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J O McNamara

Publications and source records attributed to J O McNamara.

At least 19 recordsLinked to original sources
PubMed1999

Immunoglobulin G and complement immunoreactivity in the cerebral cortex of patients with Rasmussen's encephalitis.

OBJECTIVE: To provide evidence that complement (C')-dependent processes may be involved in Rasmussen's encephalitis (RE). BACKGROUND: RE is a rare, progressive, childhood epilepsy syndrome associated with inflammation and neuronal cell loss in a single cerebral hemisphere. Recent work suggests an autoimmune immunoglobulin (Ig) G-mediated process is important in disease pathogenesis. METHODS: Brain samples from RE and complex partial epilepsy control patients were analyzed immunohistochemically. Sections were stained for IgG and the C' factors C4, C8, and the membrane attack complex (MAC). RESULTS: Brain samples from three of five patients with active, progressive RE but neither of two chronic RE nor five control epilepsy patients demonstrated immunoreactivity for IgG, C4, C8, and MAC on discrete patches of cerebrocortical neurons. Intensely activated glial fibrillary acid protein-positive astrocytes were found in areas overlapping these patches. CONCLUSION: Focally distributed IgG- and C'-positive neurons were found to colocalize with activated astrocytes, suggesting focal IgG-dependent classical C' cascade pathway activation with attendant tissue damage in this subset of RE patients. Intraparenchymal C' activation triggered by pathogenic antibodies may contribute to the development of focal inflammation, neuronal cell loss, and pharmacoresistant seizures in some patients with this disease. This process may be an important component in the initial, active phase of RE.

Cerebral Cortex↗
PubMed1999

Emerging insights into the genesis of epilepsy.

Epilepsies are a diverse collection of brain disorders that affect 1-2% of the population. Current therapies are unsatisfactory as they provide only symptomatic relief, are effective in only a subset of affected individuals, and are often accompanied by persistent toxic effects. It is hoped that insight into the cellular and molecular mechanisms of epileptogenesis will lead to new therapies, prevention, or even a cure. Emerging insights point to alterations of synaptic function and intrinsic properties of neurons as common mechanisms underlying the hyperexcitability in diverse forms of epilepsy.

Animals↗
PubMed1999

Immunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus.

Recent work suggests that limiting the activation of the trkB subtype of neurotrophin receptor inhibits epileptogenesis, but whether or where neurotrophin receptor activation occurs during epileptogenesis is unclear. Because the activation of trk receptors involves the phosphorylation of specific tyrosine residues, the availability of antibodies that selectively recognize the phosphorylated form of trk receptors permits a histochemical assessment of trk receptor activation. In this study the anatomy and time course of trk receptor activation during epileptogenesis were assessed with immunohistochemistry, using a phospho-specific trk antibody. In contrast to the low level of phosphotrk immunoreactivity constitutively expressed in the hippocampus of adult rats, a striking induction of phosphotrk immunoreactivity was evident in the distribution of the mossy fibers after partial kindling or kainate-induced seizures. The anatomic distribution, time course, and threshold for seizure-induced phosphotrk immunoreactivity correspond to the demonstrated pattern of regulation of BDNF expression by seizure activity. These results provide immunohistochemical evidence that trk receptors undergo activation during epileptogenesis and suggest that the mossy fiber pathway is particularly important in the pro-epileptogenic effects of the neurotrophins.

Animals↗
PubMed1999

Selective inhibition of kindling development by intraventricular administration of TrkB receptor body.

Recent work has shown that neurotrophin gene expression is increased after seizures evoked in the kindling model of epilepsy, but whether neurotrophins regulate kindling development is as yet unclear. In this study, we attempted to block selectively the activation of distinct neurotrophin receptors throughout kindling development in the rat via chronic intracerebroventricular administration of trk receptor bodies. The efficacy and selectivity of the trk receptor bodies were established by inhibition of neurotrophin-induced trk receptor phosphorylation in pheochromocytoma (PC12) cells and primary cultures of cortical neurons. The intracerebroventricular infusion of trkB receptor body (trkB-Fc) inhibited development of kindling in comparison with that seen with saline or human IgG controls, trkA-Fc, or trkC-Fc. These results imply that activation of trkB receptors contributes to the development of kindling, a form of activity-dependent behavioral plasticity in the adult mammalian brain.

Animals↗
PubMed1999

Seizures, cell death, and mossy fiber sprouting in kainic acid-treated organotypic hippocampal cultures.

Sprouting of the mossy fiber axons of the dentate granule cells is a structural neuronal plasticity found in the mature brain of epileptic humans and experimental animals. Mossy fiber sprouting typically arises in experimental animals after repeated seizures and may contribute to the hyperexcitability of the epileptic brain. Investigation of the molecular triggers and spatial cues involved in mossy fiber sprouting has been hampered by the lack of an optimal in vitro model for studying this rearrangement. For an in vitro model to be feasible, the circuitry and receptors involved in convulsant-induced mossy fiber sprouting would have to be localized near the granule cells, rather than being dependent on long-range brain interconnections. However, it is not known whether this is the case. We report here that that application of the convulsant, kainic acid, to organotypic hippocampal explant cultures induces seizures, neuronal cell death, and subsequent dramatic mossy fiber sprouting with a similar laminar preference and time-course to that seen in intact animals. Prolonged (48 h) but not transient (4 h) kainic acid treatment caused regionally selective neuronal cell death. Cultures treated with kainic acid for a prolonged period displayed a time- and dose-dependent increase in supragranular Timm staining reflective of increased mossy fiber innervation to this area. Direct visualization of mossy fiber axons with neurobiotin-labeling revealed that mossy fibers in kainic acid-treated cultures exhibited a dramatic increase in supragranular axonal branch points and synaptic boutons. The cellular and molecular determinants required for kainic acid-induced cell death and subsequent mossy fiber reorganization thus appear to be intrinsic to the hippocampal slice preparation, and are preserved in culture. Given the ease with which functional inhibitors or pharmacological agents may be utilized in this system, slice cultures may provide a powerful model in which to study the molecular components involved in triggering mossy fiber outgrowth and underlying its laminar specificity. Elucidation of these molecular pathways will likely have both specific utility in clarifying the functional consequences of mossy fiber sprouting, as well as general utility in understanding of synaptic reorganization in the mature central nervous system.

Animals↗
PubMed1999

Seizure disorders in mutant mice: relevance to human epilepsies.

The rate at which mutant genes producing an epileptic phenotype in mice have been identified over the past few years has been astounding. Manipulating the genome of mice has led to identification of a diversity of genes whose absence or modification either causes epileptic seizures or, conversely, limits epileptogenesis. In addition, positional cloning of genes in which spontaneously arising mutations cause epilepsy in mice has led to the identification of genes encoding voltage- and ligand-gated ion channels. Finally, engineering a mutation that mimics a rare form of human epilepsy has led to a mouse line with a phenotype similar to that of the human disease. Taken together, these discoveries promise to shed light on the mechanisms underlying genetic control of neuronal excitability, suggest candidate genes underlying genetic forms of human epilepsy, and provide a valuable model with which to elucidate how the genotype produces the phenotype of a rare form of human epilepsy.

Animals↗
PubMed1999

Experimental partial epileptogenesis.

Identification of the responsible mutant genes and of the functional consequences of the mutations in experimental preparations have begun to shed light on mechanisms underlying a rare form of partial epilepsy in humans, autosomal dominant nocturnal frontal lobe epilepsy. Likewise, study of the mechanisms of nongenetic models of a common form of human epilepsy, complex partial epilepsy of temporal lobe origin, has established the hippocampal dentate granule cells as a functional barrier to invasion of epileptiform activity into hippocampus in normal brain; this barrier is defective in an epileptic brain. Potential mechanisms by which the 'barrier function' might become flawed, such as mossy fiber sprouting, are discussed.

Animals↗
PubMed1999

Autoimmunity and neurological disease: antibody modulation of synaptic transmission.

Over the past three decades, compelling evidence has emerged that the immune system can attack the nervous system with devastating consequences for human health. Either cell-mediated or humoral (antibody-mediated) autoimmune mechanisms may predominate in effecting a given disease, and either glia or neurons may fall under immune attack. A subset of these diseases has been particularly useful for understanding fundamental neuroscience as well as mechanisms of human disease. This subset involves humoral autoimmune attack on cell surface molecules subserving transmembrane signaling of excitable cells; special emphasis is placed here on proteins involved in synaptic transmission. We begin by reviewing the prototypic humoral autoimmune disease of synaptic transmission, myasthenia gravis. This provides a context for insights obtained from the study of diseases targeting molecules that regulate synaptic transmission at the neuromuscular junction and in the central nervous system. We also explore a disease where autoimmunity produces agonist antibodies acting at two distinct G-protein-coupled receptors. We conclude with an exploration of the vital issue of access of antibodies to targets within the central nervous system and the implications that such access may have in the pathogenesis of poorly understood idiopathic central nervous system diseases.

Animals↗
PubMed1998

Measurement of NMDA receptor protein subunits in discrete hippocampal regions of kindled animals.

Kindling refers to a phenomenon in which repeated application of initially subconvulsive electrical stimulations produces limbic and clonic motor seizures of progressively increasing severity. Once established, the increased excitability is lifelong. A diversity of studies demonstrate that kindling results in long lasting (28 days) alterations of the functional and pharmacologic properties of NMDA receptors, indicating that kindling may cause changes intrinsic to the NMDA receptor itself. Our previous studies disclosed no differences in NMDA receptor subunit gene or splice isoform mRNA expression between control and kindled animals 28 days after the last kindled seizure. Here, we extend those earlier studies by measuring levels of subunit protein for NMDAR1, NR2A, and NR2B in the hippocampus of control and kindled animals, 28 days after the last kindled seizure. We report that kindling does not effect long-lasting changes in the levels of NMDA receptor subunit protein. Together these findings support the idea that alterations in NMDA receptor protein expression do not contribute to the novel properties of NMDA receptors induced by kindling.

Animals↗
PubMed1998

Increased dentate granule cell neurogenesis following amygdala kindling in the adult rat.

Structural neuronal network plasticity is associated with epileptogenesis during limbic kindling, but the full extent of network changes is not well understood. We investigated whether dentate granule cell (DGC) neurogenesis, which continues into adulthood in the rodent, is altered in the amygdala kindling model of epileptogenesis. Adult rats were stimulated to either 4-6, 9-10 or 19-20 class 4/5 (generalized) kindled seizures. 5-Bromo-2'-deoxyuridine labeling showed that cell proliferation increased in the dentate gyrus only in animals that experienced nine or more class 4/5 kindled seizures. Immunocytochemistry for neuronal markers revealed that many of the newly generated cells differentiated into DGCs in the inner aspect of the DGC layer. The lack of increased DGC neurogenesis after fewer kindled seizures or at early timepoints following kindling suggests that this process is not involved in kindling development. Instead, newly generated DGCs may be important for maintenance of the kindled state or the increased susceptibility to spontaneous recurrent seizures.

Amygdala↗
PubMed1998

A point mutation (D79N) of the alpha2A adrenergic receptor abolishes the antiepileptogenic action of endogenous norepinephrine.

Norepinephrine serves as a neurotransmitter for a population of neurons the cell bodies of which reside in a brainstem nucleus and the axons of which project widely to discrete subsets of forebrain neurons. Norepinephrine powerfully inhibits epileptogenesis in the kindling model. Pharmacological methods have demonstrated that the antiepileptogenic actions of norepinephrine are exerted via alpha2 adrenergic receptors residing on targets of noradrenergic neurons. The existence of three alpha2 adrenergic receptor subtypes together with the lack of subtype-specific ligands has precluded understanding the role of individual alpha2 adrenergic receptor subtypes in the antiepileptogenic actions of norepinephrine. Gene targeting was used to introduce a point mutation into the alpha2A adrenergic subtype in the mouse genome. The mutation produced a marked enhancement of epileptogenesis and abolished the proepileptogenic actions of the alpha2 adrenergic receptor antagonist idazoxan. These studies reveal the crucial contribution of the alpha2A receptor subtype in suppression of epileptogenesis. Development of agents that promote selective activation of the alpha2A receptor subtype may provide novel therapeutic strategies for the prophylaxis of epilepsy.

Adrenergic alpha-Agonists↗
PubMed1998

Epilepsy genetics: an abundance of riches for biologists.

Twenty-five genes have been identified in which mutations cause epileptic seizures in mice. The gene for a Na+/H+ exchanger has recently been found to underlie the spontaneous mutant slow wave epilepsy. Studies of such mutants should help elucidate the mechanisms that control neuronal excitability.

Animals↗
PubMed1998

Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo.

NMDA receptors, a class of glutamate-gated cation channels with high Ca2+ conductance, mediate fast transmission and plasticity of central excitatory synapses. We show here that gene-targeted mice expressing NMDA receptors without the large intracellular C-terminal domain of any one of three NR2 subunits phenotypically resemble mice made deficient in that particular subunit. Mice expressing the NR2B subunit in a C-terminally truncated form (NR2B(deltaC/deltaC) mice) die perinatally. NR2A(deltaC/deltaC) mice are viable but exhibit impaired synaptic plasticity and contextual memory. These and NR2C(deltaC/deltaC) mice display deficits in motor coordination. C-terminal truncation of NR2 subunits does not interfere with the formation of gateable receptor channels that can be synaptically activated. Thus, the phenotypes of our mutants appear to reflect defective intracellular signaling.

Amino Acid Sequence↗
PubMed1998

Kindling and associated mossy fibre sprouting are not affected in mice deficient of NGFI-A/NGFI-B genes.

Kindling is an animal model of epileptogenesis, whereby repeated administration of an initially subconvulsive electrical stimulation eventually leads to the development of generalized motor seizures. Once established, the kindling effect is permanent. Although the molecular basis of kindling remains incompletely understood, emerging lines of evidence suggest that the induction of immediate-early genes could represent a link between periodic short-term stimuli and the long-lasting functional and structural alterations in the brain associated with the development of seizures. A recent study showed that null mutation of the immediate-early gene c-fos impairs the structural and functional plasticities in kindling. In the present study, we examined whether two other seizure-inducible immediate-early genes--NGFI-A (also termed EGR-1, zifl268, and Krox-24) and NGFI-B (also termed Nur77)--play requisite roles in kindling. We found that neither the rate of kindling nor seizure-induced granule cell axonal sprouting was affected in mice carrying a null mutation of NGFI-A. Furthermore, double knock-out of NGFI-A and NGFI-B genes does not result in detectable changes in kindling development and associated mossy fibre sprouting. Taken together, our observations indicate that neither constitutive nor seizure-induced expression of NGFI-A or NGFI-B is uniquely required for the establishment of kindling. These findings underscore the specificity of the immediate-early genes whose transcriptional activation contributes to kindling epileptogenesis.

Animals↗
PubMed1998

Glutamate receptor GluR3 antibodies and death of cortical cells.

Rasmussen's encephalitis (RE), a childhood disease characterized by epileptic seizures associated with progressive destruction of a single cerebral hemisphere, is an autoimmune disease in which one of the autoantigens is a glutamate receptor, GluR3. The improvement of some affected children following plasma exchange that removed circulating GluR3 antibodies (anti-GluR3) suggested that anti-GluR3 gained access to the central nervous system where it exerted deleterious effects. Here, we demonstrate that a subset of rabbits immunized with a GluR3 fusion protein develops a neurological disorder mimicking RE. Anti-GluR3 IgG isolated from serum of both ill and healthy GluR3-immunized animals promoted death of cultured cortical cells by a complement-dependent mechanism. IgG immunoreactivity decorated neurons and their processes in neocortex and hippocampus in ill but not in healthy rabbits. Moreover, both IgG and complement membrane attack complex (MAC) immunoreactivity was evident on neurons and their processes in the cortex of a subset of patients with RE. We suggest that access of IgG to epitopes in the central nervous system triggers complement-mediated neuronal damage and contributes to the pathogenesis of both this animal model and RE.

Animals↗
PubMed1998

Evaluation of the alpha(2A)-adrenergic receptor gene in a heritable form of temporal lobe epilepsy.

An autosomal dominant form of human temporal lobe epilepsy (TLE) has been mapped to a region of chromosome 10q that contains the intronless alpha(2A)-adrenergic receptor (alpha(2A)AR) gene. Because mutation of the alpha(2A)AR gene in the mouse fosters epileptogenesis, we developed methods for analysis of the alpha(2A)AR coding region applicable to any pathophysiologic state in which the alpha(2A)AR could be implicated in the disease mechanism. This study rules out mutations in the alpha(2A)AR coding region as causal for this form of autosomal dominant TLE.

Animals↗