Article

Cortical parvalbumin interneurons and cognitive function in schizophrenia

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Trends in Neurosciences (Impact Factor: 13.56). 12/2011; 35(1):57-67. DOI: 10.1016/j.tins.2011.10.004
Source: PubMed

ABSTRACT

Deficits in cognitive control, a core disturbance of schizophrenia, appear to emerge from impaired prefrontal gamma oscillations. Cortical gamma oscillations require strong inhibitory inputs to pyramidal neurons from the parvalbumin basket cell (PVBC) class of GABAergic neurons. Recent findings indicate that schizophrenia is associated with multiple pre- and postsynaptic abnormalities in PVBCs, each of which weakens their inhibitory control of pyramidal cells. These findings suggest a new model of cortical dysfunction in schizophrenia in which PVBC inhibition is decreased to compensate for an upstream deficit in pyramidal cell excitation. This compensation is thought to rebalance cortical excitation and inhibition, but at a level insufficient to generate the gamma oscillation power required for high levels of cognitive control.

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Available from: Jill R Glausier, Mar 31, 2014
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    • "Individuals with a lower inhibition/excitation ratio tend to suppress ongoing neural activity more efficiently and allocate sufficient attentional resources, resulting in precise task performance. These findings may have important implications for neuropsychiatric diseases, as altered neurotransmitter function has been reported in psychiatric disorders, such as schizophrenia or attention deficit hyperactivity disorder (Falkenberg et al., 2014;Lewis et al., 2012;Molina et al., 2005;Naaijen et al., 2015). Several studies have reported deficits in DMN suppression during the n-back task in patients with schizophrenia (Lindenberg et al., 2001). "

    Full-text · Dataset · Jan 2016
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    • "Individuals with a lower inhibition/excitation ratio tend to suppress ongoing neural activity more efficiently and allocate sufficient attentional resources, resulting in precise task performance. These findings may have important implications for neuropsychiatric diseases, as altered neurotransmitter function has been reported in psychiatric disorders, such as schizophrenia or attention deficit hyperactivity disorder (Falkenberg et al., 2014;Lewis et al., 2012;Molina et al., 2005;Naaijen et al., 2015). Several studies have reported deficits in DMN suppression during the n-back task in patients with schizophrenia (Lindenberg et al., 2001). "
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    ABSTRACT: Detailed studies on the association between neural oscillations and the neurotransmitters gamma-aminobutyric acid (GABA) and glutamate have been performed in vitro. In addition, recent functional magnetic resonance imaging studies have characterized these neurotransmitters in task-induced deactivation processes during a working memory (WM) task. However, few studies have investigated the relationship between these neurotransmitters and task-induced oscillatory changes in the human brain. Here, using combined magnetoencephalography (MEG) and magnetic resonance spectroscopy (MRS), we investigated the modulation of GABA and glutamate + glutamine (Glx) concentrations related to task-induced oscillations in neural activity during a WM task. We first acquired resting-state MRS and MEG data from 20 healthy male volunteers using the n-back task. Time-frequency analysis was employed to determine the power induced during the encoding and retention phases in perigenual anterior cingulate cortex (pg-ACC), mid-ACC, and occipital cortex (OC). Statistical analysis showed that increased WM load was associated with task-induced oscillatory modulations (TIOMs) of the theta-gamma band relative to the zero-back condition (TIOM0B) in each volume of interest during the encoding phase of the n-back task. The task-induced oscillatory modulations in the two-back condition relative to the zero-back condition (TIOM2B-0B) were negatively correlated with the percent rate change of the correct hit rate for 2B-0B, but positively correlated with GABA/Glx. The positive correlation between TIOM2B-0B and GABA/Glx during the WM task indicates the importance of the inhibition/excitation ratio. In particular, a low inhibition/excitation ratio is essential for the efficient inhibition of irrelevant neural activity, thus producing precise task performance.
    Full-text · Article · Jan 2016 · NeuroImage
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    • "Alternatively , this pattern of results may reflect two functionally distinct pathways that either receive afferents from or send efferents to a shared, α2-subunit-rich region. GABA A receptors containing the α2-subunit are localized on the axon initial segment (AIS) of pyramidal cells in the hippocampus, dorsolateral prefrontal cortex, and possibly the amygdala (Nusser et al. 1996; Fritschy et al. 1998a; b; Loup et al. 1998; Kemppainen and Pitkanen 2000; Freund and Katona 2007; Cruz et al. 2009; Lewis et al. 2012; Ehrlich et al. 2013). Future studies should assess whether midazolam application to the AIS may affect the production and rhythmicity of action potentials , particularly in the amygdala and hippocampus. "
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    ABSTRACT: Rationale: Benzodiazepines (BZDs) are prescribed to reduce anxiety, agitation, and muscle spasms and for their sedative-hypnotic and anticonvulsant effects. Under specific conditions, BZDs escalate aggression in some individuals. Specific effects of BZDs have been linked to the α-subunit subtype composition of GABAA receptors. Objectives: Point-mutated mice rendered selectively insensitive to BZDs at α1-, α2-, or α3-containing GABAA receptors were used to determine which α-subunit subtypes are necessary for BZDs to escalate aggression and social approach and to reduce fear-motivated behavior. Methods: During resident-intruder confrontations, male wild-type (WT) and point-mutated α1(H101R), α2(H101R), and α3(H126R) mice were treated with midazolam (0-1.7 mg/kg, i.p.) and evaluated for aggression in an unfamiliar environment. Separate midazolam-treated WT and point-mutated mice were assessed for social approach toward a female or investigated in a 6-day fear-potentiated startle procedure. Results: Moderate doses of midazolam (0.3-0.56 mg/kg, i.p.) escalated aggression in WT and α3(H126R) mutants and increased social approach in WT and α1(H101R) mice. The highest dose of midazolam (1.0 mg/kg) reduced fear-potentiated startle responding. All mice were sensitive to the sedative effect of midazolam (1.7 mg/kg) except α1(H101R) mutants. Conclusions: Midazolam requires BZD-sensitive α1- and α2-containing GABAA receptors in order to escalate aggression and α2- and α3-containing receptors to reduce social anxiety-like behavior. GABAA receptors containing the α1-subunit are crucial for BZD-induced sedation, while α2-containing GABAA receptors may be a shared site of action for the pro-aggressive and anxiolytic effects of BZDs.
    Full-text · Article · Sep 2015 · Psychopharmacology
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