Markram, H. et al. Interneurons of the neocortical inhibitory system. Nat. Rev. Neurosci. 5, 793-807

Laboratory of Neural Microcircuitry, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Nature reviews Neuroscience (Impact Factor: 31.43). 11/2004; 5(10):793-807. DOI: 10.1038/nrn1519
Source: PubMed


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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    • "However , the study of GABAergic interneurons, and the co-culture of these two neuronal subtypes, is warranted to better recapitulate cortical development. An important characteristic of cortical glutamatergic neurons is their ability to generate unipolar pyramidal neuronal morphology; interneurons develop multipolar morphologies (Dotti et al., 1988; Gaspard et al., 2008; Markram et al., 2004). Previously it has been shown that cortical neurons differentiated from hESCs also generate unipolar pyramidal neuronal morphologies (Gaspard et al., 2008). "
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    ABSTRACT: Over recent years tremendous progress has been made towards understanding the molecular and cellular mechanism by which estrogens exert enhancing effects on cognition, and how they act as a neuroprotective or neurotrophic agent in disease. Currently, much of this work has been carried out in animal models with only a limited number of studies using native human tissue or cells. Recent advances in stem cell technology now make it possible to reprogram somatic cells from humans into induced pluripotent stem cells (iPSCs), which can subsequently be differentiated in neurons of specific lineages. Importantly, the reprogramming of cells allows for the generation of iPSCs that retains the genetic "makeup" of the donor. Therefore, it is possible to generate iPSC-derived neurons from patients diagnosed with specific diseases, that harbor the complex genetic background associated with the disorder. Here, we review the iPSC technology and how its currently being used to model neural development and neurological diseases. Furthermore, we explore whether this cellular system could be used to understand the role of estrogens in human neurons, and present preliminary data in support of this. We further suggest that the use of iPSC technology offers a novel system in which to not only further understand estrogens' effects in human cells, but in which to investigate the mechanism by which estrogens are beneficial in disease. Developing a greater understanding of these mechanisms in native human cells will also aid in the development of safer and more effective estrogen-based therapeutics. Copyright © 2015. Published by Elsevier Inc.
    Hormones and Behavior 07/2015; 26. DOI:10.1016/j.yhbeh.2015.06.014 · 4.63 Impact Factor
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    • "The mammalian cortex is composed of two major classes of cells: glutamatergic excitatory pyramidal neurons (PNs) and GABAergic inhibitory interneurons (Somogyi et al., 1998). Among different types of cortical interneurons (Kawaguchi and Kubota, 1997; Markram et al., 2004), parvalbumin-containing fast-spiking basket cells are the most common type of GABAergic interneurons (Uematsu et al., 2008). Interactions between fast-spiking interneurons (FSIs) and PNs contribute to the fundamental properties of the cortical networks, and an investigation of the properties of the excitatory inputs in these cell types is required to understand how neural circuitry works. "
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    ABSTRACT: Properties of excitatory synaptic responses in fast-spiking interneurons (FSIs) and pyramidal neurons (PNs) are different; however, the mechanisms and determinants of this diversity have not been fully investigated. In the present study, voltage-clamp recording of miniature excitatory post-synaptic currents (mEPSCs) was performed of layer 2-3 FSIs and PNs in the medial prefrontal cortex of rats aged 19-22 days. The average mEPSCs in the FSIs exhibited amplitudes that were two times larger than those of the PNs and with much faster rise and decay. The mEPSC amplitude distributions in both cell types were asymmetric and in FSIs, the distributions were more skewed and had two-times larger coefficients of variation than in the PNs. In PNs but not in FSIs, the amplitude distributions were fitted well by different skewed unimodal functions that have been used previously for this purpose. In the FSIs, the distributions were well approximated only by a sum of two such functions, suggesting the presence of at least two subpopulations of events with different modal amplitudes. According to our estimates, two-thirds of the mEPSCs in FSIs belong to the high-amplitude subpopulation, and the modal amplitude in this subpopulation is approximately two times larger than that in the low-amplitude subpopulation. Using different statistical models, varying binning size, and data subsets, we confirmed the robustness and consistency of these findings. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
    Neuroscience 06/2015; 301. DOI:10.1016/j.neuroscience.2015.06.034 · 3.36 Impact Factor
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    • "The H101 GAD-67 antibody has been shown to detect a similar number of GABA cells as other anti- GABA antibodies (Akema et al., 2005). Parvalbumin is a calcium-binding protein that is found in basket and chandelier subtype GABAergic cells (Conde et al., 1994; Gabbott et al., 1997) that directly modulate efferent signaling of cortical pyramidal neurons (Miles et al., 1996; Markram et al., 2004; Lewis et al., 2005). Specificity of the PV 25 anti-parvalbumin antibody has been validated in immunohistochemistry studies of cortical and muscle tissue from wild-type versus parvalbumin knockout mice (Schwaller et al., 1999, 2004). "
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    ABSTRACT: Neural function within the medial prefrontal cortex (mPFC) regulates normal cognition, attention and impulse control, implicating neuroregulatory abnormalities within this region in mental dysfunction related to schizophrenia, depression and drug abuse. Both serotonin -2A (5-HT2A) and -2C (5-HT2C) receptors are known to be important in neuropsychiatric drug action and are distributed throughout the mPFC. However, their interactive role in serotonergic cortical regulation is poorly understood. While the main signal transduction mechanism for both receptors is stimulation of phosphoinositide production, they can have opposite effects downstream. 5-HT2A versus 5-HT2C receptor activation oppositely regulates behavior and can oppositely affect neurochemical release within the mPFC. These distinct receptor effects could be caused by their differential cellular distribution within the cortex and/or other areas. It is known that both receptors are located on GABAergic and pyramidal cells within the mPFC, but it is not clear whether they are expressed on the same or different cells. The present work employed immunofluorescence with confocal microscopy to examine this in layers V-VI of the prelimbic mPFC. The majority of GABA cells in the deep prelimbic mPFC expressed 5-HT2C receptor immunoreactivity. Furthermore, most cells expressing 5-HT2C receptor immunoreactivity notably co-expressed 5-HT2A receptors. However, 27% of 5-HT2C receptor immunoreactive cells were not GABAergic, indicating that a population of prelimbic pyramidal projection cells could express the 5-HT2C receptor. Indeed, some cells with 5-HT2C and 5-HT2A receptor co-labeling had a pyramidal shape and were expressed in the typical layered fashion of pyramidal cells. This indirectly demonstrates that 5-HT2C and 5-HT2A receptors may be commonly co-expressed on GABAergic cells within the deep layers of the prelimbic mPFC and perhaps co-localized on a small population of local pyramidal projection cells. Thus a complex interplay of cortical 5-HT2A and 5-HT2C receptor mechanisms exists, which if altered, could modulate efferent brain systems implicated in mental illness. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 03/2015; 297. DOI:10.1016/j.neuroscience.2015.03.050 · 3.36 Impact Factor
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