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      PV Interneurons: Critical Regulators of E/I Balance for Prefrontal Cortex-Dependent Behavior and Psychiatric Disorders

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          Abstract

          Elucidating the prefrontal cortical microcircuit has been challenging, given its role in multiple complex behaviors, including working memory, cognitive flexibility, attention, social interaction and emotional regulation. Additionally, previous methodological limitations made it difficult to parse out the contribution of certain neuronal subpopulations in refining cortical representations. However, growing evidence supports a fundamental role of fast-spiking parvalbumin (PV) GABAergic interneurons in regulating pyramidal neuron activity to drive appropriate behavioral responses. Further, their function is heavily diminished in the prefrontal cortex (PFC) in numerous psychiatric diseases, including schizophrenia and autism. Previous research has demonstrated the importance of the optimal balance of excitation and inhibition (E/I) in cortical circuits in maintaining the efficiency of cortical information processing. Although we are still unraveling the mechanisms of information representation in the PFC, the E/I balance seems to be crucial, as pharmacological, chemogenetic and optogenetic approaches for disrupting E/I balance induce impairments in a range of PFC-dependent behaviors. In this review, we will explore two key hypotheses. First, PV interneurons are powerful regulators of E/I balance in the PFC, and help optimize the representation and processing of supramodal information in PFC. Second, diminishing the function of PV interneurons is sufficient to generate an elaborate symptom sequelae corresponding to those observed in a range of psychiatric diseases. Then, using this framework, we will speculate on whether this circuitry could represent a platform for the development of therapeutic interventions in disorders of PFC function.

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          Most cited references133

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          Neocortical excitation/inhibition balance in information processing and social dysfunction.

          Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.
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            Interneurons of the neocortical inhibitory system.

            Mammals adapt to a rapidly changing world because of the sophisticated cognitive functions that are supported by the neocortex. The neocortex, which forms almost 80% of the human brain, seems to have arisen from repeated duplication of a stereotypical microcircuit template with subtle specializations for different brain regions and species. The quest to unravel the blueprint of this template started more than a century ago and has revealed an immensely intricate design. The largest obstacle is the daunting variety of inhibitory interneurons that are found in the circuit. This review focuses on the organizing principles that govern the diversity of inhibitory interneurons and their circuits.
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              Reconstruction and Simulation of Neocortical Microcircuitry.

              We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm(3) containing ~31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ~8 million connections with ~37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies.
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                Author and article information

                Contributors
                Journal
                Front Neural Circuits
                Front Neural Circuits
                Front. Neural Circuits
                Frontiers in Neural Circuits
                Frontiers Media S.A.
                1662-5110
                16 May 2018
                2018
                : 12
                : 37
                Affiliations
                [1] 1Department of Neurobiology and Anatomy, College of Medicine, Drexel University , Philadelphia, PA, United States
                [2] 2Department of Neurology and Neurological Sciences, School of Medicine, Stanford University , Stanford, CA, United States
                Author notes

                Edited by: Vito Di Maio, Istituto di Scienze Applicate e Sistemi Intelligenti Eduardo Caianiello (CNR), Italy

                Reviewed by: Aleksey V. Zaitsev, Institute of Evolutionary Physiology and Biochemistry (RAS), Russia; Lucy Maree Palmer, Universität Bern, Switzerland; Scott S. Bolkan, Princeton University, United States

                *Correspondence: Brielle R. Ferguson briellef@ 123456stanford.edu Wen-Jun Gao wg38@ 123456drexel.edu
                Article
                10.3389/fncir.2018.00037
                5964203
                29867371
                e98b0580-97ba-41f7-a5c0-19a48180ea31
                Copyright © 2018 Ferguson and Gao.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 February 2018
                : 17 April 2018
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 164, Pages: 13, Words: 11357
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: R01085666 and F31MH111361
                Categories
                Neuroscience
                Review

                Neurosciences
                excitation/inhibition balance,gaba,pv interneurons,prefrontal cortex,cognition,psychiatric disorders

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