T L Babb

Children's Hospital of Michigan, Detroit, Michigan, United States

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Publications (124)433.21 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We used the pilocarpine model of chronic spontaneous recurrent seizures to evaluate the time course of supragranular dentate sprouting and to assess the relation between several changes that occur in epilep tic tissue with different behavioral manifestations of this experimental model of temporal lobe epilepsy. Pilo carpine-induced status epilepticus (SE) invariably led to cell loss in the hilus of the dentate gyrus (DG) and to spontaneous recurrent seizures. Cell loss was often also noted in the DG and in hippocampal subfields CA1 and CA3. The seizures began to appear at a mean of 15 days after SE induction (silent period), recurred at variable frequencies for each animal, and lasted for as long as the animals were allowed to survive (325 days). The granule cell layer of the DG was dispersed in epileptic animals, and neo-Timm stains showed supra-and intragranular mossy fiber sprouting. Supragranular mossy fiber sprout ing and dentate granule cell dispersion began to appear early after SE (as early as 4 and 9 days, respectively) and reached a plateau by 100 days. Animals with a greater degree of cell loss in hippocampal field CAS showed later onset of chronic epilepsy (r= 0.83, p < 0.0005), suggest ing that CA3 represents one of the routes for seizure spread. These results demonstrate that the pilocarpine model of chronic seizures replicates several of the fea tures of human temporal lobe epilepsy (hippocampal cell loss, suprar and intragranular mossy fiber sprouting, den tate granule cell dispersion, spontaneous recurrent sei zures) and that it may be a useful model for studying this human condition. The results also suggest that even though a certain amount of cell loss in specific areas may be essential for chronic seizures to occur, excessive cell loss may hinder epileptogenesis.
    Epilepsia 08/2005; 34(6):985 - 995. · 3.96 Impact Factor
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    ABSTRACT: Purpose: The cellular mechanisms that may contribute to epilepsy in resected human cortical dysplasia (CD) were compared with the in utero radiated rat CD model. In human and rat focal hippocampal epilepsy, postsynaptic N-methyl-d-aspartate receptors are up-regulated and presynaptic axon collaterals hyperinnervate them. We hypothesized that in both human and rat CD: (a) the N-methyl-d-aspartate receptor subunits NR1 and NR2A/B would be increased and coassembled, and (b) aberrant axons would be in regions of CD.Methods: Tests for presynaptic and postsynaptic changes in human and rat CD included the following: (a) cytology, (b) immunocytochemistry, (c) coimmunoprecipitation, (d) double-labeled immunofluorescence, and (e) Timm histochemistry of hippocampal mossy fibers. Within-patient comparisons were made between epileptic tissue, identified by subdural electro-encephalographic seizure onsets, and nonepileptic tissue remote from the focus but within the therapeutic resection. Rats were radiated at embryonic day 17, and offspring were studied postnatally. Statistical comparisons were made against normal rats matched for age and tissue processing.Results: In focal CD patients, NR2A/B subunits and their coassemblies with NR1 were increased significantly more than for the remote nonepileptic cortex. Confocal microscopy showed that NR1-NR2A/B colabeled single dysplastic neurons in both human and rat. In CD rats, mossy fibers innervated the anomalously oriented hippocampal neurons.Conclusions: Human epileptic CD exhibits a spectrum of abnormal cell orientations and laminations that must require plastic axodendritic changes during development. These altered circuits and receptors could account for the seizures and cognitive deficits found in patients with CD. The radiated rat CD model with cortical dyslaminations and NR2A/B subunit increases would allow the development and testing of drugs targeted at only the NR2A/B subunit or at decoupling the NR1-NR2 coassembly, which could provide a specific antiepileptic drug for dysplastic circuits without inducing general depression of all brain neurons.
    Epilepsia 08/2005; 41(s6):S76 - S81. · 3.96 Impact Factor
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    ABSTRACT: Purpose: This study was designed to quantify the relation between expressions of NMDA receptor (NMDAR) subunits (1 and 2A/B) and the epileptogenicity in human focal cortical dysplasia.Methods: Immunoblotting and immunoprecipitation were used to quantify these receptor subunits in tissue resected from EEG-verified epileptic and distal nonepileptic frontal cortical areas in each of three patients as determined by chronic subdural electrode recordings. In each patient, adjacent sections were immunostained to verify that the numbers of dysplastic neurons were greater in epileptic than in nonepileptic cortex.Results: In all patients, NMDAR2A/B expressions and their coassemblies with NMDAR1 were increased in epileptic dysplastic cortex compared with the relatively normal appearing nonepileptic cortex. For all three patients, there were no significant differences in NMDAR1 protein expressions between the two EEG groups.Conclusions: These results suggest that increased NMDAR1-NMDAR2A/B coassembly contributes to hyperexcitability in dysplastic cortical neurons and focal seizure onsets.
    Epilepsia 08/2005; 40(12):1683 - 1687. · 3.96 Impact Factor
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    ABSTRACT: The NMDA receptor is one of the ionotropic glutamate receptors essential for excitatory neurotransmission and synaptic plasticity. The present study examined the ontogenies of NMDAR1 and NMDAR2B during development (embryonic days: (E) 14, 15, 16, 17 and postnatal days: (P) 0, 5, 10, 20, and 60). The immunoreactivities of both NMDAR1 and NMDAR2B were visualized and semi- quantified simultaneously using batch-matched procedures during the developmental period. In addition, the heteromeric coassembly of NMDAR1 (NR1) and NMDAR2B (NR2B) was analyzed throughout development using immunocoprecipitation blots. Differential developmental expressions were observed between the two NMDA receptor subunits. Although both NR1 and NR2B were already expressed on cortical neurons at E14, NR1 immunoreactivity was lower than NR2B but increased up to P20 then was lower at the last sampling day (P60). By comparison, the high NR2B immunoreactivity at E14 increased until P5, and until the next sample day (P60). Despite the early embryonic protein expressions in prenatal cortex both NR1 and NR2B immunocoprecipitation analyses showed that NR1-NR2B coassembly was not initially detectable until birth (P0), and increased up to P20. This suggests that the physically interactive NMDAR1-2B complex may contribute to the plasticity of early postnatal development characterized by axonal dendritic synaptogenesis.
    Epilepsy Research 01/2005; 64(1-2):23-30. · 2.24 Impact Factor
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    ABSTRACT: Recent MRI-based volume reconstruction studies in intractable temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) suggested atrophy that extends to the adjacent neocortical areas. To study the extent of temporal lobe volume (TLV) abnormalities in patients with pathologically confirmed HS (with or without cortical dysplasia [CD]) who underwent anterior temporal lobectomy for the treatment of drug-resistant TLE. Fifty patients (right TLE: n = 24; left TLE: n = 26) were found to have HS (hippocampal cell loss of >30%). Associated neocortical CD was seen in 20 patients (43%). MRI-based TLVs and hippocampal and hemispheric volume reconstructions in all patients were compared between pathologic groups and with volumes acquired from 10 age-matched control subjects. TLVs ipsilateral to the epileptogenic zone in patients with TLE were smaller than TLVs in control subjects (p < 0.01). In patients with left TLE, TLVs ipsilateral to the epileptogenic zone were smaller than contralateral TLVs (left: 66.6 +/- 8.3 cm3, right: 74.9 +/- 10.0 cm3; p < 0.001). In patients with right TLE, there were no significant asymmetries. The contralateral TLVs (regardless of the side of surgery) were smaller in the HS + CD group than the HS group (HS + CD group: 74.9 +/- 8.6 cm3, HS group: 79.7 +/- 6.6 cm3; p < 0.05). Patients with HS + CD had a tendency to have less hippocampal atrophy and slightly smaller TLVs ipsilateral to the epileptogenic zone, accounting for significantly smaller TLV/hippocampal volume ratios compared with patients with HS alone. Drug-resistant TLE due to HS is associated with extrahippocampal temporal lobe atrophy. The presence of bilateral temporal lobe atrophy is suggestive of a more widespread (bilateral) temporal lobe involvement in patients with HS and CD.
    Neurology 05/2004; 62(10):1729-35. · 8.30 Impact Factor
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    ABSTRACT: Cortical dysplasias (CDs) increasingly are recognized as pathologic substrates in patients with medically intractable epilepsy. Several studies have demonstrated the intrinsic epileptogenicity of these lesions, but the cellular and molecular mechanisms responsible for seizure initiation remain unknown. The increased availability of surgically resected neocortical tissue has provided the opportunity for direct histopathologic and electrocorticographic correlations. Moreover, the description of various animal models of CDs allowed the testing of various mechanistic hypotheses. It is likely that the mechanisms of epileptogenicity in CDs are multifactorial. In this article, the authors summarize current knowledge of the molecular and cellular mechanisms of epileptogenicity in focal CDs based on human and animal data. In particular, they focus on the roles of glutamate (NMDA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and gamma-aminobutyric acid receptors identified in animal models and resected human neocortex.
    Neurology 04/2004; 62(6 Suppl 3):S9-13. · 8.30 Impact Factor
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    ABSTRACT: There have been difficulties in achieving a uniform terminology in the literature regarding issues of classification with respect to focal cortical dysplasias (FCDs) associated with epilepsy. S: To review and refine the current terminology and classification issues of potential clinical relevance to epileptologists, neuroradiologists, and neuropathologists dealing with FCD. A panel discussion of epileptologists, neuropathologists, and neuroradiologists with special expertise in FCD was held. The panel proposed 1) a specific terminology for the different types of abnormal cells encountered in the cerebral cortex of patients with FCD; 2) a reappraisal of the different histopathologic abnormalities usually subsumed under the term "microdysgenesis," and suggested that this terminology be abandoned; and 3) a more detailed yet straightforward classification of the various histopathologic features that usually are included under the heterogeneous term of "focal cortical dysplasia." The panel hopes that these proposals will stimulate the debate toward more specific clinical, imaging, histopathologic, and prognostic correlations in patients with FCD associated with epilepsy.
    Neurology 04/2004; 62(6 Suppl 3):S2-8. · 8.30 Impact Factor
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    ABSTRACT: Medically intractable temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS), with or without cortical dysplasia (CD), is associated with atrophy of the hippocampal formation and regional fluorodeoxyglucose positron-emission tomography (FDG-PET) hypometabolism. The relation between areas of functional and structural abnormalities is not well understood. We investigate the relation between FDG-PET metabolism and temporal lobe (TL) and hippocampal atrophy in patients with histologically proven isolated HS and HS associated with CD. Twenty-three patients underwent en bloc resection of the mesial and anterolateral neocortical structures. Ten patients were diagnosed with isolated HS; 13 patients had associated microscopic CD. Temporal lobe volumes (TLVs) and hippocampal volumes were measured. Magnetic resonance imaging (MRI) and PET were co-registered, and regions of interest (ROIs) determined as gray matter of the mesial, lateral, and anterior temporal lobe. All patients (HS with or without CD) had significant ipsilateral PET hypometabolism in all three regions studied (p < 0.0001). In patients with isolated HS, the most prominent hypometabolism was in the anterior and mesial temporal lobe, whereas in dual pathology, it was in the lateral temporal lobe. TLVs and hippocampal volumes were significantly smaller on the epileptogenic side (p < 0.05). The PET asymmetries ipsilateral/contralateral to the epileptogenic zone and TLV asymmetries correlated significantly for the anterior and lateral temporal lobes (p < 0.05) in the HS+CD group, but not in the isolated HS group. Mesial temporal hypometabolism was not significantly different between the two groups. Temporal neocortical microscopic CD with concurrent HS is associated with more prominent lateral temporal metabolic dysfunction compared with isolated HS in TL atrophy. Further studies are needed to confirm these findings and correlate the PET hypometabolic patterns with outcome data in patients operated on for HS with or without CD.
    Epilepsia 04/2003; 44(4):559-64. · 3.91 Impact Factor
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    ABSTRACT: The EEG characteristics of isolated hippocampal sclerosis (HS) and HS associated with other types of temporal lobe pathology are not well defined. The pathologic substrate may be an important variable in determining seizure-free outcome. The objective of this study was to define the distribution of epileptiform discharges in patients with HS and HS associated with microscopic dysplasia, and to examine their relationship with hippocampal atrophy and cell loss. Thirty-four patients (15 women and 19 men; mean age, 30.6 +/- 11.2 years), all with good outcomes after temporal lobectomy (Engel classes I and II), were included. The characteristics studied were frequency and distribution of spikes, MRI-based hippocampal volume ratios, and quantitative hippocampal cell density in various subregions. The isolated HS group showed a trend to a higher percentage of epileptiform discharges maximal at the anterior temporal electrodes (89.87 +/- 17.0%; 79.5 +/- 28.2% in the dual-pathology group). The isolated HS group had, on average, significantly more cell loss (P < 0.001). There was a significant negative correlation between the amount of cell loss in the CA1 area and both anterior temporal spikes and hippocampal ratios (P < 0.05). Isolated HS and dual pathology show minimal differences in interictal spike distribution and frequency. More widespread spike distributions in severe isolated HS compared with patients with less cell loss is probably the result of less organized limbic circuitry.
    Journal of Clinical Neurophysiology 04/2002; 19(2):157-62. · 1.45 Impact Factor
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    ABSTRACT: Hippocampal sclerosis (HS) is characterized by hippocampal atrophy and increased signal on T2-weighted images and on fluid-attenuated inversion recovery (FLAIR) images. To quantitate cell loss and compare it with signal abnormalities on FLAIR images. Thirty-one patients with temporal lobe resection, pathologically proven HS, and Engel class I and II outcome were included: 20 with HS only and 11 with HS associated with pathologically proven cortical dysplasia (dual pathology). The signal intensity on FLAIR was rated as present or absent in the hippocampus and correlated with the neuronal losses in the hippocampus. FLAIR signal increases were present in 77% (24/31) of all patients studied. In patients with isolated HS, 90% (18/20) had ipsilateral signal increases, but in patients with dual pathology, only 55% (6/11; p < 0.02) showed FLAIR signal increase. Hippocampal cell losses were significantly higher in the isolated HS group. The average cell loss in patients with FLAIR signal abnormalities was 64.8 +/- 8.0% as compared with only 32.7 +/- 5.1% in patients with no FLAIR signal abnormalities. There was a significant positive correlation between the presence of signal abnormality and average hippocampal cell loss in both pathologic groups. Ipsilateral FLAIR signal abnormalities occur in the majority of patients with isolated HS but are less frequent in those with dual pathology. The presence of increased FLAIR signal is correlated with higher hippocampal cell loss.
    Neurology 09/2001; 57(6):1029-32. · 8.30 Impact Factor
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    ABSTRACT: To characterize the clinical, EEG, MRI, and histopathologic features and explore seizure outcome in pediatric candidates for epilepsy surgery who have temporal lobe epilepsy (TLE) caused by hippocampal sclerosis (HS). The authors studied 17 children (4 to 12 years of age) and 17 adolescents (13 to 20 years of age) who had anteromesial temporal resection between 1990 and 1998. All patients had seizures characterized by decreased awareness and responsiveness. Automatisms were typically mild to moderate in children and moderate to marked in adolescents. Among adolescents, interictal spikes were almost exclusively unilateral anterior temporal, as opposed to children in whom anterior temporal spikes were associated with mid/posterior temporal, bilateral temporal, extratemporal, or generalized spikes in 60% of cases. MRI showed hippocampal sclerosis on the side of EEG seizure onset in all patients. Fifty-four percent of children and 56% of adolescents had significant asymmetry of total hippocampal volumes, whereas the remaining patients had only focal atrophy of the hippocampal head or body. Subtle MRI abnormalities of ipsilateral temporal neocortex were seen in all children and 60% of adolescents studied with FLAIR images. On histopathology, there was an unexpectedly high frequency of dual pathology with mild to moderate cortical dysplasia as well as HS, seen in 79% of children and adolescents. Seventy-eight percent of patients were free of seizures at follow-up (mean, 2.6 years). A tendency for lower seizure-free outcome was observed in patients with bilateral temporal interictal sharp waves or bilateral HS on MRI. The presence of dual pathology did not portend poor postsurgical outcome. TLE caused by HS similar to those in adults were seen in children as young as 4 years of age. Focal hippocampal atrophy seen on MRI often was not reflected in total hippocampal volumetry. Children may have an especially high frequency of dual pathology, with mild to moderate cortical dysplasia as well as HS, and MRI usually, but not always, predicts this finding. Postsurgical seizure outcome is similar to that in adult series.
    Neurology 07/2001; 56(12):1643-9. · 8.30 Impact Factor
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    ABSTRACT: Human cortical dysplasia (CD) is a frequent cause of medically intractable focal epilepsy. The neurotransmitter mechanisms of epileptogenicity in these lesions have been attributed to changes in various glutamate receptor subtypes. Increased N-methyl-D-aspartate (NMDA) receptor (NR) 2A/B coassembled with NR1 subunits has been shown in focal epileptic CD. The purpose of this study is to correlate in situ CD epileptogenicity and the expression of various glutamate receptor subtypes. The histopathological, morphological, and immunocytochemical findings in cortical tissue resected from five patients with medically intractable epilepsy and CD were correlated with electroencephalographic data recorded from subdural grids. The NMDA antibodies identified subunits NR1 (splicing variants 1a, 1b, 2a, and 2b) and NR2A/B. Epileptogenic specimens displayed the following common features: (a) widespread histological abnormalities of horizontal and columnar dyslamination, neurons with inverted polarity, and more extensive dendritic changes; (b) significantly higher NR2A/B immunoreactivity in both the dysplastic somata and all their dendritic processes; and (c) no statistically significant change in NR1 subunit expression but a more pronounced staining of the apical dendrites in highly epileptogenic cortex. These abnormalities were either absent or minimal in resected specimens that did not show evidence of severe in vivo epileptogenicity. These studies provide direct evidence for a major contribution of the NR2A/B subunit in CD-induced epileptogenicity.
    Epilepsia 09/2000; 41(8):971-6. · 3.91 Impact Factor
  • N Mikuni, T L Babb, C Wylie, Z Ying
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    ABSTRACT: We examined the time course of NMDAR1 (NR1) immunoreactivity (IR) in the rat inner molecular layer of the dentate gyrus following unilateral intrahippocampal (hilar) kainic acid (KA) lesions and compared them to progressive aberrant mossy fiber (MF) sprouting into the inner molecular layer (IML). The results demonstrated that NR1 receptors in the IML of the KA side were decreased as early as 3 days after KA-induced denervation, then significantly increased at postinjection day (PID) 7. The densities of NR1 IR in the IML continued to increase up to 5 months. By comparison, MF sprouting did not occur significantly in the IML until PID 17, 10 days after NR1 IR was significantly increased. Recurrent MF-IML neoinnervation significantly increased on days 17, 60, and 150. This progressive MF innervation was significantly correlated with NR1 increases. These results suggest that NR1 receptors were decreased soon after KA-induced deafferentation of granule cell dendrites in the IML; however, they were replaced by new NR1 receptors at increased densities in the granule cell dendrites, which may have released neurotrophic factors to stimulate growth cones of MFs to reinnervate the IML. The progressive increases of NR1 and MFs in the IML suggest that such neosynaptogenesis would contribute monosynaptic recurrent excitatory mechanisms for focal hippocampal hyperexcitability and seizure onsets.
    Experimental Neurology 06/2000; 163(1):271-7. · 4.65 Impact Factor
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    ABSTRACT: The cellular mechanisms that may contribute to epilepsy in resected human cortical dysplasia (CD) were compared with the in utero radiated rat CD model. In human and rat focal hippocampal epilepsy, postsynaptic N-methyl-D-aspartate receptors are up-regulated and presynaptic axon collaterals hyperinnervate them. We hypothesized that in both human and rat CD: (a) the N-methyl-D-aspartate receptor subunits NR1 and NR2A/B would be increased and coassembled, and (b) aberrant axons would be in regions of CD. Tests for presynaptic and postsynaptic changes in human and rat CD included the following: (a) cytology, (b) immunocytochemistry, (c) coimmunoprecipitation, (d) double-labeled immunofluorescence, and (e) Timm histochemistry of hippocampal mossy fibers. Within-patient comparisons were made between epileptic tissue, identified by subdural electro-encephalographic seizure onsets, and nonepileptic tissue remote from the focus but within the therapeutic resection. Rats were radiated at embryonic day 17, and offspring were studied postnatally. Statistical comparisons were made against normal rats matched for age and tissue processing. In focal CD patients, NR2A/B subunits and their coassemblies with NR1 were increased significantly more than for the remote nonepileptic cortex. Confocal microscopy showed that NR1-NR2A/B colabeled single dysplastic neurons in both human and rat. In CD rats, mossy fibers innervated the anomalously oriented hippocampal neurons. Human epileptic CD exhibits a spectrum of abnormal cell orientations and laminations that must require plastic axodendritic changes during development. These altered circuits and receptors could account for the seizures and cognitive deficits found in patients with CD. The radiated rat CD model with cortical dyslaminations and NR2A/B subunit increases would allow the development and testing of drugs targeted at only the NR2A/B subunit or at decoupling the NR1-NR2 coassembly, which could provide a specific antiepileptic drug for dysplastic circuits without inducing general depression of all brain neurons.
    Epilepsia 02/2000; 41 Suppl 6:S76-81. · 3.91 Impact Factor
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    ABSTRACT: Intracranial depth electrode EEG records of 478 seizures, recorded in 68 patients undergoing diagnostic monitoring with depth electrodes, were evaluated to investigate the correlates of electrographic onset patterns in patients with temporal lobe seizures. The seizure onsets in 78% of these patients were identified as either hypersynchronous onsets, beginning with low-frequency, high-amplitude spikes, or low-voltage fast (LVF) onsets, increasing in amplitude as the seizure progressed. The number of patients (35) having hypersynchronous seizure onsets was nearly twice that of patients (18) having LVF onsets. Three major differences were seen among patients with the two seizure-onset patterns. When compared with patients having LVF onsets, patients with hypersynchronous seizure onsets had a significantly greater probability of having (1) focal rather than regional seizure onsets (p < 0.01), (2) seizures spreading more slowly to the contralateral mesial temporal lobe (p < 0.003), and (3) cell counts in resected hippocampal tissue showing greater neuronal loss (p < 0.001). The results provide evidence that the most frequent electrographic abnormality associated with mesial temporal seizures is local hypersynchrony, a condition associated with major neuronal loss in the hippocampus. The results also indicate that LVF seizure onsets more frequently represent widely distributed discharges, which interact with and spread more rapidly to surrounding neocortical areas.
    Neural plasticity. 01/2000; 7(1-2):49-63.
  • Neurosurgery 01/2000; 47(2):504-505. · 2.53 Impact Factor
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    ABSTRACT: Cortical dysplasia (CD) is now recognized as one of the major causes of pediatric focal neocortical epilepsy, and surgical procedures have been considered early in life. However, the mechanisms involved in seizure generation and intractability in these patients are still unknown. We analyzed with immunocytochemistry for various antibodies the brain tissue from 4 children (10 months to 6 years old) with focal epilepsy due to focal CD in order to study the inhibitory and excitatory circuits in dysplastic areas. Our group had similar histopathological and clinical characteristics. In all patients we found areas of cortical disorganization with dysplastic neurons and balloon cells. We studied distributions of glial cells with glial fibrillary acidic protein (GFAP) and neurons with microtubule-associated protein 2 (MAP-2). Gliosis was present in all cases, and GFAP stained also some balloon cells. Dysplastic neurons were darkly stained by MAP-2, and we also found balloon cells weakly stained with MAP-2 in the same areas where GFAP was positive, suggesting coexpression of neuronal and glial markers in some of these cells. There was an increased expression of glutamate receptors, especially GluR2/3, but also N-methyl-D-aspartate receptors in dysplastic cortex. The inhibitory circuit does not seem to be decreased, rather we notice an increased amount of glutamate-decarboxylase-positive terminals around some of the big neurons. We discuss the possible role of these findings as mechanisms of epilepsy.
    Developmental Neuroscience 12/1999; 21(3-5):271-80. · 3.41 Impact Factor
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    ABSTRACT: We determined whether age or seizure types were associated with hippocampal neuron loss, mossy fiber (MF) and GABAergic synaptic reorganizations or postsynaptic receptor densities. Children and adolescents were grouped into: (1) nonhippocampal sclerosis (non-HS; n = 11) and (2) hippocampal sclerosis (HS; n = 11). The most important results showed that: (1) regardless of the etiology of the seizures, there were greater cell losses in Ammon's horn with older ages in years; in the non-HS group, cell losses were greater with the older ages or with longer epilepsy durations; however, in the HS patients, the cell losses were not related to the patients' ages or epilepsy durations; (2) in both HS and non-HS, CA1 had greater cell losses than CA4; (3) in HS, CA1 and CA4 had greater cell losses than those in non-HS; (4) in non-HS, MF sprouting was greater with ages or with longer epilepsy durations; by contrast, in HS, MF sprouting was not related to the patients' age or epilepsy duration; (5) densities for AMPA GluR1, GABA-Abeta and for GABA axonal terminals were positively increased with age. These findings support the hypothesis that hippocampal cell losses and aberrant synaptic reorganizations are greater in the hippocampi of adolescents than in children, even for non-HS pathologies.
    Developmental Neuroscience 12/1999; 21(3-5):236-47. · 3.41 Impact Factor
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    ABSTRACT: NR1 and NR2 are the two gene families for the NMDA receptor. In vitro studies show that while NR2 alone is nonfunctional, NR1 alone produces weak currents to glutamate or NMDA. We previously showed by immunocytochemistry (ICC) that in normal appearing, nonepileptic human cortical neurons, only NR1 and not NR2 proteins were expressed, in contrast to the presence of both NR1 and NR2 in normal rat cortical neurons. We also showed, in dysplastic epileptic cortex, that both NR1 and NR2 were highly expressed using ICC on adjacent 30-microm sections. However, the relative coexpressions of NR1 and NR2 proteins in single neurons in single sections of human epileptic cortex were unknown. In this study, we used double-labeled immunofluorescence and confocal microscopy to examine the distribution and coexpression of subunit proteins for NR1 and NR2A/B in both nondysplastic (control comparison) and dysplastic regions of human brain resected for the treatment of intractable epilepsy (11 patients). In nondysplastic regions, cortical neurons did not have immunoreactivity (ir) for NR2A/B, whereas NR1-ir was abundant. By contrast, dysplastic neurons in the regions with epileptic cortical dysplasia showed intense NR2A/B-ir in the somata and their dendritic processes. These same NR2A/B-ir dysplastic neurons were colabeled by NR1. These results demonstrate directly that dysplastic neurons express both NR2A/B and NR1 proteins, whereas nondysplastic cortical neurons express only NR1 proteins. Selective coexpression of NR2A/B and NR1 in dysplastic neurons suggests that NR2A/B may form heteromeric NR1-NR2 coassemblies and hyperexcitability in dysplastic neurons that could contribute to focal seizure onset.
    Experimental Neurology 11/1999; 159(2):409-18. · 4.65 Impact Factor
  • N Mikuni, T L Babb, W Christi
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    ABSTRACT: The N-methyl-D-aspartate receptors (NMDAR) produce physiologically functional channels for enhanced excitatory neurotransmission when they exist as heteromeric complexes containing the NMDAR1 subunit combined with NMDAR2. We examined the expressions of NMDAR1 and 2A/B protein in the kainic acid induced rat chronic epileptic hippocampus. Immunoreactivities of both NMDAR1 and NDMAR2A/B were increased in the inner molecular layer of the dentate gyrus, while they were decreased in the hilar and CA3/4 pyramidal zones. Immunoblot analysis demonstrated that the overall level of NMDAR1-2A/B coassembly was increased in the whole hippocampus. These results indicate that the increase of the NMDAR1-2A/B complex in the inner molecular layer is a significant cellular mechanism that contributes to focal hyperexcitability in rat chronic hippocampal epilepsy.
    Neuroscience Letters 07/1999; 267(3):165-8. · 2.03 Impact Factor

Publication Stats

7k Citations
433.21 Total Impact Points

Institutions

  • 2005
    • Children's Hospital of Michigan
      Detroit, Michigan, United States
    • Wayne State University
      • Department of Pediatrics
      Detroit, MI, United States
  • 1977–2005
    • University of California, Los Angeles
      • • Brain Research Institute
      • • Department of Neurology
      Los Angeles, CA, United States
  • 2001–2002
    • Cleveland Clinic
      • Neurological Institute
      Cleveland, OH, United States
  • 1995
    • Emory University
      • Department of Neurology
      Atlanta, GA, United States
  • 1986–1995
    • Children's Hospital Los Angeles
      • DIvision of Neurology
      Los Angeles, California, United States
  • 1978–1995
    • University of Southern California
      • • Department of Neurology
      • • Department of Neurological Surgery
      Los Angeles, California, United States
  • 1993
    • Tohoku University
      • Department of Neurosurgery
      Sendai, Kagoshima, Japan
  • 1978–1991
    • Laureate Institute for Brain Research
      Tulsa, Oklahoma, United States
  • 1978–1984
    • CSU Mentor
      Long Beach, California, United States
  • 1976–1982
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States