Article

Imaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver

The New York State Psychiatric Institute, New York, NY 10032, USA.
Neuron (Impact Factor: 15.98). 04/2013; 78(1):81-93. DOI: 10.1016/j.neuron.2013.02.011
Source: PubMed

ABSTRACT The hippocampus in schizophrenia is characterized by both hypermetabolism and reduced size. It remains unknown whether these abnormalities are mechanistically linked. Here we addressed this question by using MRI tools that can map hippocampal metabolism and structure in patients and mouse models. In at-risk patients, hypermetabolism was found to begin in CA1 and spread to the subiculum after psychosis onset. CA1 hypermetabolism at baseline predicted hippocampal atrophy, which occurred during progression to psychosis, most prominently in similar regions. Next, we used ketamine to model conditions of acute psychosis in mice. Acute ketamine reproduced a similar regional pattern of hypermetabolism, while repeated exposure shifted the hippocampus to a hypermetabolic basal state with concurrent atrophy and pathology in parvalbumin-expressing interneurons. Parallel in vivo experiments using the glutamate-reducing drug LY379268 and direct measurements of extracellular glutamate showed that glutamate drives both neuroimaging abnormalities. These findings show that hippocampal hypermetabolism leads to atrophy in psychotic disorder and suggest glutamate as a pathogenic driver. VIDEO ABSTRACT:

Download full-text

Full-text

Available from: Jeffrey A Lieberman, Jul 02, 2015
2 Followers
 · 
143 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cuprizone (CPZ) is a copper chelating agent able to selectively insult mature oligodendrocytes (OLs) in brains of rodents. The CPZ-exposed mice show behavioral changes and have been employed to examine a putative role of altered OLs in the pathophysiology of schizophrenia. The aims of this study were to examine the brain metabolites in the CPZ-exposed mice during the early stage and to measure some antioxidant enzymes, lipid peroxidation and hydrogen peroxide (H2O2) in brain tissue. C57BL/6 mice were fed normal or CPZ-containing diet for 7 days. On days 7 and 8, mice were subjected to behavioral tests. On days 9 and 10, mice were subjected to 1H-MRS procedure. On day 10 mice were sacrificed and their brain tissue was processed for biochemical analyses. CPZ-exposure for 7 days caused an anxiety-like behavior, but had no effect on the social interaction and spatial working memory in C57BL/6 mice. The treatment significantly decreased levels of GPC+PCh, ml, NAA, NAA+NAAG, and PCr in the thalamus and hippocampus. It impaired the activities of some antioxidant enzymes, but did not increase levels of MDA and H2O2. This first 1H-MRS study with CPZ-exposed mice provided neurochemical evidence for mitochondrial dysfunction in brain cells of living mice during the early stage of CPZ-exposure. The results are of relevance to the pathophysiology of schizophrenia in which mitochondrial dysfunction of neural cells and altered OLs are two important players.
    Neurochemistry International 04/2014; DOI:10.1016/j.neuint.2014.02.004 · 2.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Jung's writings on schizophrenia are almost completely ignored or forgotten today. The purpose of this paper, along with a follow-up article, is to review the primary themes found in Jung's writings on schizophrenia, and to assess the validity of his theories about the disorder in light of our current knowledge base in the fields of psychopathology, cognitive neuroscience and psychotherapy research. In this article, five themes related to the aetiology and phenomenology of schizophrenia from Jung's writings are discussed:1) abaissement du niveau mental; 2) the complex; 3) mandala imagery; 4) constellation of archetypes and 5) psychological versus toxic aetiology. Reviews of the above areas suggest three conclusions. First, in many ways, Jung's ideas on schizophrenia anticipated much current thinking and data about the disorder. Second, with the recent (re)convergence of psychological and biological approaches to understanding and treating schizophrenia, the pioneering ideas of Jung regarding the importance of both factors and their interaction remain a useful and rich, but still underutilized resource. Finally, a more concerted effort to understand and evaluate the validity of Jung's concepts in terms of evidence from neuroscience could lead both to important advances in analytical psychology and to developments in therapeutic approaches that would extend beyond the treatment of schizophrenia.
    The Journal of analytical psychology 02/2014; 59(1):98-129. DOI:10.1111/1468-5922.12057 · 0.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dopamine has been thought to be central to the pathophysiology of schizophrenia for the last four decades. However, the last decade or so has seen a considerable advance in understanding of dopamine's role in the neurobiology of schizophrenia. This has been informed by advances in neuroimaging, preclinical models, and the study of the prodrome to schizophrenia. Studies using these approaches have identified that the major locus of dopaminergic dysfunction is presynaptic, characterized by elevated dopamine synthesis and release capacity. Moreover, this is seen in the prodrome to the illness, is linked to the symptoms, and increases with the onset of frank symptoms. It has also become clear that there is no marked alteration in dopamine transporter or D2/3 receptor availability in schizophrenia in general, and, similarly, there do not seem to be D2/3 receptor alterations in people at high clinical risk of psychosis. These findings highlight the enduring role of dopamine in the onset of schizophrenia. They suggest that presynaptic dopamine dysregulation underlies the onset of psychosis and are in line with an integrative model accounting for many of the genetic and environmental risk factors for schizophrenia.
    Advances in pharmacology (San Diego, Calif.) 01/2013; 68:199-220. DOI:10.1016/B978-0-12-411512-5.00010-5