Amygdalocortical Circuitry in Schizophrenia: From Circuits to Molecules

Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, MA, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 8.68). 04/2010; 35(5):1239. DOI: 10.1038/npp.2010.22
Source: PubMed


Schizophrenia is a disorder in which disturbances in the integration of emotion with cognition plays a central role and probably involves several different regions, including the dorsolateral prefrontal cortex, the rostral anterior cingulate cortex, the hippocampal formation, and basolateral amygdala (BLA). Recent brain imaging studies have reported changes in volume, whereas postmortem studies point to dysfunction of the GABA and glutamate systems in these regions. Microarray-based profiles indicate that complex changes in the expression of genes associated with synaptic transmission and ion channels are involved in GABA cell dysfunction in schizophrenics. Molecular abnormalities vary considerably on the basis of sector and layer, suggesting that the unique connectivity of intrinsic and extrinsic afferents may critical in regulating the activity of genes in specific subpopulations of GABA cells. Projections of the BLA may be of particular importance to the induction of abnormal circuitry in schizophrenia, as their ingrowth during late adolescence and early adulthood may help to 'trigger' the onset of illness in susceptible individuals. A preponderance of cellular and molecular abnormalities has been found in the stratum oriens (SO) of sectors CA3/2 in which BLA afferents provide a robust innervation. These observations have lead to the development of a rodent model for the study of abnormal circuitry in this disorder. For example, single-cell recordings in hippocampal slices exposed to increased activation from the BLA have shown decreases in GABA currents in pyramidal neurons in SO of CA3/2, but not CA1, and support the validity of this model. Overall, the postmortem studies of neural circuitry abnormalities in schizophrenia are beginning to implicate specific cellular, molecular, and electrophysiological mechanism in specific subtypes of cortical neurons defined by their afferent and efferent connectivity within key corticolimbic regions

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Available from: Francine Benes, Dec 22, 2014
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    • "Post-mortem studies have provided strong evidence for an altered GABA system in the disorder. One of the most consistent finding has been the reductions of glutamic acid decarboxylase-67 (Akbarian and Huang, 2006; Benes, 2010; Lewis et al., 2012; Nakazawa et al., 2012), a synthetic enzyme for GABA, observed in multiple brain regions associated with critical cognitive functions, including the dorsolateral prefrontal cortex, anterior cingulate cortex (ACC), motor cortex, visual cortex, and hippocampus. Few studies have examined in vivo GABA function in schizophrenia, and while the results have been somewhat mixed (Taylor and Tso, 2014), it remains an important goal to show how GABAergic abnormalities observed in post-mortem studies may be related to the behavioral phenotype of schizophrenia. "
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    ABSTRACT: The involvement of the gamma-aminobutyric acid (GABA) system in schizophrenia is suggested by postmortem studies and the common use of GABA receptor-potentiating agents in treatment. In a recent study, we used a benzodiazepine challenge to demonstrate abnormal GABAergic function during processing of negative visual stimuli in schizophrenia. This study extended this investigation by mapping GABAergic mechanisms associated with face processing and social appraisal in schizophrenia using a benzodiazepine challenge. Fourteen stable, medicated schizophrenia/schizoaffective patients (SZ) and 13 healthy controls (HC) underwent functional MRI using the blood oxygenation level-dependent (BOLD) technique while they performed the Socio-emotional Preference Task (SePT) on emotional face stimuli ("Do you like this face?"). Participants received single-blinded intravenous saline and lorazepam (LRZ) in two separate sessions separated by 1-3weeks. Both SZ and HC recruited medial prefrontal cortex/anterior cingulate during the SePT, relative to gender identification. A significant drug by group interaction was observed in the medial occipital cortex, such that SZ showed increased BOLD signal to LRZ challenge, while HC showed an expected decrease of signal; the interaction did not vary by task. The altered BOLD response to LRZ challenge in SZ was significantly correlated with increased negative affect across multiple measures. The altered response to LRZ challenge suggests that abnormal face processing and negative affect in SZ are associated with altered GABAergic function in the visual cortex, underscoring the role of impaired visual processing in socio-emotional deficits in schizophrenia.
    Schizophrenia Research 09/2015; 168(1). DOI:10.1016/j.schres.2015.08.022 · 3.92 Impact Factor
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    • "The ACC is a critical component of the cortico-limbic circuitry in the brain, which is considered to be disrupted in schizophrenia (Benes, 2010; Beneyto and Lewis, 2011). Abnormal function of the ACC would be predicted to disrupt several aspects of emotional and cognitive processing , which are important components of the clinical presentation of schizophrenia. "
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    ABSTRACT: GABAergic dysfunction has been strongly implicated in the pathophysiology of schizophrenia. In this study, we analyzed the expression levels of several GABAergic genes in the anterior cingulate cortex (ACC) of postmortem subjects with schizophrenia (n=21) and a comparison group of individuals without a history of psychiatric illness (n=18). Our analyses revealed a significant sex by diagnosis effect, along with significant differences in GABAergic gene expression based on medication status. Analyses revealed that in male groups, the expression of GABAergic genes was generally lower in schizophrenia cases compared to the controls, with significantly lower expression levels of GABA-Aα5, GABA-Aβ1, and GABA-Aε. In females, the expression of GABAergic genes was higher in the schizophrenia cases, with significantly higher expression of the GABA-Aβ1 and GAD67 genes. Analysis of the effect of medication in the schizophrenia subjects revealed significantly higher expression of GABA-Aα1-3, GABA-Aβ2, GABA-Aγ2, and GAD67 in the medicated group compared to the unmedicated group. These data show that sex differences in the expression of GABAergic genes occur in the ACC in schizophrenia. Therefore, our data support previous findings of GABAergic dysfunction in schizophrenia and emphasize the importance of considering sex in analyses of the pathophysiology of schizophrenia. Sex differences in the GABAergic regulation of ACC function may contribute to the differences observed in the symptoms of male and female patients with schizophrenia. In addition, our findings indicate that antipsychotic medications may alter GABAergic signaling in the ACC, supporting the potential of GABAergic targets for the development of novel antipsychotic medication. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 02/2015; 167(1). DOI:10.1016/j.schres.2015.01.025 · 3.92 Impact Factor
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    • "This finding is not restricted to the auditory modality however, as when presented with conflicting visual emotion cues and asked to make a single judgement of the emotion displayed, patients with schizophrenia have again shown decreased activity in the dorsolateral prefrontal cortex, and also decreased activity in the anterior cingulate cortex (Lee et al., 2014). Beyond its involvement in cognitive control, the anterior cingulate is also thought to provide 'the interface for emotion and cognition' (Allman et al., 2001), which fits with Bene's thoughts above on the central disturbance in schizophrenia (Benes, 2010). The use of traditional emotional Stroop tasks has also shown decreased dorsolateral prefrontal cortex activity during passive stimulation with emotion-related conflict (Epstein et al., 1999). "
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    ABSTRACT: Our ability to make sense of emotional cues is of paramount importance for understanding state of mind and communicative intent. However, emotional cues often conflict with each other; this presents a significant challenge for people with schizophrenia. We conducted a theoretical review to determine the extent and types of impaired processing of emotion-related conflict in schizophrenia; we evaluated the relationship with medication and symptoms, and considered possible mediatory mechanisms. The literature established that people with schizophrenia demonstrated impaired function: (i) when passively exposed to emotion cues whilst performing an unrelated task, (ii) when selectively attending to one source of emotion cues whilst trying to ignore interference from another source, and (iii) when trying to resolve conflicting emotion cues and judge meta-communicative intent. These deficits showed associations with both negative and positive symptoms. There was limited evidence for antipsychotic medications attenuating impaired emotion perception when there are conflicting cues, with further direct research needed. Impaired attentional control and context processing may underlie some of the observed impairments. Neuroanatomical correlates are likely to involve interhemispheric transfer via the corpus callosum, limbic regions such as the amygdala, and possibly dorsolateral prefrontal and anterior cingulate cortex through their role in conflict processing.
    Psychiatry Research 08/2014; 220(1-2). DOI:10.1016/j.psychres.2014.07.077 · 2.47 Impact Factor
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