Neurogliaform sejtek funkcionális analízise az agykérgi információ-feldolgozásban = Functional analysis of neurogliaform cells in cortical information processing

Kísérleteinkben azonosított agykérgi idegsejtek szerepét vizsgáltuk a neuronhálózatban. Azt találtuk, hogy a neurogliaform sejtek a nemcsak egymással alakítanak ki elektromos szinapszisokat, ahogyan az a többi gátló sejttípusnál megfigyelhető, hanem több GABAerg sejtpopulációval is elektromos szinaptikus összeköttetést hoznak létre. Kimutattuk, hogy a neurogliaform sejtek egyetlen akciós potenciálja elegendő az agykérgi lassú GABAA válaszok kialakítására, amelyek igen szokatlan tulajdonságokkal rendelkeznek: rendkívül lassú kinetika, alacsony GABA koncentráció és a transzmitter diffúziója a szinaptikus résen kívülre. Adaptáltuk az agyszeleteken végzett szimultán többszörös patch clamp technikát emberi agykéreg vizsgálatára. Bizonyítottuk, hogy az emberi agykéregben is működnek elektromos szinapszisok és hogy az emberi neurogliaform sejtek, a patkányban leírtakhoz hasonlóan lassú, GABAA és GABAB receptorokon át működő gátlást alakítanak ki. Elsőként alkalmaztunk ugyanazon probléma vizsgálatára nagyfelbontású immuncitokémiai és elektrofiziológiai módszerekkel kombinált kétfoton képalkotást és eddig ismeretlen, térszelektív eltávolító mechanizmust tártunk fel az idegsejteken belüli jeltovábbításban kiemelt szerepet játszó kálcium ionok térbeli eloszlását meghatározó folyamatokban. Kimutattuk, hogy a kandeláber sejtek, amelyeket a leghatékonyabb gátló sejtnek hittek az agykéregben, a ma ismert leghatékonyabb serkentő sejtek lehetnek az ember és a patkány agykérgében egyaránt. | We investigated the function of identified neurons in microcircuits of the cerebral cortex. We found that neurogliaform cells form homologous electrical synapses among themselves, similar to other types of cortical interneuron. However, neurogliaform cells also establish heterologous electrical synapses with different GABAergic cells. We also showed that neurogliaform cells are specialized to a unique form of GABAergic communication. A single action potential of a neurogliaform cells is sufficient to trigger the so-called slow GABAA responses in the cortex, which have unique synaptic properties: extremely slow kinetics, low GABA concentration and the diffusion of the transmitter outside the synaptic cleft. We have adapted the in vitro multiple patch clamp method to study samples taken from adult human cerebral cortex. We recorded the first synaptic interactions in the human cortex and showed that electrical synapses exist between human neurons. We also confirmed that human neurogliaform cells, similar to the rat, elicit slow, GABA and GABAB receptor mediated responses. We pioneered the combination of high resolution immunocytochemistry with two-photon imaging and revealed a novel, spatially selective extrusion mechanism in the regulation of intracellular calcium dynamics. We showed that chandelier cells, which were considered to be most powerful inhibitory neurons of the nervous system, can act as uniquely effective excitatory neurons in the human and rat cerebral cortex

Complex Events Initiated by Individual Spikes in the Human Cerebral Cortex

Synaptic interactions between neurons of the human cerebral cortex were not directly studied to date. We recorded the first dataset, to our knowledge, on the synaptic effect of identified human pyramidal cells on various types of postsynaptic neurons and reveal complex events triggered by individual action potentials in the human neocortical network. Brain slices were prepared from nonpathological samples of cortex that had to be removed for the surgical treatment of brain areas beneath association cortices of 58 patients aged 18 to 73 y. Simultaneous triple and quadruple whole-cell patch clamp recordings were performed testing mono- and polysynaptic potentials in target neurons following a single action potential fired by layer 2/3 pyramidal cells, and the temporal structure of events and underlying mechanisms were analyzed. In addition to monosynaptic postsynaptic potentials, individual action potentials in presynaptic pyramidal cells initiated long-lasting (37 ± 17 ms) sequences of events in the network lasting an order of magnitude longer than detected previously in other species. These event series were composed of specifically alternating glutamatergic and GABAergic postsynaptic potentials and required selective spike-to-spike coupling from pyramidal cells to GABAergic interneurons producing concomitant inhibitory as well as excitatory feed-forward action of GABA. Single action potentials of human neurons are sufficient to recruit Hebbian-like neuronal assemblies that are proposed to participate in cognitive processes

Electrophysiological Heterogeneity of Fast-Spiking Interneurons: Chandelier versus Basket Cells

In the prefrontal cortex, parvalbumin-positive inhibitory neurons play a prominent role in the neural circuitry that subserves working memory, and alterations in these neurons contribute to the pathophysiology of schizophrenia. Two morphologically distinct classes of parvalbumin neurons that target the perisomatic region of pyramidal neurons, chandelier cells (ChCs) and basket cells (BCs), are generally thought to have the same "fast-spiking" phenotype, which is characterized by a short action potential and high frequency firing without adaptation. However, findings from studies in different species suggest that certain electrophysiological membrane properties might differ between these two cell classes. In this study, we assessed the physiological heterogeneity of fast-spiking interneurons as a function of two factors: species (macaque monkey vs. rat) and morphology (chandelier vs. basket). We showed previously that electrophysiological membrane properties of BCs differ between these two species. Here, for the first time, we report differences in ChCs membrane properties between monkey and rat. We also found that a number of membrane properties differentiate ChCs from BCs. Some of these differences were species-independent (e.g., fast and medium afterhyperpolarization, firing frequency, and depolarizing sag), whereas the differences in the first spike latency between ChCs and BCs were species-specific. Our findings indicate that different combinations of electrophysiological membrane properties distinguish ChCs from BCs in rodents and primates. Such electrophysiological differences between ChCs and BCs likely contribute to their distinctive roles in cortical circuitry in each species. © 2013 Povysheva et al

The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Despite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV+) interneurons in schizophrenia, their functional consequences remain elusive. Since PV+ interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV+ interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV+ interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits. Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.Peer reviewe

Functional specification of CCK plus interneurons by alternative isoforms of Kv4.3 auxiliary subunits

CCK-expressing interneurons (CCK+INs) are crucial for controlling hippocampal activity. We found two firing phenotypes of CCK+INs in rat hippocampal CA3 area; either possessing a previously undetected membrane potential-dependent firing or regular firing phenotype, due to different low-voltage-activated potassium currents. These different excitability properties destine the two types for distinct functions, because the former is essentially silenced during realistic 8-15 Hz oscillations. By contrast, the general intrinsic excitability, morphology and gene-profiles of the two types were surprisingly similar. Even the expression of Kv4.3 channels were comparable, despite evidences showing that Kv4.3-mediated currents underlie the distinct firing properties. Instead, the firing phenotypes were correlated with the presence of distinct isoforms of Kv4 auxiliary subunits (KChIP1 vs. KChIP4e and DPP6S). Our results reveal the underlying mechanisms of two previously unknown types of CCK+INs and demonstrate that alternative splicing of few genes, which may be viewed as a minor change in the cells' whole transcriptome, can determine cell-type identity

Specificity of Synaptic Connectivity between Layer 1 Inhibitory Interneurons and Layer 2/3 Pyramidal Neurons in the Rat Neocortex

Understanding the structure and function of the neocortical microcircuit requires a description of the synaptic connectivity between identified neuronal populations. Here, we investigate the electrophysiological properties of layer 1 (L1) neurons of the rat somatosensory neocortex (postnatal day 24–36) and their synaptic connectivity with supragranular pyramidal neurons. The active and passive properties of visually identified L1 neurons (n = 266) suggested division into 4 groups according to the Petilla classification scheme with characteristics of neurogliaform cells (NGFCs) (n = 72), classical-accommodating (n = 137), fast-spiking (n = 23), and burst-spiking neurons (n = 34). Anatomical reconstructions of L1 neurons supported the existence of 4 major neuronal groups. Multiparameter unsupervised cluster analysis confirmed the existence of 4 groups, revealing a high degree of similarity with the Petilla scheme. Simultaneous recordings between synaptically connected L1 neurons and L2/3 pyramidal neurons (n = 384) demonstrated neuronal class specificity in both excitatory and inhibitory connectivity and the properties of synaptic potentials. Notably, all groups of L1 neurons received monosynaptic excitatory input from L2/3 pyramidal neurons (n = 33), with the exception of NGFCs (n = 68 pairs tested). In contrast, NGFCs strongly inhibited L2/3 pyramidal neurons (n = 12 out 27 pairs tested). These data reveal a high specificity of excitatory and inhibitory connections in the superficial layers of the neocortex

Of Mice and Men, and Chandeliers

How does the human neocortex reliably propagate information through neural circuits? One mechanism appears to involve relying on strong connections from pyramidal neurons to interneurons and a depolarizing action of cortical chandelier cells

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission