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: 15.05). 04/2013; 78(1):81-93. DOI: 10.1016/j.neuron.2013.02.011
Source: PubMed


Video 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.

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    • "The volume of the hippocampus, in particular its anterior pole, is decreased in patients and it is also more metabolically active (Heckers and Konradi, 2010; Small et al., 2011). A recent study in individuals at risk for developing schizophrenia found that the hypermetabolism precedes the reduction in hippocampal volume and also predicts transition to the illness (Schobel et al., 2013). Research in animal models suggests that hyperactivity in the hippocampus could be responsible for the increased dopamine release observed in patients, which in turn is thought to cause the positive symptoms of the disease (Lodge and Grace, 2009; Winton-Brown et al., 2014; Modinos et al., 2015). "
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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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