Yelena Kustova

Bio: Yelena Kustova is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Gliosis & Hippocampus. The author has an hindex of 12, co-authored 15 publications receiving 375 citations.

Extracellular Glutamate Levels Are Chronically Elevated in the Brains of LP‐BM5‐Infected Mice: A Mechanism of Retrovirus‐Induced Encephalopathy

Abstract: Mice infected with the LP-BM5 leukemia retrovirus mixture develop a progressive immunodeficiency with associated behavioral, histological, and neurochemical alterations consistent with glutamatergic hyperactivation. To gain insight into the contribution of excitatory amino acids to the neurodegeneration observed in these mice, their concentrations were measured in the CSF and striatal microdialysates. Glutamate concentrations were significantly elevated in CSF but not plasma as early as 4 weeks postinoculation. Steady-state glutamate levels in striatal microdialysates were increased threefold and could be reduced 40% by application of L-alpha-aminoadipate, an inhibitor of microglial glutamate transport. Stimulation of infected mice with KCl/L-trans-2,4-pyrrolidine dicarboxylate further increased glutamate levels 170-270% above those evoked in control mice. Tetrodotoxin suppressed the depolarization-evoked increase in glutamate by 88% in control mice, but it had only negligible effects in 40% of infected mice. Analysis of glutamate transport and catabolism suggests that abnormal astrocytic function does not contribute to the increase in basal extracellular glutamate levels. These findings are the first direct evidence that infection with an immunodeficiency-inducing retrovirus leads to a chronic elevation of extracellular free glutamate levels in the brain, which contributes to the neurodegenerative and cognitive deficits observed in these mice.

The influence of a targeted deletion of the IFNgamma gene on emotional behaviors.

Abstract: Evidence suggests that interferon-gamma (IFNγ) plays an important role in CNS function and development. While the paucity of agents that selectively modify IFNγ production or interaction with its receptors makes analyses of its potential behavioral relevance difficult, mice with null mutations of the IFNγ gene have been used to investigate the potential role of IFNγ in emotional behaviors. C57Bl/6 (B6) mice with null mutations of the IFNγ gene (IFNγ (−/−)) showed significantly increased emotionality compared to the wild-type (IFNγ (+/+)) B6 mice. This was manifested in performance in the elevated plus maze as well as increased defecation scores and decreased locomotor activity both in novel environments and following a sonic stimulus. In contrast, the general level of emotionality of both IFNγ (+/+) and (−/−) BALB/c (C) mice was substantially greater than that of either of the B6 mouse groups. While C IFNγ (−/−) showed increased immobility in response to novelty, other indices of emotionality of C IFNγ (−/−) mice were not significantly different from those of the C IFNγ (+/+) mice. In summary, the lack of IFNγ appears to contribute to increased emotionality, but the basal behaviors of the parental strain (e.g., BALBc) may overshadow the expression of this emotionality. While mice with null mutations of the IFNγ gene may be useful tools for investigating the role of IFNγ in brain function and behavior, the influence of the parent strain genome(s) on the behaviors in question must be taken into account.

Increased Brain Levels of Platelet‐Activating Factor in a Murine Acquired Immune Deficiency Syndrome Are NMDA Receptor‐Mediated

Abstract: Mice infected with the LP-BM5 murine leukemia virus (MuLV) develop an immunodeficiency syndrome (murine AIDS) and an encephalopathy characterized by impaired spatial learning and memory. Because platelet-activating factor (PAF) has been implicated in the pathogenesis of HIV-associated dementia complex, brain PAF levels were measured in LP-BM5 MuLV-infected mice. PAF levels in cerebral cortex and hippocampus were significantly increased at 6 and 12 weeks after LP-BM5 MuLV inoculation, whereas significant increases in striatal and cerebellar PAF levels were observed only at 12 weeks after inoculation. Administration of the NMDA antagonist MK-801 significantly reduced the increased PAF levels in the cerebral cortex and hippocampus of LP-BM5 MuLV-infected mice. These results indicate that the LP-BM5 MuLV-induced increases in brain PAF levels are the results of NMDA receptor activation and are consistent with the hypothesis that elevated CNS PAF levels contribute to the behavioral deficits observed in LP-BM5 MuLV-infected mice.

Astrocyte–endothelial interactions and blood–brain barrier permeability*

Abstract: The blood–brain barrier (BBB) is formed by brain endothelial cells lining the cerebral microvasculature, and is an important mechanism for protecting the brain from fluctuations in plasma composition, and from circulating agents such as neurotransmitters and xenobiotics capable of disturbing neural function. The barrier also plays an important role in the homeostatic regulation of the brain microenvironment necessary for the stable and co-ordinated activity of neurones. The BBB phenotype develops under the influence of associated brain cells, especially astrocytic glia, and consists of more complex tight junctions than in other capillary endothelia, and a number of specific transport and enzyme systems which regulate molecular traffic across the endothelial cells. Transporters characteristic of the BBB phenotype include both uptake mechanisms (e.g. GLUT-1 glucose carrier, L1 amino acid transporter) and efflux transporters (e.g. P-glycoprotein). In addition to a role in long-term barrier induction and maintenance, astrocytes and other cells can release chemical factors that modulate endothelial permeability over a time-scale of seconds to minutes. Cell culture models, both primary and cell lines, have been used to investigate aspects of barrier induction and modulation. Conditioned medium taken from growing glial cells can reproduce some of the inductive effects, evidence for involvement of diffusible factors. However, for some features of endothelial differentiation and induction, the extracellular matrix plays an important role. Several candidate molecules have been identified, capable of mimicking aspects of glial-mediated barrier induction of brain endothelium; these include TGFβ, GDNF, bFGF, IL-6 and steroids. In addition, factors secreted by brain endothelial cells including leukaemia inhibitory factor (LIF) have been shown to induce astrocytic differentiation. Thus endothelium and astrocytes are involved in two-way induction. Short-term modulation of brain endothelial permeability has been shown for a number of small chemical mediators produced by astrocytes and other nearby cell types. It is clear that endothelial cells are involved in both long- and short-term chemical communication with neighbouring cells, with the perivascular end feet of astrocytes being of particular importance. The role of barrier induction and modulation in normal physiology and in pathology is discussed.