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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 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:

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    • "For example, a difference in the participation of the left and right hippocampi in episodic memory encoding is well-established (Igloi et al. 2010), with the right hippocampus providing placelearning navigation using environmental cues and the left hippocampus mediating self-navigation based on body movements. Additionally, it is interesting to note that the left hippocampus seems to be more affected in schizophrenic patients, compared to the right: basal metabolic activity in the left hippocampus is increased in schizophrenia and predicts psychosis and positive symptom severity (Schobel et al. 2013). Also, hippocampal laterality in NMDA receptor distribution and function has been reported in schizophrenia with a left-sided loss of glutamate receptors (Harrison et al. 2003; Kerwin et al. 1988). "
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    ABSTRACT: Aberrant prefrontal-hippocampal (PFC-HC) connectivity is disrupted in several psychiatric and at-risk conditions. Advances in rodent functional imaging have opened the possibility that this phenotype could serve as a translational imaging marker for psychiatric research. Recent evidence from functional magnetic resonance imaging (fMRI) studies has indicated an increase in PFC-HC coupling during working-memory tasks in both schizophrenic patients and at-risk populations, in contrast to a decrease in resting-state PFC-HC connectivity. Acute ketamine challenge is widely used in both humans and rats as a pharmacological model to study the mechanisms of N-methyl-D-aspartate (NMDA) receptor hypofunction in the context of psychiatric disorders. We aimed to establish whether acute ketamine challenge has consistent effects in rats and humans by investigating resting-state fMRI PFC-HC connectivity and thus to corroborate its potential utility as a translational probe. Twenty-four healthy human subjects (12 females, mean age 25 years) received intravenous doses of either saline (placebo) or ketamine (0.5 mg/kg body weight). Eighteen Sprague-Dawley male rats received either saline or ketamine (25 mg/kg). Resting-state fMRI measurements took place after injections, and the data were analyzed for PFC-HC functional connectivity. In both species, ketamine induced a robust increase in PFC-HC coupling, in contrast to findings in chronic schizophrenia. This translational comparison demonstrates a cross-species consistency in pharmacological effect and elucidates ketamine-induced alterations in PFC-HC coupling, a phenotype often disrupted in pathological conditions, which may give clue to understanding of psychiatric disorders and their onset, and help in the development of new treatments.
    Psychopharmacology 07/2015; DOI:10.1007/s00213-015-4022-y · 3.99 Impact Factor
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    • "Thus, ketamine's long-lasting therapeutic effects in CUS-treated rats and in depressed patients may result from a restoration of glutamate transmission and plasticity in the mPFC to a level that is optimal for cognitive function (Li et al. 2011; Cornwell et al. 2012). Conversely, ketamine may induce cognitive impairments while the drug is on board by over stimulating glutamate signaling in this region (Moghaddam and Javitt 2012; Schobel et al. 2013). "
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    ABSTRACT: Acute low-dose administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, produces rapid and sustained antidepressant-like effects in humans and rodents. Recently, we found that the long-lasting effect of ketamine on the forced swim test requires ventral hippocampal (vHipp) activity at the time of drug administration. The medial prefrontal cortex (mPFC), a target of the vHipp dysregulated in depression, is important for cognitive flexibility and response strategy selection. Deficits in cognitive flexibility, the ability to modify thoughts and behaviors in response to changes in the environment, are associated with depression. We have shown that chronic stress impairs cognitive flexibility on the attentional set-shifting test (AST) and induces a shift from active to passive response strategies on the shock-probe defensive burying test (SPDB). In this study, we tested the effects of ketamine on chronic stress-induced changes in cognitive flexibility and coping behavior on the AST and SPDB, respectively. Subsequently, we investigated vHipp-mPFC plasticity as a potential mechanism of ketamine's therapeutic action. Ketamine reversed deficits in cognitive flexibility and restored active coping behavior in chronically stressed rats. Further, high frequency stimulation in the vHipp replicated ketamine's antidepressant-like effects on the forced swim test and AST, but not on the SPDB. These results show that ketamine restores cognitive flexibility and coping response strategy compromised by stress. Activity in the vHipp-mPFC pathway may represent a neural substrate for some of the antidepressant-like behavioral effects of ketamine, including cognitive flexibility, but other circuits may mediate the effects of ketamine on coping response strategy.
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    • "Another example of different biometric characteristics depending on the stage of the disorder can be found in the intra-hippocampal atrophy progression during psychotic transition in SZ. Shoebel and colleagues [95] highlighted an important new neurobiological marker involved in the transition to psychosis and potentially recurring after subsequent psychotic exacerbations. They tested longitudinal changes in the cerebral blood flow to map spatial and temporal patterns of hippocampal metabolism and structure from the prodromal stage to consolidation of the psychosis. "
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