroclinical phenotype of a recessive mutation on mouse Chromosome 15, stargazer (stg), that produces epilepsy. The salient epileptic phenotype is a syndrome of spontaneous, prolonged, generalized spike-wave cortical discharges with behavioral arrest. A second, complex, seizure pattern featuring movements during the discharge can also appear. The stg/stg mutant phenotype confirms the general principal that inherited epilepsies sharing similar cortical excitability patterns can be transmitted by single gene loci residing on different chromosomes and provides new evidence that the severity of seizure expression depends on the specific mutant gene affected.
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Persistent hypersynchronization of neocortical neurons in the mocha mutant of mouse.
A recessive mutation in the mouse at the mocha locus (mh, chromosome 10) modulates the synchronous synaptic activation of neocortical neurons, resulting in a constant 6-7 Hz (theta) wave pattern in the electrocorticogram. The gene-linked brain rhythm is unaffected by motor behavior and cannot be desynchronized by sensory stimuli. This exemplary neurological mutation affecting cortical excitability is the first to reveal clearly that the predominance of a specific pattern of spontaneous brain wave activity can be inherited as a recessive trait.
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Mutational analysis of inherited epilepsies.
Single-gene mutations in mice initiate specific heritable neuronal diseases featuring different patterns of epilepsy. Thirteen chromosomal loci for convulsive seizures and four loci for spike-wave seizures have been assigned. Within this genetic framework, a few general principles are emerging. Mutations located on different chromosomes may result in identical seizure patterns. Interactions between specific genes, demonstrated by the synthesis of compound heterozygotes, can express intermediate syndromes. Interactions with unknown genes in the background can mask neurological disease expression. Analysis of the cellular phenotypes of epileptic mutants is a direct strategy to define naturally occurring defects in central synaptic pathways involved in cortical synchronization. In one allele of the tottering locus, a pathogenetic lesion linking noradrenergic hyperinnervation with cortical spike-wave discharges has been identified. The tottering gene initiates an overgrowth within all target innervation areas of axon terminals originating from the locus coeruleus (LC). Selective neonatal denervation of the excess noradrenergic axons permanently prevents the subsequent appearance of cortical spike-wave seizures in the adult animal. Partial lesions of central noradrenergic afferent fibers in adults temporarily reverse the seizure disorder. Other criteria defining the relationship between the mutant gene and the electrophysiologic traits and the role of central noradrenergic pathways in neuronal synchronization are reviewed. Isolating and tracing the developmental expression of epileptic mutations permits a formal classification of gene-linked excitability defects, a derivation of basic rules governing their inheritance, and the design of strategies to correct the gene error. By allowing phenotypic comparisons with over 60 known human inherited neurological diseases associated with seizures, these models may directly contribute to advances in the clinical management of epileptic gene expression.
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Isolating single genes of the inherited epilepsies.
Defined gene mutations in mice offer a singular opportunity to learn how individual genes alter excitability and plasticity within the developing central nervous system. The search for mutant loci that initiate abnormal synchronous discharges characteristic of the epilepsies is a simple method of identifying some of these genes. This method provides a coherent framework for the design of strategies to isolate and correct the biochemical lesion prior to the clinical expression of the disease. The tottering mutation is the first to yield new clues as to the mechanisms of inherited epileptogenesis.
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Mutant mouse tottering: selective increase of locus ceruleus axons in a defined single-locus mutation.
The central catecholamine neuron system in the mutant mouse tottering was examined by fluorescence histochemistry and biochemical analysis of catecholamine content. This single-locus neurological mutation expresses a reproducible alteration in central nervous system physiology characterized by spontaneous spike-wave and focal motor seizures in the absence of any previously recognized disturbance of cellular organization or brain size. Histochemical analysis showed a significant increase in the number of noradrenergic axons in terminal fields innervated by the nucleus locus ceruleus when compared with the wild type. A concomitant 100-200% rise in norepinephrine levels is found in the same areas, including hippocampus, cerebellum, and dorsal lateral geniculate. Catecholamine fibers and transmitter content in areas innervated by a second major noradrenergic system arising from the brainstem lateral tegmental neurons are unaltered. The terminal axons and transmitter content were both unchanged in nuclei receiving a dense dopaminergic innervation. Despite the hypertrophy of the locus ceruleus axonal plexus, the number and size of locus ceruleus cell somata were identical in both wild-type and tottering mice. These findings are consistent with a specific gene-linked alteration of developmental events controlling the number of axons produced by a single neuronal population in the mammalian brain.
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Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering.
Mice with the mutant gene tottering (tg, chromosome 8, autosomal recessive) show, in adolescence, abnormal bursts of bilaterally synchronous spike waves as revealed in electrocorticograms recorded over long periods. The spike waves are accompanied by behavioral "absence" attacks and intermittent focal motor seizures showing somatotopic progression. Cerebral metabolic activity during seizures was assayed by autoradiography of brain sections from mice injected intravenously with 14C-labeled 2-deoxyglucose. Metabolic activity was increased bilaterally in selected brainstem structures. Spontaneous electrocorticographic and clinical seizures of this general pattern were recognized hitherto only in humans.
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Analysis of inherited epilepsy using single locus mutations in mice.
The neurological expression of mutations at defined gene loci in isogenic mice provides a singular opportunity to investigate the developmental pathophysiology of inherited central nervous system (CNS) diseases. Analysis of the single locus mutants that are currently available shows that CNS diseases that include spontaneous seizures as symptoms can be inherited as simple recessive traits. Mutant gene dose is highly correlated with the spontaneous occurrence of seizures. Single gene defects at one of multiple chromosomal loci may give rise to similar epileptic patterns. One mutation, tottering (tg, chromosome 8, recessive) produces in young mice a focal motor seizure pattern with a somatotopic progression, and behavioral absence seizures accompanied by abnormal bursts of bilaterally synchronous, spike-wave discharges in the electrocorticogram. Spontaneous electrographic and clinical seizures of this general pattern bear close resemblance to common forms of human epilepsy. Defined alterations in restricted neuronal pathways of the mouse brain produced by single locus mutations can be used to infer general principles of inherited epileptogenesis, and may provide specific biological test systems for the development of more selective chemical antagonists of seizure activity.
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Cortical slow potentials and the occipital EEG in congenital blindness.
In a group of 7 congenitally blind adults, electroencephalographic occipital alpha rhythms were absent, but slow negative cortical potentials (CNV) were recorded over the visual cortex and were similar to those of normally sighted controls. Frontal and central CNV amplitudes, but not auditory evoked potentials or reaction times, were decreased significantly in the blind. The results confirm the presence of a developmental EEG abnormality following early blindness, and demonstrate the independance of slow potential generation from rhythmic 8--12 c/sec EEG activity in deafferented visual cortex. Non-sensory specific, event-related potentials such as the Contingent Negative Variation may prove to be useful psychophysiological probes of residual cortical function in brain regions which are deprived of primary sensory input.
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Development of focal seizures in cerebral cortex: role of axon terminal bursting.
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Animals↗
Excitability changes in thalamocortical relay neurons during synchronous discharges in cat neocortex.
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Animals↗
Presynaptic origin of penicillin after discharges at mammalian nerve terminals.
The site of origin and mechanism underlying the generation of repetitive after-discharges produced by penicillin was studied in the isolated rat phrenic nerve-hemidiaphragm preparation. Application of low concentrations of sodium penicillin to the bathing solution initiated bursts of antidromic action potentials originating at or near the motor nerve terminals following single orthodromic stimuli to the nerve. Afterdischarges could not be elicited by direct stimulation of the muscle fibers alone, or when the nerve trunk was isolated from the neuromuscular junction and exposed to penicillin. D-Tubocurarine applied in doses sufficient to abolish postsynaptic responses did not diminish penicillin-induced after discharges. At concentrations which most reliably produced repetitive firing (5000 IU/ml; 8.5 mM), penicillin did not accelerate the frequency of spontaneous transmitter release (MEPPs), yet significantly increased the relative excitability of nerve endings to extracellular stimulation. It is concluded that penicillin acts directly and preferentially on presynaptic nerve terminals to induce repetitive afterdischarges which arise independently of postsynaptic depolarization, transmitter-mediated potassium efflux, or muscle fiber contraction. The results suggest that the convulsant effects of penicillin at a mammalian neuromuscular junction are due to non-depolarizing alterations in the intrinsic excitability of the terminal membrane which increase the probability of suprathreshold depolarizations during the recovery period of spike electrogenesis. Several models of the mechanisms which might produce hyperexcitability at presynaptic nerve terminals are discussed.
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Anatomic localization of topically applied [14C]penicillin during experimental focal epilepsy in cat neocortex.
14C-labeled penicillin was topically applied to the suprasylvian gyri of adult cats in order to study the distribution of the convulsant agent at the onset of focal epileptogenesis. Using radioassay and autoradiographic techniques, a steep gradient of penicillin was found. At the time interictal EEG spike discharges appeared, 95% of the labeled drug was in the uppermost cortical layers (laminae I-III). Analysis of the concentration profiles obtained by scintillation counting showed that penetration of penicillin into brain occurs primarily by passive diffusion. An apparent diffusion coefficient for penicillin in neocortex of 1.5 sq. mm/h was calculated using modifications of standard diffusion equations. It is apparent that with a rapidly acting topical convulsant such as penicillin, the dimensions of the neuronal pool actually in contact with the drug will change significantly over time. The changing boundaries of the epileptic neuronal aggregate must be taken into account when interpreting observations made within and around such experimentally produced epileptic foci.
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Transcallosal effects of a cortical epileptiform focus.
Unit activity in anesthetized cats was studied in cortical regions contralateral to the site of an acute epileptiform focus. Orthodromic effects of transcallosal discharge varied in extracellular records; however, in intracellular records, most cells displayed an EPSP-IPSP sequence. In a small proportion of cells, antidromic activation was also observed. The significance of this 'backfiring' phenomenon, and some factors possibly involved in generation of 'backfiring' activity, are discussed.
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Single locus mutations in mice expressing generalized spike-wave absence epilepsies.
Studies in mutant mice are beginning to reveal important general principles regarding the heredity of the spike-wave cortical synchronization trait. First, a defect at a single gene locus is sufficient to produce a generalized spike-wave seizure disorder. Second, the EEG pattern itself is genetically heterogeneous, and can arise from mutations in at least five independent loci. Third, the intervening cellular excitability mechanisms underlying the generation of spike-wave cortical discharges are not identical. Fourth, each of the mutant genes gives rise to syndromes that can differ in their seizure frequency, sensitivity to antiepileptic drugs, and severity of the associated neurological phenotype. Fifth, primary defects can be distinguished from secondary cellular alterations resulting from pathological neuronal synchronization. The patterns of these secondary changes vary according to the specific mutant allele, and may give rise to distinctive secondary phenotypes. The reproducibility of these defined genetic models may facilitate age-dependent antiepileptic drug discovery by defining novel targets for therapy at different developmental stages of the seizure disorder.
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A single gene error of noradrenergic axon growth synchronizes central neurones.
One strategy for deciphering inherited neurological disease is to examine the expression of individual genes controlling the assembly and physiology of specific cell groups within the developing mammalian central nervous system (CNS). This neurogenetic approach, using defined single-locus mutations arising on coisogeneic mouse strains, has recently been used to analyse a major class of neuronal membrane diseases involving abnormal excitability, the epilepsies, and to identify examples of hereditary variation in signalling properties at central synapses. An interesting mutation, the Tottering (tg) gene, causes a delayed onset, recessive neurological disorder in the mouse featuring a stereotyped triad of ataxia, intermittent myoclonus and cortical spike-wave discharges accompanied by behavioural absence seizures which resemble petit mal epilepsy. Axon branches of the locus coeruleus, a noradrenergic brain-stem nucleus, hyperinnervate specific target regions of the tg brain. The number of parent coerulean perikarya is unaffected, indicating a true proliferation of the terminal axonal arbor. With the exception of this unusually precise error of axonal growth, no other cytopathology has been identified in the tg brain. Here I present evidence that selective lesions of the central noradrenergic axons early in development limit the expression of the disease.
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