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


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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    • "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.
    Psychopharmacology 09/2015; DOI:10.1007/s00213-015-4069-9 · 3.88 Impact Factor
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    • "Moreover, mutations in Nlgn2 have been linked to schizophrenia (Sun et al., 2011), which shows a high comorbidity with anxiety disorders (Braga et al., 2013). Interestingly , schizophrenia is also associated with deficits in PV-positive interneuron function (Lewis et al., 2012), raising the intriguing possibility that alterations in the function of Nlgn2 may contribute to the comorbid anxiety symptoms in schizophrenia specifically through their effect on perisomatic inhibitory synapses. Further investigation of the precise link between Nlgn2 and behavioral phenotypes related to psychiatric disorders may provide essential insights into underlying molecular mechanisms and potential drug targets for the treatment of these disorders. "
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    ABSTRACT: Neuroligin 2 (Nlgn2) is a synaptic adhesion protein that plays a central role in the maturation and function of inhibitory synapses. Nlgn2 mutations have been associated with psychiatric disorders such as schizophrenia, and in mice, deletion of Nlgn2 results in a pronounced anxiety phenotype. To date, however, the molecular and cellular mechanisms linking Nlgn2 deletion to psychiatric phenotypes remain completely unknown. The aim of this study was therefore to define the role of Nlgn2 in anxiety-related neural circuits. To this end, we used a combination of behavioral, immunohistochemical, and electrophysiological approaches in Nlgn2 knockout (KO) mice to expand the behavioral characterization of these mice and to assess the functional consequences of Nlgn2 deletion in the amygdala. Moreover, we investigated the differential activation of anxiety-related circuits in Nlgn2 KO mice using a cFOS activation assay following exposure to an anxiogenic stimulus. We found that Nlgn2 is present at the majority of inhibitory synapses in the basal amygdala, where its deletion affects postsynaptic structures specifically at perisomatic sites and leads to impaired inhibitory synaptic transmission. Following exposure to an anxiogenic environment, Nlgn2 KO mice show a robust anxiety phenotype as well as exacerbated induction of cFOS expression specifically in CaMKII-positive projection neurons, but not in parvalbumin- or somatostatin-positive interneurons. Our data indicate that Nlgn2 deletion predominantly affects inhibitory synapses onto projection neurons in basal amygdala, resulting in decreased inhibitory drive onto these neurons and leading to their excessive activation under anxiogenic conditions. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 06/2015; DOI:10.1016/j.neuropharm.2015.06.016 · 5.11 Impact Factor
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    • "Finally, PV+ neurons involvement in SCZ is in accordance with the generic role of cortical gain and excitation/inhibition balance, that has been recently proposed to underlie false inference in SCZ (e.g., Adams et al., 2013; Jardri and Denève, 2013). PV+ neuron dysfunction can be primary or secondary to the dysfunction of other pathways and neuromodulators (for a review, Lewis et al., 2012), genetically inherited or environmentally induced (Jiang et al., 2013; Stansfield et al., 2015). While PV dysfunction has recently been proposed as a substrate for cognitive dysfunction in SCZ (e.g., Lewis, 2014), we here focus on its possible connection to the development of positive symptoms and to current theoretical approaches that attempts to explain the complex phenomenology of the disorder. "
    Frontiers in Psychology 04/2015; 6(April):1-5. DOI:10.3389/fpsyg.2015.00478 · 2.80 Impact Factor
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