Benes FM. Emerging principle of altered neural circuitry in schizophrenia. Brain Res Brain Res Rev 31: 251-269

Laboratory for Structural Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02178, USA
Brain Research Reviews (Impact Factor: 5.93). 03/2000; 31(2):251-269. DOI: 10.1016/S0165-0173(99)00041-7


This paper presents an overview of recent microscopic studies that have sought to define how limbic circuitry may be altered in postmortem schizophrenic brain. The discussion is organized around several basic questions regarding the manner in which interconnections within and between the anterior cingulate cortex and hippocampal formation and involving the glutamate, GABA and dopamine systems may contribute to the pathophysiology of this disorder. The answers to these questions are used to derive several conclusions regarding circuitry changes in schizophrenia: 1) Schizophrenia is not a `typical' degenerative disorder, but rather it is one in which excitotoxicity may contribute to neuronal pathology, whether or not cell death occurs; 2) Three or more neurotransmitter systems may be simultaneously altered within a single microcircuit; 3) Each transmitter system may show circuitry changes in more than one region, but such changes may vary on a region-by-region basis; 4) The pathophysiology of schizophrenia may involve `mis-wirings' in intrinsic circuits (microcircuitry) within a given region, but significant changes are probably also present at the level of interconnections between two or more regions within a network (macrocircuitry); 5) While some microscopic findings appear to be selectively present in schizophrenia and be related to a susceptibility gene for this disorder, others may also be present in patients with bipolar disorder; 6) Although some of the circuitry changes seen in schizophrenia and bipolar disorder seem to be associated with neuroleptic exposure, most are not and may reflect the influence of non-specific environmental factors such as pre- and/or postnatal stress; 7) Normal postnatal changes at the level of both macro- and microcircuitry within the limbic system may serve as `triggers' for the onset of schizophrenia during adolescence. Taken together, these emerging principles can provide a framework for future postmortem studies of schizophrenic brain.

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    • "Frontal eye fields, inferior parietal cortex, and acetylcholine (Ach) activity are associated with orienting (Corbetta et al., 2008; Davidson and Marrocco, 2000). Executive control of attention involves the anterior cingulate cortex and the dorsolateral prefrontal cortex (Fan et al., 2005) and is related to ventral tegmental area and dopamine (DA) function (Benes, 2000). There is consensus about the causal relation between deficits in the three attentional networks (and corresponding neurotransmission) and impaired attentional functions (Petersen and Posner, 2012). "
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    ABSTRACT: Attentional deficits are prominent in the cognitive profile of patients with schizophrenia. However, it remains unclear whether treatment with clozapine, an atypical antipsychotic and first-line intervention used to reduce positive and negative symptoms of psychosis, improves the attentional functions. We used the revised attention network test to measure alerting, orienting, and executive control of attention both pre- and post-treatment with clozapine in patients with schizophrenia (n=32) and compared performance to healthy controls (n=32). Results revealed that there were deficits in all three attentional functions pre-treatment, and while clozapine improved the orienting function in patients with schizophrenia, there was no evidence for improvement in the alerting and executive control of attention. The enhancement of the orienting function by clozapine may increase the ability of patients with schizophrenia to orient towards objects and thoughts of interest. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 08/2015; 168(1). DOI:10.1016/j.schres.2015.08.009 · 3.92 Impact Factor
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    • "It has been reported that memories of fearful experiences can lead to pathogenic conditions such as anxiety and phobias (Orsini & Maren, 2012). According to previous researches, stimulation of the hippocampus with NMDA may disrupt particular hippocampal functions (Bast & Feldon, 2003; Berke & Eichenbaum, 2001), and impair processing of sensory stimuli, which is the core deficit in neuropsychiatric disorders such as schizophrenia and anxiety disorders (Bast & Feldon, 2003; Benes, 2000; Grace, 2000). Previous reports in animal models have also shown that intra-VH infusions of NMDA agonists increase locomotor activity (Bast, Zhang & Feldon, 2001; Swerdlow et al., 2001), and their antagonists decrease level of anxiety (Rezvanfard, Zarrindast & Bina, 2009). "
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    ABSTRACT: Introduction: In this study, we investigated the role of N-Methyl-D-Aspartate (NMDA) receptors in the ventral hippocampus (VH) and their possible interactions with GABA A system on anxiety-like behaviors. Methods: We used an elevated-plus maze test (EPM) to assess anxiety-like behaviors and locomotor activity in male Wistar rats. Results: The results showed that intra-VH infusions of different doses of NMDA (0.25 and 0.5 µg/rat) increased locomotor activity, and also induced anxiolytic-like behaviors, as revealed by a tendency to increase percentage of open arm time (%OAT), and a significant increase in percentage of open arm entries (%OAE). The results also showed that intra-VH infusions of muscimol (0.5 and 1 µg/rat) or bicuculline (0.5 and 1 µg/rat) did not significantly affect anxiety-like behaviors, but bicuculline at dose of 1 µg/rat increased locomotor activity. Intra-VH co-infusions of muscimol (0.5 µg/rat) along with low doses of NMDA (0.0625 and 0.125 µg/rat) showed a tendency to increase %OAT, %OAE and locomotor activity; however, no interaction was observed between the drugs. Interestingly, intra-VH co-infusions of bicuculline (0.5 µg/rat) along with effective doses of NMDA (0.25 and 0.5 µg/rat) decreased %OAT, %OAE and locomotor activity, and a significant interaction between two drugs was observed. Discussion: It can be concluded that GABAergic system may mediate the anxiolytic-like effects and increase in locomotor activity induced by NMDA in the VH.
    Autonomic neuroscience: basic & clinical 11/2014; 5(4). · 1.56 Impact Factor
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    • "Because these disorders are only diagnosable in patients, the human brain becomes by necessity the primary object of investigation. A clear example of the success of this strategy is the involvement of GABAergic interneurons in the pathophysiology of disorders such as schizophrenia, bipolar disorder and autism (Benes et al., 1992; Akbarian et al., 1995; Woo et al., 1998; Lewis et al., 1999; Benes, 2000; Volk et al., 2000; Benes and Berretta, 2001; Cotter et al., 2002; Heckers et al., 2002; Costa et al., 2004; Guidotti et al., 2005; Lewis et al., 2005; Torrey et al., 2005; Akbarian and Huang, 2006; Fatemi et al., 2009; Lawrence et al., 2010; Blatt and Fatemi, 2011; Fatemi et al., 2011; Guidotti et al., 2011) (see also articles included in this Special Issue). The postulated role of the GABA system in schizophrenia, the main focus of this Special Issue, has originated from a variety of technological approaches to the study of the human brain that include both in vivo brain imaging and postmortem investigations of the human brain. "
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    ABSTRACT: In the past 25 years, research on the human brain has been providing a clear path toward understanding the pathophysiology of psychiatric illnesses. The successes that have been accrued are matched by significant difficulties identifying and controlling a large number of potential confounding variables. By systematically and effectively accounting for unwanted variance in data from imaging and postmortem human brain studies, meaningful and reliable information regarding the pathophysiology of human brain disorders can be obtained. This perspective paper focuses on postmortem investigations to discuss some of the most challenging sources of variance, including diagnosis, comorbidity, substance abuse and pharmacological treatment, which confound investigations of the human brain.
    Schizophrenia Research 11/2014; 167(1). DOI:10.1016/j.schres.2014.10.019 · 3.92 Impact Factor
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