Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Trends in Neurosciences (Impact Factor: 12.9). 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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    • "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 · 4.82 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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    • "Expression of parvalbumin-expressing GABAergic interneurons are integral to higher-order forms of behavioral control and have been implicated in attentional set-shifting (Bissonette et al. 2014) and working memory (Timofeeva and Levin 2011). These cognitive functions are mediated by the dorsolateral PFC, and deficits in these various high-order cognitive processes are also core features of neuropsychiatric diseases including schizophrenia (Curley and Lewis 2012; Lewis et al. 2012). Therefore, we sought to determine whether intermittent access to sucrose during adolescence leads to long-lasting changes in their level of expression. "
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    ABSTRACT: In this study we sought to determine the effect of daily sucrose consumption in young rats on their subsequent performance in tasks that involve the prefrontal cortex and hippocampus. High levels of sugar consumption have been associated with the development of obesity, however less is known about how sugar consumption influences behavioral control and high-order cognitive processes. Of particular concern is the fact that sugar intake is greatest in adolescence, an important neurodevelopmental period. We provided sucrose to rats when they were progressing through puberty and adolescence. Cognitive performance was assessed in adulthood on a task related to executive function, a rodent analog of the Stroop task. We found that sucrose-exposed rats failed to show context-appropriate responding during incongruent stimulus compounds presented at test, indicative of impairments in prefrontal cortex function. Sucrose exposed rats also showed deficits in an on object-in-place recognition memory task, indicating that both prefrontal and hippocampal function was impaired. Analysis of brains showed a reduction in expression of parvalbumin-immunoreactive GABAergic interneurons in the hippocampus and prefrontal cortex, indicating that sucrose consumption during adolescence induced long-term pathology, potentially underpinning the cognitive deficits observed. These results suggest that consumption of high levels of sugar-sweetened beverages by adolescents may also impair neurocognitive functions affecting decision-making and memory, potentially rendering them at risk for developing mental health disorders. © 2015 Reichelt et al.; Published by Cold Spring Harbor Laboratory Press.
    Learning & memory (Cold Spring Harbor, N.Y.) 04/2015; 22(4):215-24. DOI:10.1101/lm.038000.114 · 4.38 Impact Factor
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