Hippocampal dysfunction in schizophrenia is widely acknowledged, yet the mechanism of such dysfunction remains debated. In this study we investigate the excitatory and inhibitory hippocampal neurotransmission using two complementary methodologies, proton magnetic resonance spectroscopy (MRS) and tissue biochemistry, sampling individuals with schizophrenia in vivo and postmortem hippocampal tissue in vitro. The results show significantly lower glutamate concentrations in hippocampus in schizophrenia, an in vivo finding mirrored by lower GluN1 protein levels selectively in the dentate gyrus (DG) in vitro. In a mouse model with a DG knockout of the GRIN1 gene, we further confirmed that a selective decrease in DG GluN1 is sufficient to decrease the glutamate concentrations in the whole hippocampus. Gamma-aminobutyric acid (GABA) concentrations and GAD67 protein were not significantly different in hippocampus in schizophrenia. Similarly, GABA concentrations in the hippocampi of mice with a DG knockout of the GRIN1 gene were not significantly different from wild type. These findings provide strong evidence implicating the excitatory system within hippocampus in the pathophysiology of schizophrenia, particularly indicating the DG as a site of pathology.

Self-awareness (SA) is one of the core domains of higher cortical functions and is frequently compromised in schizophrenia. Deficits in SA have been associated with functional and psychosocial impairment in this patient population. However, despite its clinical significance, only a few studies have examined the neural substrates of self-referential processing in schizophrenia. The aim of this study was to assess self-awareness in schizophrenia using a functional magnetic resonance imaging (fMRI) paradigm designed to elicit judgments of self-reference in a simulated social context. While scanned, volunteers looked at visually-displayed sentences that had the volunteer’s own first name (self-directed sentence-stimulus) or an unknown other person’s first name (other-directed sentence stimulus) as the grammatical subject of the sentence. The volunteers were asked to discern whether each sentence-stimulus was about the volunteer personally (during a self-referential cue epoch) or asked whether each statement was about someone else (during an other-referential cue epoch). We predicted that individuals with schizophrenia would demonstrate altered functional activation to self- and other-directed sentence-stimuli as compared to controls. Fifteen controls and seventeen schizophrenia volunteers completed clinical assessments and SA fMRI task on a 3T Philips 3.0 T Achieva system. The results showed significantly greater activation in schizophrenia compared to controls for cortical midline structures in response to self- vs. other-directed sentence-stimuli. These findings support results from earlier studies and demonstrate selective alteration in the activation of cortical midline structures associated with evaluations of self-reference in schizophrenia as compared to controls.

Background Schizophrenia involves alterations in hippocampal function. The implications of these alterations for memory function in the illness remain poorly understood. Furthermore, it remains unknown how memory is impacted by drug treatments for schizophrenia. The goal of this study was to delineate specific memory processes that are disrupted in schizophrenia and explore how they are affected by medication. We specifically focus on memory generalization - the ability to flexibly generalize memories in novel situations. Methods Individuals with schizophrenia (n=56) and healthy controls (n=20) were tested on a computerized memory generalization paradigm. Participants first engage in trial-by-error associative learning. They are then asked to generalize what they learned by responding to novel stimulus combinations. Individuals with schizophrenia were tested on or off anti-psychotic medication, using a between-subject design that eliminates concerns about learning-set effects. Results Individuals with schizophrenia were selectively impaired in their ability to generalize knowledge, despite having intact learning and memory accuracy. This impairment was found only in individuals tested off medication. Individuals tested on medication generalized almost as well as healthy controls. This between-group difference was selective to memory generalization. Conclusion These findings suggest that individuals with schizophrenia have a selective alteration in the ability to flexibly generalize past experience towards novel learning environments. This alteration is unaccompanied by global memory defect. Additionally, the results indicate a robust generalization difference based on medication status. These results suggest that hippocampal abnormalities in schizophrenia may be alleviated with anti-psychotic medication, with important implications for understanding adaptive memory-guided behavior.

Objective We investigated functional brain response differences to food in women with either BMI <25kg/m2 (lean) or >35kg/m2 (severe obesity). Methods Thirty women 18-65 years old from academic medical centers participated. Baseline brain perfusion was measured with arterial spin labeling. Brain activity was measured via blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) in response to food cues, and appeal to cues rated. Subjective hunger/fullness was reported pre- and post-imaging. After a standard meal, measures were repeated. Results When fasting, brain perfusion did not differ significantly between groups; and both groups significantly increased activity in the neo- and limbic cortices and midbrain compared to baseline (p<0.05, family-wise-error whole-brain corrected). Once fed, the lean group showed significantly decreased activation in these areas, especially the limbic cortex, while the group with severe obesity showed no such decreases (p<0.05, family-wise-error whole-brain corrected). After eating, appeal ratings of food decreased only in lean women. Within groups, hunger decreased (p<0.001) and fullness increased (p<0.001) fasted to fed. Conclusion While fasting, brain response to food cues in women did not differ significantly despite BMI. After eating, brain activity quickly diminished in lean women but remained elevated in women with severe obesity. These brain activation findings confirm previous studies.

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