K E Isenberg

Washington University in St. Louis, Saint Louis, MO, United States

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Publications (49)252.77 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Glucose transporters play a critical role in mammalian brain energy metabolism because glucose is the principal brain energy source and these transporters promote glucose movement into neural cells. When glucose is unavailable, fructose can serve as an alternative energy source. Using real-time polymerase chain reaction and actin as a reference mRNA, we investigated the impact of fructose feeding on rat brain and other tissue mRNA expression of glucose transporter 5 which has high affinity for fructose. Brain mRNA levels of glucose transporter 5 increased 1.5-fold in 35-day old rats after 7 days of fructose feeding compared with controls, whereas it increased 2.5-fold in jejunum. Semi-quantitative analysis of protein expression by immunofluorescence of glucose transporter 5 in rat hippocampi indicated a 2.4-fold increase. We demonstrated the specificity of fructose feeding on glucose transporter 5 expression by showing that the expression of the neuronal glucose transporter 3 and insulin-regulated glucose transporter 4 were unaffected. In addition, the expression of glucose transporter 5 increased in fructose fed older adult rats (8-months and 12-months old) when compared with controls. These results suggest that short-term fructose feeding increases the expression of glucose transporter 5 in both young and aging adult rats. Increased brain expression of glucose transporter 5 is likely to be important in the role of fructose as an alternative energy source.
    Neuroscience 08/2006; 140(3):889-95. DOI:10.1016/j.neuroscience.2006.02.071 · 3.33 Impact Factor
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    ABSTRACT: We investigated conditions that promote basal and activity-dependent neuronal apoptosis in postnatal rat hippocampal cultures. Low-density mixed cultures of astrocytes and neurons exhibited lower sensitivity than high-density cultures to basal neuronal death and activity-sensitive neuronal death, induced with glutamate receptor blockers, sodium channel blockers, or calcium channel blockers. Although elevations of [Ca(2+)](i) protect neurons from apoptosis, low-density microcultures and mass cultures exhibited only minor differences in resting [Ca(2+)](i) and Ca(2+) current density, suggesting that these variables are unlikely to explain differences in susceptibility. Astrocytes, rather than neurons, were implicated in the neuronal loss. Several candidate molecules implicated in other astrocyte-dependent neurotoxicity models were excluded, but heat inactivation experiments suggested that a heat-labile factor is critically involved. In sum, our results suggest the surprising result that astrocytes can be negative modulators of neuronal survival during development and when the immature nervous system is challenged with drugs that dampen electrical excitability.
    Neuroscience 02/2005; 131(2):349-58. DOI:10.1016/j.neuroscience.2004.11.025 · 3.33 Impact Factor
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    ABSTRACT: Fetal alcohol exposure causes severe neuropsychiatric problems, but mechanisms of the ethanol-associated changes in central nervous system development are unclear. In vivo, ethanol's interaction with N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid type A (GABA(A)) receptors may cause increased apoptosis in the immature forebrain. We examined whether ethanol affects survival of neonatal hippocampal neurons in primary cultures. A 6-day ethanol exposure killed hippocampal neurons with an LD50 of approximately 25 mM. Elevated extracellular potassium or insulin-related growth factor 1 inhibited cell loss. Although potentiation of GABA(A) receptors or complete block of NMDA receptors also kills hippocampal neurons, pharmacological studies suggest that ethanol's interaction with GABA(A) and NMDA receptors is not sufficient to explain ethanol's effects on neuronal survival. Ca(2+) influx in response to depolarization was depressed >50% by chronic ethanol treatment. We suggest that chronic ethanol may promote neuronal loss through a mechanism affecting Ca(2+) influx in addition to effects on postsynaptic GABA and glutamate receptors.
    Neurobiology of Disease 08/2002; 10(3):396-409. · 5.20 Impact Factor
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    ABSTRACT: Neuroactive steroids rapidly modulate gamma-aminobutyric acid (GABA) and glutamate receptors. GABA-enhancing steroids have potential clinical utility as anesthetics, hypnotics, anticonvulsants and anxiolytics. Furthermore, GABAergic neurosteroids may participate in regulating mood and the effects of alcohol on the nervous system, suggesting a potential role in major psychiatric disorders. Neuroactive steroids that alter the function of glutamate receptors could be useful for treating neurodegenerative disorders, and as cognitive enhancers. Recent progress in developing water-soluble steroids and steroids with enhanced oral efficacy foster optimism that certain neuroactive steroids will be developed for clinical use.
    IDrugs: the investigational drugs journal 10/2000; 3(9):1053-63. · 2.33 Impact Factor
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    ABSTRACT: Neurotransmitters can have both toxic and trophic functions in addition to their role in neural signaling. Surprisingly, chronic blockade of GABA(A) receptor activity for 5-8 d in vitro enhanced survival of hippocampal neurons, suggesting that GABA(A) receptor overactivation may be neurotoxic. Potentiating GABA(A) receptor activity by chronic treatment with the endogenous neurosteroid (3alpha,5alpha)-3-hydroxypregnan-20-one caused massive cell loss over 1 week in culture. Other potentiators of GABA(A) receptors, including benzodiazepines, mimicked the cell loss, suggesting that potentiating endogenous GABA activity is sufficient to produce neuronal death. Neurosteroid-treated neurons had lower resting intracellular calcium levels than control cells and produced smaller calcium rises in response to depolarizing challenges. Manipulating intracellular calcium levels with chronic elevated extracellular potassium or with the calcium channel agonist Bay K 8644 protected neurons. The results may have implications for the mechanisms of programmed cell death in the developing CNS as well as implications for the long-term consequences of chronic GABAmimetic drug use during development.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2000; 20(9):3147-56. · 6.75 Impact Factor
  • Journal of Ect 04/2000; 16(1):68-70. DOI:10.1097/00124509-200003000-00009 · 1.39 Impact Factor
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    ABSTRACT: The main reason for the inconsistent findings in schizophrenia research is the lack of diagnostic conformity. This has not changed markedly following the introduction of modern operational diagnostic systems. Taking schizophrenia as a disease entity or assuming schizophrenia spectrum psychoses to represent a continuum of diseases without any clear dividing lines, the results of family and twin studies point to a multifactorial etiology based on a polygenic mode of transmission. Further, then it has to be assumed a familial continuum from schizophrenia to affective psychosis and other spectrum disorders. However, in family and twin studies based on Leonhard's classification, there is clearcut evidence that schizophrenic spectrum psychoses have to be divided into clinical and etiological subgroups with a completely different genetic background. For example, systematic catatonia is, for the most part, a sporadic disease, whereas periodic catatonia aggregates in families in a manner consistent with a major gene effect. Further, the results indicate that schizophrenic spectrum psychoses consist of three main valid categories: cycloid psychoses, unsystematic schizophrenias and systematic schizophrenias. In the case of cycloid psychosis and systematic schizophrenias, genetic loading seem to be very low, while "environmental" factors, for example, birth complications, may play an important etiological role. Unsystematic schizophrenias, however, are predominantly inherited and "environmental" factors are not very prominent.
    The World Journal of Biological Psychiatry 02/2000; 25(7):A14. DOI:10.1016/0006-3223(89)91514-X · 4.23 Impact Factor
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    ABSTRACT: Although inhibitors of glutamate transport prolong synaptic currents at many glutamate synapses, the cause of the current prolongation is unclear. Transport inhibitors may prolong synaptic currents by simply interfering with synaptic glutamate binding to transporters, by inhibiting substrate translocation, or by promoting accumulation of ambient glutamate, which may act cooperatively at receptors with synaptic glutamate. We show that reversal of the membrane potential of astrocytes surrounding the synapse prolongs synaptic currents but does not decrease the apparent affinity of transporters or significantly alter glutamate-dependent kinetics of macroscopic transporter currents in excised membrane patches. Positive membrane potentials do not affect binding of a nontransported glutamate analog, nor do positive membrane potentials alter the number of transporters available to bind analog. We also test the hypothesis that glutamate accumulation during uptake inhibition by transporter substrates is the direct cause of synaptic current prolongations. Transporter substrates elevate ambient glutamate near synapses by fostering reverse transport of endogenous glutamate. However, increases in ambient glutamate cannot account for the prolongations of synaptic currents, because a nonsubstrate transport inhibitor does not foster reverse uptake yet it prolongs synaptic currents. Moreover, exogenous glutamate does not mimic synaptic current prolongations induced by substrate inhibitors. These results provide strong support for a major role of substrate translocation in determining the time course of the glutamate concentration transient at excitatory synapses.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 12/1999; 19(21):9242-51. · 6.75 Impact Factor
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    ABSTRACT: 3beta-hydroxysteroid dehydrogenase/steroid delta5-->4-isomerase (3beta-HSD/isomerase) was expressed by baculovirus in Spodoptera fungiperda (Sf9) insect cells from cDNA sequences encoding human wild-type I (placental) and the human type I mutants - H261R, Y253F and Y253,254F. Western blots of SDS-polyacrylamide gels showed that the baculovirus-infected Sf9 cells expressed the immunoreactive wild-type, H261R, Y253F or Y253,254F protein that co-migrated with purified placental 3beta-HSD/isomerase (monomeric Mr=42,000 Da). The wild-type, H261R and Y253F enzymes were each purified as a single, homogeneous protein from a suspension of the Sf9 cells (5.01). In kinetic studies with purified enzyme, the H261R mutant enzyme had no 3beta-HSD activity, whereas the Km and Vmax values of the isomerase substrate were similar to the values obtained with the wild-type and native enzymes. The Vmax (88 nmol/min/mg) for the conversion of 5-androstene-3,17-dione to androstenedione by the Y253F isomerase activity was 7.0-fold less than the mean Vmax (620 nmol/min/mg) measured for the isomerase activity of the wild-type and native placental enzymes. In microsomal preparations, isomerase activity was completely abolished in the Y253,254F mutant enzyme, but Y253,254F had 45% of the 3beta-HSD activity of the wild-type enzyme. In contrast, the purified Y253F, wild-type and native enzymes had similar Vmax values for substrate oxidation by the 3beta-HSD activity. The 3beta-HSD activities of the Y253F, Y253,254F and wild-type enzymes reduced NAD+ with similar kinetic values. Although NADH activated the isomerase activities of the H261R and wild-type enzymes with similar kinetics, the activation of the isomerase activity of H261R by NAD+ was dramatically decreased. Based on these kinetic measurements, His261 appears to be a critical amino acid residue for the 3beta-HSD activity, and Tyr253 or Tyr254 participates in the isomerase activity of human type I (placental) enzyme.
    The Journal of Steroid Biochemistry and Molecular Biology 10/1998; 66(5-6):327-34. DOI:10.1016/S0960-0760(98)00058-2 · 4.05 Impact Factor
  • Chanvit Pornnoppadol, Keith Isenberg
    Journal of Ect 07/1998; 14(2):124-6. DOI:10.1097/00124509-199806000-00013 · 1.39 Impact Factor
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    ABSTRACT: To address the question of the relative contributions of glial and neuronal glutamate transport in the vertebrate CNS, we studied the distribution of forebrain glutamate transporters in rat hippocampal microcultures, a preparation in which physiological functions of glutamate transporters have been well characterized. Two of the three transporters, GLAST (EAAT1) and EAAC1 (EAAT3), are localized to microculture glia and neurons, respectively, as expected. However, we find strong immunoreactivity for the third glutamate transporter GLT-1 (EAAT2), a putatively glial transporter, in microculture neurons and in a small subset of microculture glia. Indistinguishable immunohistochemical staining patterns for GLT-1 were obtained with antibodies directed against both the N terminal and C terminal of the GLT-1 protein. Double-labeling experiments suggest that neuronal GLT-1 protein is primarily localized to the dendrites of excitatory neurons. Neuronal electrogenic transport currents in response to D-aspartate applications were occluded by the selective GLT-1 inhibitor dihydrokainate. In contrast, glia exhibited a larger transporter current density than did neurons, and the glial transport current was less sensitive to dihydrokainate. Neuronal transport currents were potentiated less than were glial currents when the chaotropic anion thiocyanate was substituted for gluconate in the whole-cell recording pipette, consistent with the previously reported lower anion permeability of EAAC1 and GLT-1 compared with that of GLAST. After microculture glia were rendered nonviable, excitatory autaptic currents (EACs) were prolonged in the presence of dihydrokainate, suggesting that neuronal GLT-1 is capable of participating in the clearance of synaptically released glutamate. Our results suggest that the initially proposed characterization of GLT-1 as a purely glial transporter is too simplistic and that under certain conditions functional GLT-1 protein can be expressed in brain neurons. The study suggests that changes in GLT-1 levels that occur with pathology or experimental manipulations cannot be assumed to be glial.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/1998; 18(12):4490-9. · 6.75 Impact Factor
  • Anthony R. Miller, Keith E. Isenberg
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    ABSTRACT: We report the case of a 58-year-old woman with depression and hypertension in whom aphasia, right-sided hemiparesis, and a possible right visual field defect were identified during recovery from right unilateral electroconvulsive therapy (ECT). The neurologic deficits resolved over a 3-day period; the patient was diagnosed with a reversible ischemic neurologic deficit (RIND). Review of the patient literature suggests that such cerebrovascular events in the setting of ECT are extremely rare and possibly decreasing in frequency. Reasons for such a decrease may include improved screening for predisposing cardiovascular conditions and the widespread use of neuromuscular blockade, ventilatory support, and cardiovascular monitoring during the procedure. Prompt recognition of cerebrovascular events is important to prevent complications such as cerebral edema, seizures, and aspiration, as well as to use new treatments for stroke.
    Journal of Ect 04/1998; 14(1):42-8. DOI:10.1097/00124509-199803000-00007 · 1.39 Impact Factor
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    ABSTRACT: A professionally led multifamily psychoeducation program for families with a schizophrenic member was designed according to participating families' reported concerns. The families provided information on their problems, needs, coping, and requirements from the program. They expressed more concern about "negative" symptoms of schizophrenia (e.g., social withdrawal) than about positive ones (e.g., hallucinations). Participants' overall positive response to the program is discussed in terms of further development of a multifamily psychoeducation model with family-generated content.
    American Journal of Orthopsychiatry 02/1998; 68(1):39-46. DOI:10.1037/h0080268 · 1.50 Impact Factor
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    ABSTRACT: Pulver et al. [1994a] reported modest linkage evidence for a dominantly (D) inherited "schizophrenia gene" in the vicinity of IL2RB on chromosome 22q12, and Coon et al. [1994] adduced moderate evidence under a recessive (R) model. We report here a replication study to test the hypothesis that one of these two models (or a third, intermediate (I) model) adequately describes the co-segregation of schizophrenia and chromosome 22q12 markers in an independent sample of 23 multiplex families. Altogether nine transmission models were evaluated. The models differed depending on whether the 15 family members with a diagnosis of schizophrenia spectrum disorders were considered unaffected (a "narrow" (N) definition), affected (a "wide" (W) definition), or declared "unknown" (U). The entire region between D22S268 and D22S307 is excluded (i.e., lod <-2) for models RN, RW, RU, and IW. Lod scores for the remaining models are uniformly negative; albeit, equivocal with respect to the dominant hypothesis over a small region between D22S268 and IL2RB. Nonparametric analysis under both diagnostic criteria also failed to yield any evidence for a susceptibility locus in this region of chromosome 22.
    American Journal of Medical Genetics 07/1997; 74(4):361-4. DOI:10.1002/(SICI)1096-8628(19970725)74:43.0.CO;2-S · 3.23 Impact Factor
  • Schizophrenia Research 11/1996; 22(1):89-90. DOI:10.1016/0920-9964(96)00033-3 · 4.43 Impact Factor
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    ABSTRACT: The effects of the enantiomers of the neurosteroid, 3 alpha-hydroxy-5 alpha-pregnan-20-one (DHP), and the benz[e]indene, BI-1, on gamma-aminobutyric acid (GABA) responses were studied using whole-cell recording techniques in cultured rat hippocampal neurons and human embryonic kidney cells (HEK-293) transfected with either alpha 1 beta 2 gamma 2 or alpha 6 beta 2 gamma 2 GABAA receptor subunits. At 10 microM, the (+)-enantiomers enhanced currents gated by 2 microM GABA in all cells, whereas the (-)-enantiomers were significantly less effective. The enhancement of 2 microM GABA responses in HEK-293 cells transfected with alpha 6 beta 2 gamma 2 subunits was about half that of hippocampal neurons or HEK-293 cells transfected with alpha 1 beta 2 gamma 2. The lower sensitivity of alpha 6 beta 2 gamma 2 receptors for (+)-DHP and (+)-BI-1 is accounted for by their greater apparent affinity for GABA. When the GABA concentration was decreased to 0.5 microM to take into account the four-fold higher apparent affinity of alpha 6 beta 2 gamma 2 receptors, these receptors exhibited enhancement similar to alpha 1 beta 2 gamma 2 receptors. These results indicate that both native and recombinant GABAA receptors have enantioselective sites at which neurosteroids and benz[e]indenes modulate GABA responses, and that differences in agonist affinity contribute to apparent differences in steroid sensitivity among GABAA receptors.
    Neuropharmacology 02/1996; 35(9-10):1161-8. DOI:10.1016/S0028-3908(96)00035-4 · 4.82 Impact Factor
  • S H Dinwiddie, K E Isenberg
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    ABSTRACT: Eight patients receiving electroconvulsive therapy (ECT) were anesthetized with alfentanil, 25 mcg/kg, plus 20 mg methohexital, alternating with standard methohexital anesthesia. Combination alfentanil-methohexital anesthesia was associated with a 45% increase in EEG seizure duration. Preliminary evidence suggests that ECT anesthesia using short-acting opiate compounds may prove to be a promising alternative to standard modified ECT, especially for patients with brief seizures.
    Convulsive therapy 10/1995; 11(3):170-6.
  • T Schwarz, J Loewenstein, K E Isenberg
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    ABSTRACT: Maintenance electroconvulsive therapy (M-ECT) is used to prevent recurrence of depression. Indications regarding patient selection criteria and efficacy are uncertain, in part because data are lacking. Comparison of M-ECT patients (N = 21) with controls demonstrates that M-ECT is chosen for patients whose course is characterized by multiple hospitalizations and failure to adequately respond to other therapies. M-ECT patients were exposed, on average, to 10 different psychotropic medications, including five trials of tricyclic antidepressants. Greater than half of their cumulative hospitalizations were for ECT. Their rate of rehospitalization decreased by 67% after institution of prophylactic M-ECT, demonstrating treatment efficacy. A tendency toward relapse and rehospitalization remains when M-ECT patients are compared to controls.
    Convulsive therapy 04/1995; 11(1):14-23.
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    ABSTRACT: Neuronal nicotinic acetylcholine receptor subunits alpha 3 (PCA48E) and beta 4S (ZPC13) were expressed in human embryonic kidney (HEK)-293 cells by calcium phosphate transfection. In the presence of atropine, acetylcholine (ACh) induced fast activating currents which exhibited desensitization and inward rectification. The EC50 for ACh was 202 +/- 32 microM with a Hill coefficient of 1.9 +/- 0.4. The rank order of nicotinic agonist potency was 1,1-dimethyl-4-phenylpiperozinium (DMPP) > cytisine = nicotine approximately equal to ACh. The maximal response elicited by DMPP was substantially less than that elicited by other agonists, suggesting that DMPP is a partial agonist. ACh (500 microM) responses were very effectively blocked by equimolar concentrations (100 microM) of the ganglionic antagonists d-tubocurarine, mecamylamine and hexamethonium. Equal concentrations of the potent muscle receptor antagonist decamethonium and the competitive antagonist dihydro-beta-erythroidine were much less effective. alpha bungaro-toxin (1 microM) had little effect on ACh-induced responses. This physiological and pharmacological profile is consistent with a ganglionic nicotinic response.
    Molecular Brain Research 02/1995; 28(1):101-9. · 2.00 Impact Factor
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    ABSTRACT: Neuronal nicotinic acetylcholine receptor subunits α3 (PCA48E) and β4S (ZPC13) were expressed in human embryonic kidney (HEK)-293 cells by calcium phosphate transfection. In the presence of atropine, acetylcholine (ACh) induced fast activating currents which exhibited desensitization and inward rectification. The EC50 for ACh was 202 ± 32 μM with a Hill coefficient of 1.9 ± 0.4. The rank order of nicotinic agonist potency was 1,1-dimethyl-4-phenylpiperozinium (DMPP) > cytisine = nicotine ≊ ACh. The maximal response elicited by DMPP was substantially less than that elicited by other agonists, suggesting that DMPP is a partial agonist. ACh (500 μM) responses were very effectively blocked by equimolar concentrations (100 μM) of the ganglionic antagonists d-tubocurarine, mecamylamine and hexamethonium. Equal concentrations of the potent muscle receptor antagonist decamethonium and the competitive antagonist dihydro-β-erythroidine were much less effective. α bungarotoxin (1 μM) had little effect on ACh-induced responses. This physiological and pharmacological profile is consistent with a ganglionic nicotinic response.
    Molecular Brain Research 01/1995; 28(1):101-109. DOI:10.1016/0169-328X(94)00189-L · 2.00 Impact Factor

Publication Stats

1k Citations
252.77 Total Impact Points


  • 1989–2006
    • Washington University in St. Louis
      • Department of Psychiatry
      Saint Louis, MO, United States
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 1993
    • University of Texas at Dallas
      Richardson, Texas, United States
    • University of Vienna
      Wien, Vienna, Austria
  • 1992
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States