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

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... Full description

Journal Title: Neuron 2013-04-10, Vol.78 (1), p.81-93
Main Author: Schobel, Scott A
Other Authors: Chaudhury, Nashid H , Khan, Usman A , Paniagua, Beatriz , Styner, Martin A , Asllani, Iris , Inbar, Benjamin P , Corcoran, Cheryl M , Lieberman, Jeffrey A , Moore, Holly , Small, Scott A
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0896-6273
Link: https://www.ncbi.nlm.nih.gov/pubmed/23583108
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title: Imaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver
format: Article
creator:
  • Schobel, Scott A
  • Chaudhury, Nashid H
  • Khan, Usman A
  • Paniagua, Beatriz
  • Styner, Martin A
  • Asllani, Iris
  • Inbar, Benjamin P
  • Corcoran, Cheryl M
  • Lieberman, Jeffrey A
  • Moore, Holly
  • Small, Scott A
subjects:
  • Amino acids
  • Amino Acids - pharmacology
  • Animals
  • Atrophy - chemically induced
  • Behavior
  • Brain Mapping
  • Bridged Bicyclo Compounds, Heterocyclic - pharmacology
  • Diagnostic imaging
  • Disease Models, Animal
  • Excitatory Amino Acid Agonists - pharmacology
  • Excitatory Amino Acid Antagonists - pharmacology
  • Female
  • Follow-Up Studies
  • Functional Laterality - drug effects
  • Glutamate
  • Glutamic Acid - metabolism
  • Hippocampus - blood supply
  • Hippocampus - drug effects
  • Hippocampus - pathology
  • Histology
  • Humans
  • Hypotheses
  • Imaging, Three-Dimensional
  • Ketamine - toxicity
  • Magnetic Resonance Imaging
  • Male
  • Medical imaging
  • Metabolism
  • Methods
  • Mice
  • Mice, Inbred C57BL
  • Neuroscience(all)
  • Psychotic Disorders - etiology
  • Psychotic Disorders - pathology
  • Rodents
  • Schizophrenia
  • Studies
  • Time Factors
ispartof: Neuron, 2013-04-10, Vol.78 (1), p.81-93
description: 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. [Display omitted] ► In psychotic disorder and a mouse model, hippocampal hypermetabolism predicts atrophy ► The longitudinal pattern of hypermetabolism and atrophy overlap and spread ► Excess extracellular glutamate drives hypermetabolism and leads to hippocampal interneuronal pathology and atrophy ► Regulating glutamate release in the model prevents hypermetabolism and atrophy Schobel et al. use functional and structural MRI in individuals at high risk for psychosis to show that hippocampal hypermetabolism predicts hippocampal atrophy across progression to first episode psychosis. A rodent model shows that alterations in extracellular glutamate may contribute to these abnormalities.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0896-6273
fulltext: fulltext
issn:
  • 0896-6273
  • 1097-4199
url: Link


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titleImaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver
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creatorSchobel, Scott A ; Chaudhury, Nashid H ; Khan, Usman A ; Paniagua, Beatriz ; Styner, Martin A ; Asllani, Iris ; Inbar, Benjamin P ; Corcoran, Cheryl M ; Lieberman, Jeffrey A ; Moore, Holly ; Small, Scott A
creatorcontribSchobel, Scott A ; Chaudhury, Nashid H ; Khan, Usman A ; Paniagua, Beatriz ; Styner, Martin A ; Asllani, Iris ; Inbar, Benjamin P ; Corcoran, Cheryl M ; Lieberman, Jeffrey A ; Moore, Holly ; Small, Scott A
descriptionThe 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. [Display omitted] ► In psychotic disorder and a mouse model, hippocampal hypermetabolism predicts atrophy ► The longitudinal pattern of hypermetabolism and atrophy overlap and spread ► Excess extracellular glutamate drives hypermetabolism and leads to hippocampal interneuronal pathology and atrophy ► Regulating glutamate release in the model prevents hypermetabolism and atrophy Schobel et al. use functional and structural MRI in individuals at high risk for psychosis to show that hippocampal hypermetabolism predicts hippocampal atrophy across progression to first episode psychosis. A rodent model shows that alterations in extracellular glutamate may contribute to these abnormalities.
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subjectAmino acids ; Amino Acids - pharmacology ; Animals ; Atrophy - chemically induced ; Behavior ; Brain Mapping ; Bridged Bicyclo Compounds, Heterocyclic - pharmacology ; Diagnostic imaging ; Disease Models, Animal ; Excitatory Amino Acid Agonists - pharmacology ; Excitatory Amino Acid Antagonists - pharmacology ; Female ; Follow-Up Studies ; Functional Laterality - drug effects ; Glutamate ; Glutamic Acid - metabolism ; Hippocampus - blood supply ; Hippocampus - drug effects ; Hippocampus - pathology ; Histology ; Humans ; Hypotheses ; Imaging, Three-Dimensional ; Ketamine - toxicity ; Magnetic Resonance Imaging ; Male ; Medical imaging ; Metabolism ; Methods ; Mice ; Mice, Inbred C57BL ; Neuroscience(all) ; Psychotic Disorders - etiology ; Psychotic Disorders - pathology ; Rodents ; Schizophrenia ; Studies ; Time Factors
ispartofNeuron, 2013-04-10, Vol.78 (1), p.81-93
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8Lieberman, Jeffrey A
9Moore, Holly
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descriptionThe 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. [Display omitted] ► In psychotic disorder and a mouse model, hippocampal hypermetabolism predicts atrophy ► The longitudinal pattern of hypermetabolism and atrophy overlap and spread ► Excess extracellular glutamate drives hypermetabolism and leads to hippocampal interneuronal pathology and atrophy ► Regulating glutamate release in the model prevents hypermetabolism and atrophy Schobel et al. use functional and structural MRI in individuals at high risk for psychosis to show that hippocampal hypermetabolism predicts hippocampal atrophy across progression to first episode psychosis. A rodent model shows that alterations in extracellular glutamate may contribute to these abnormalities.
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titleImaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver
authorSchobel, Scott A ; Chaudhury, Nashid H ; Khan, Usman A ; Paniagua, Beatriz ; Styner, Martin A ; Asllani, Iris ; Inbar, Benjamin P ; Corcoran, Cheryl M ; Lieberman, Jeffrey A ; Moore, Holly ; Small, Scott A
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atitleImaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver
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issn0896-6273
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abstractThe 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. [Display omitted] ► In psychotic disorder and a mouse model, hippocampal hypermetabolism predicts atrophy ► The longitudinal pattern of hypermetabolism and atrophy overlap and spread ► Excess extracellular glutamate drives hypermetabolism and leads to hippocampal interneuronal pathology and atrophy ► Regulating glutamate release in the model prevents hypermetabolism and atrophy Schobel et al. use functional and structural MRI in individuals at high risk for psychosis to show that hippocampal hypermetabolism predicts hippocampal atrophy across progression to first episode psychosis. A rodent model shows that alterations in extracellular glutamate may contribute to these abnormalities.
copUnited States
pubElsevier Inc
pmid23583108
doi10.1016/j.neuron.2013.02.011
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