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Sample records for interneurons

  1. Inhibition by Somatostatin Interneurons in Olfactory Cortex

    PubMed Central

    Large, Adam M.; Kunz, Nicholas A.; Mielo, Samantha L.; Oswald, Anne-Marie M.

    2016-01-01

    Inhibitory circuitry plays an integral role in cortical network activity. The development of transgenic mouse lines targeting unique interneuron classes has significantly advanced our understanding of the functional roles of specific inhibitory circuits in neocortical sensory processing. In contrast, considerably less is known about the circuitry and function of interneuron classes in piriform cortex, a paleocortex responsible for olfactory processing. In this study, we sought to utilize transgenic technology to investigate inhibition mediated by somatostatin (SST) interneurons onto pyramidal cells (PCs), parvalbumin (PV) interneurons, and other interneuron classes. As a first step, we characterized the anatomical distributions and intrinsic properties of SST and PV interneurons in four transgenic lines (SST-cre, GIN, PV-cre, and G42) that are commonly interbred to investigate inhibitory connectivity. Surprisingly, the distributions SST and PV cell subtypes targeted in the GIN and G42 lines were sparse in piriform cortex compared to neocortex. Moreover, two-thirds of interneurons recorded in the SST-cre line had electrophysiological properties similar to fast spiking (FS) interneurons rather than regular (RS) or low threshold spiking (LTS) phenotypes. Nonetheless, like neocortex, we find that SST-cells broadly inhibit a number of unidentified interneuron classes including putatively identified PV cells and surprisingly, other SST cells. We also confirm that SST-cells inhibit pyramidal cell dendrites and thus, influence dendritic integration of afferent and recurrent inputs to the piriform cortex. Altogether, our findings suggest that SST interneurons play an important role in regulating both excitation and the global inhibitory network during olfactory processing. PMID:27582691

  2. Inhibition by Somatostatin Interneurons in Olfactory Cortex.

    PubMed

    Large, Adam M; Kunz, Nicholas A; Mielo, Samantha L; Oswald, Anne-Marie M

    2016-01-01

    Inhibitory circuitry plays an integral role in cortical network activity. The development of transgenic mouse lines targeting unique interneuron classes has significantly advanced our understanding of the functional roles of specific inhibitory circuits in neocortical sensory processing. In contrast, considerably less is known about the circuitry and function of interneuron classes in piriform cortex, a paleocortex responsible for olfactory processing. In this study, we sought to utilize transgenic technology to investigate inhibition mediated by somatostatin (SST) interneurons onto pyramidal cells (PCs), parvalbumin (PV) interneurons, and other interneuron classes. As a first step, we characterized the anatomical distributions and intrinsic properties of SST and PV interneurons in four transgenic lines (SST-cre, GIN, PV-cre, and G42) that are commonly interbred to investigate inhibitory connectivity. Surprisingly, the distributions SST and PV cell subtypes targeted in the GIN and G42 lines were sparse in piriform cortex compared to neocortex. Moreover, two-thirds of interneurons recorded in the SST-cre line had electrophysiological properties similar to fast spiking (FS) interneurons rather than regular (RS) or low threshold spiking (LTS) phenotypes. Nonetheless, like neocortex, we find that SST-cells broadly inhibit a number of unidentified interneuron classes including putatively identified PV cells and surprisingly, other SST cells. We also confirm that SST-cells inhibit pyramidal cell dendrites and thus, influence dendritic integration of afferent and recurrent inputs to the piriform cortex. Altogether, our findings suggest that SST interneurons play an important role in regulating both excitation and the global inhibitory network during olfactory processing. PMID:27582691

  3. Neural circuits: Interacting interneurons regulate fear learning.

    PubMed

    Ozawa, Takaaki; Johansen, Joshua P

    2014-08-01

    A recent study has found that, during associative fear learning, different sensory stimuli activate subsets of inhibitory interneurons in distinct ways to dynamically regulate glutamatergic neural activity and behavioral memory formation. PMID:25093560

  4. The compartmental restriction of cerebellar interneurons

    PubMed Central

    Consalez, G. Giacomo; Hawkes, Richard

    2013-01-01

    The Purkinje cells (PC's) of the cerebellar cortex are subdivided into multiple different molecular phenotypes that form an elaborate array of parasagittal stripes. This array serves as a scaffold around which afferent topography is organized. The ways in which cerebellar interneurons may be restricted by this scaffolding are less well-understood. This review begins with a brief survey of cerebellar topography. Next, it reviews the development of stripes in the cerebellum with a particular emphasis on the embryological origins of cerebellar interneurons. These data serve as a foundation to discuss the hypothesis that cerebellar compartment boundaries also restrict cerebellar interneurons, both excitatory [granule cells, unipolar brush cells (UBCs)] and inhibitory (e.g., Golgi cells, basket cells). Finally, it is proposed that the same PC scaffold that restricts afferent terminal fields to stripes may also act to organize cerebellar interneurons. PMID:23346049

  5. Synaptic kainate currents reset interneuron firing phase

    PubMed Central

    Yang, Ellen J; Harris, Alexander Z; Pettit, Diana L

    2007-01-01

    Hippocampal interneuron activity has been linked to epileptogenesis, seizures and the oscillatory synaptic activity detected in behaving rats. Interneurons fire at specific times in the rhythmic cycles that comprise these oscillations; however, the mechanisms controlling these firing patterns remain unclear. We have examined the role of synaptic input in modulating the firing of spontaneously active rat hippocampal interneurons. We find that synaptic glutamate receptor currents of 20–30 pA increase instantaneous firing frequency and reset the phase of spontaneously firing CA1 stratum oriens interneurons. Kainate receptor (KAR)-mediated currents are particularly effective at producing this phase reset, while AMPA receptor currents are relatively ineffective. The efficacy of KAR-mediated currents is probably due to their 3-fold longer decay. Given the small amplitude of the currents needed for this phase reset, coincident activation of only a few KAR-containing synapses could synchronize firing in groups of interneurons. These data suggest that KARs are potent modulators of circuit behaviour and their activation alters hippocampal interneuron output. PMID:17068102

  6. Revisiting enigmatic cortical calretinin-expressing interneurons

    PubMed Central

    Cauli, Bruno; Zhou, Xiaojuan; Tricoire, Ludovic; Toussay, Xavier; Staiger, Jochen F.

    2014-01-01

    Cortical calretinin (CR)-expressing interneurons represent a heterogeneous subpopulation of about 10–30% of GABAergic interneurons, which altogether total ca. 12–20% of all cortical neurons. In the rodent neocortex, CR cells display different somatodendritic morphologies ranging from bipolar to multipolar but the bipolar cells and their variations dominate. They are also diverse at the molecular level as they were shown to express numerous neuropeptides in different combinations including vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), neurokinin B (NKB) corticotrophin releasing factor (CRF), enkephalin (Enk) but also neuropeptide Y (NPY) and somatostatin (SOM) to a lesser extent. CR-expressing interneurons exhibit different firing behaviors such as adapting, bursting or irregular. They mainly originate from the caudal ganglionic eminence (CGE) but a subpopulation also derives from the dorsal part of the medial ganglionic eminence (MGE). Cortical GABAergic CR-expressing interneurons can be divided in two main populations: VIP-bipolar interneurons deriving from the CGE and SOM-Martinotti-like interneurons originating in the dorsal MGE. Although bipolar cells account for the majority of CR-expressing interneurons, the roles they play in cortical neuronal circuits and in the more general metabolic physiology of the brain remained elusive and enigmatic. The aim of this review is, firstly, to provide a comprehensive view of the morphological, molecular and electrophysiological features defining this cell type. We will, secondly, also summarize what is known about their place in the cortical circuit, their modulation by subcortical afferents and the functional roles they might play in neuronal processing and energy metabolism. PMID:25009470

  7. Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

    PubMed Central

    Xenias, Harry S.; Ibáñez-Sandoval, Osvaldo; Koós, Tibor

    2015-01-01

    Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH–Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)–TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP–TH interneurons. Optogenetic activation of striatal EGFP–TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons. PMID:25904808

  8. Production and organization of neocortical interneurons

    PubMed Central

    Sultan, Khadeejah T.; Brown, Keith N.; Shi, Song-Hai

    2013-01-01

    Inhibitory GABA (γ-aminobutyric acid)-ergic interneurons are a vital component of the neocortex responsible for shaping its output through a variety of inhibitions. Consisting of many flavors, interneuron subtypes are predominantly defined by their morphological, physiological, and neurochemical properties that help to determine their functional role within the neocortex. During development, these cells are born in the subpallium where they then tangentially migrate over long distances before being radially positioned to their final location in the cortical laminae. As development progresses into adolescence, these cells mature and form chemical and electrical connections with both glutamatergic excitatory neurons and other interneurons ultimately establishing the cortical network. The production, migration, and organization of these cells are determined by vast array of extrinsic and intrinsic factors that work in concert in order to assemble a proper functioning cortical inhibitory network. Failure of these cells to undergo these processes results in abnormal positioning and cortical function. In humans, this can bring about several neurological disorders including schizophrenia, epilepsy, and autism spectrum disorders. In this article, we will review previous literature that has revealed the framework for interneuron neurogenesis and migratory behavior as well as discuss recent findings that aim to elucidate the spatial and functional organization of interneurons within the neocortex. PMID:24312011

  9. Subtype-selective electroporation of cortical interneurons

    PubMed Central

    De Marco Garcia, Natalia V.; Fishell, Gord

    2014-01-01

    The study of central nervous system (CNS) maturation relies on genetic targeting of neuronal populations. However, the task of restricting the expression of genes of interest to specific neuronal subtypes has proven remarkably challenging due to the relative scarcity of specific promoter elements. GABAergic interneurons constitute a neuronal population with extensive genetic and morphological diversity. Indeed, more than 11 different subtypes of GABAergic interneurons have been characterized in the mouse cortex1. Here we present an adapted protocol for selective targeting of GABAergic populations. We achieved subtype-selective targeting of GABAergic interneurons by using the enhancer element of the homeobox transcription factors Dlx5 and Dlx6, homologues of the Drosophila distal-less (Dll) gene2,3, to drive the expression of specific genes through in utero electroporation. PMID:25177832

  10. Interneuron Progenitor Transplantation to Treat CNS Dysfunction

    PubMed Central

    Chohan, Muhammad O.; Moore, Holly

    2016-01-01

    Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field. PMID:27582692

  11. Firing regulation of fast-spiking interneurons by autaptic inhibition

    NASA Astrophysics Data System (ADS)

    Guo, Daqing; Chen, Mingming; Perc, Matjaž; Wu, Shengdun; Xia, Chuan; Zhang, Yangsong; Xu, Peng; Xia, Yang; Yao, Dezhong

    2016-05-01

    Fast-spiking (FS) interneurons in the brain are self-innervated by powerful inhibitory GABAergic autaptic connections. By computational modelling, we investigate how autaptic inhibition regulates the firing response of such interneurons. Our results indicate that autaptic inhibition both boosts the current threshold for action potential generation and modulates the input-output gain of FS interneurons. The autaptic transmission delay is identified as a key parameter that controls the firing patterns and determines multistability regions of FS interneurons. Furthermore, we observe that neuronal noise influences the firing regulation of FS interneurons by autaptic inhibition and extends their dynamic range for encoding inputs. Importantly, autaptic inhibition modulates noise-induced irregular firing of FS interneurons, such that coherent firing appears at an optimal autaptic inhibition level. Our results reveal the functional roles of autaptic inhibition in taming the firing dynamics of FS interneurons.

  12. Multifunctional and specialized spinal interneurons for turtle limb movements.

    PubMed

    Berkowitz, Ari

    2010-06-01

    The turtle spinal cord can help reveal how vertebrate central nervous system (CNS) circuits select and generate an appropriate limb movement in each circumstance. Both multifunctional and specialized spinal interneurons contribute to the motor patterns for the three forms of scratching, forward swimming, and flexion reflex. Multifunctional interneurons, activated during all of these motor patterns, can have axon terminal arborizations in the ventral horn, where they likely contribute to limb motor output. Specialized interneurons can be specialized for a behavior, as opposed to a phase or motor synergy. Interneurons specialized for scratching can be hyperpolarized throughout swimming. Interneurons specialized for flexion reflex can be hyperpolarized throughout scratching and swimming. Some structure-function correlations have been revealed: flexion reflex-selective interneurons had somata exclusively in the dorsal horn, in contrast to scratch-activated interneurons. Transverse interneurons, defined by quantitative morphological criteria, had higher peak firing rates, narrower action potentials, briefer afterhyperpolarizations, and larger membrane potential oscillations than scratch-activated interneurons with different dendritic morphologies. Future investigations will focus on how multifunctional and specialized spinal interneurons interact to generate each motor output. PMID:20536926

  13. Inhibitory interneurons in visual cortical plasticity.

    PubMed

    van Versendaal, Daniëlle; Levelt, Christiaan N

    2016-10-01

    For proper maturation of the neocortex and acquisition of specific functions and skills, exposure to sensory stimuli is vital during critical periods of development when synaptic connectivity is highly malleable. To preserve reliable cortical processing, it is essential that these critical periods end after which learning becomes more conditional and active interaction with the environment becomes more important. How these age-dependent forms of plasticity are regulated has been studied extensively in the primary visual cortex. This has revealed that inhibitory innervation plays a crucial role and that a temporary decrease in inhibition is essential for plasticity to take place. Here, we discuss how different interneuron subsets regulate plasticity during different stages of cortical maturation. We propose a theory in which different interneuron subsets select the sources of neuronal input that undergo plasticity. PMID:27193323

  14. THE DISTINCT TEMPORAL ORIGINS OF OLFACTORY BULB INTERNEURON SUBTYPES

    PubMed Central

    Batista-Brito, Renata; Close, Jennie; Machold, Robert; Ekker, Mark; Fishell, Gord

    2008-01-01

    Olfactory bulb (OB) interneurons are a heterogeneous population produced beginning in embryogenesis and continuing through adulthood. Understanding how this diversity arises will provide insight into how olfactory bulb microcircuitry is established as well as adult neurogenesis. Specific spatial domains have been shown to contribute specific interneuron subtypes. However, the temporal profile by which OB interneuron subtypes are produced is unknown. Using inducible genetic fate mapping of Dlx1/2 precursors, we analyzed the production of seven OB interneuron subtypes and find that the generation of each subpopulation has a unique temporal signature. Within the glomerular layer, while the production of TH-positive interneurons is maximal during early embryogenesis, it decreases thereafter. By contrast, the generation of CB interneurons is maximal during late embryogenesis and declines postnatally, while CR cell production is low during embryogenesis and increases postnatally. PV interneurons within the external plexiform layer are produced only perinatally, while the generation of 5T4-positive granule cells in the mitral cell layer does not change significantly over time. CR-positive granule cells are not produced at early embryonic timepoints, but constitute a large percentage of the granule cells born after birth. Blanes cells by contrast are produced in greatest number during embryogenesis. Taken together we provide the first comprehensive analysis of the temporal generation of olfactory bulb interneuron subtypes and demonstrate that the timing by which these populations are produced is tightly orchestrated. PMID:18400896

  15. Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties

    PubMed Central

    Casale, Amanda E.; Foust, Amanda J.; Bal, Thierry

    2015-01-01

    The role of interneurons in cortical microcircuits is strongly influenced by their passive and active electrical properties. Although different types of interneurons exhibit unique electrophysiological properties recorded at the soma, it is not yet clear whether these differences are also manifested in other neuronal compartments. To address this question, we have used voltage-sensitive dye to image the propagation of action potentials into the fine collaterals of axons and dendrites in two of the largest cortical interneuron subtypes in the mouse: fast-spiking interneurons, which are typically basket or chandelier neurons; and somatostatin containing interneurons, which are typically regular spiking Martinotti cells. We found that fast-spiking and somatostatin-expressing interneurons differed in their electrophysiological characteristics along their entire dendrosomatoaxonal extent. The action potentials generated in the somata and axons, including axon collaterals, of somatostatin-expressing interneurons are significantly broader than those generated in the same compartments of fast-spiking inhibitory interneurons. In addition, action potentials back-propagated into the dendrites of somatostatin-expressing interneurons much more readily than fast-spiking interneurons. Pharmacological investigations suggested that axonal action potential repolarization in both cell types depends critically upon Kv1 channels, whereas the axonal and somatic action potentials of somatostatin-expressing interneurons also depend on BK Ca2+-activated K+ channels. These results indicate that the two broad classes of interneurons studied here have expressly different subcellular physiological properties, allowing them to perform unique computational roles in cortical circuit operations. SIGNIFICANCE STATEMENT Neurons in the cerebral cortex are of two major types: excitatory and inhibitory. The proper balance of excitation and inhibition in the brain is critical for its operation. Neurons

  16. Wide Dispersion and Diversity of Clonally Related Inhibitory Interneurons

    PubMed Central

    Harwell, Corey C.; Fuentealba, Luis C.; Gonzalez-Cerrillo, Adrian; Parker, Phillip R.L.; Gertz, Caitlyn C.; Mazzola, Emanuele; Turrero Garcia, Miguel; Alvarez-Buylla, Arturo; Cepko, Constance L.; Kriegstein, Arnold

    2015-01-01

    The mammalian neocortex is composed of two major neuronal cell types with distinct origins: excitatory pyramidal neurons and inhibitory interneurons, generated in dorsal and ventral progenitor zones of the embryonic telencephalon respectively. Thus, inhibitory neurons migrate relatively long distances to reach their destination in the developing forebrain. The role of lineage in the organization and circuitry of interneurons is still not well understood. Utilizing a combination of genetics, retroviral fate mapping and lineage-specific retroviral barcode labeling, we find that clonally related interneurons can be widely dispersed while unrelated interneurons can be closely clustered. These data suggest that migratory mechanisms related to the clustering of interneurons occur largely independent of their clonal origin. PMID:26299474

  17. Wide Dispersion and Diversity of Clonally Related Inhibitory Interneurons.

    PubMed

    Harwell, Corey C; Fuentealba, Luis C; Gonzalez-Cerrillo, Adrian; Parker, Phillip R L; Gertz, Caitlyn C; Mazzola, Emanuele; Garcia, Miguel Turrero; Alvarez-Buylla, Arturo; Cepko, Constance L; Kriegstein, Arnold R

    2015-09-01

    The mammalian neocortex is composed of two major neuronal cell types with distinct origins: excitatory pyramidal neurons and inhibitory interneurons, generated in dorsal and ventral progenitor zones of the embryonic telencephalon, respectively. Thus, inhibitory neurons migrate relatively long distances to reach their destination in the developing forebrain. The role of lineage in the organization and circuitry of interneurons is still not well understood. Utilizing a combination of genetics, retroviral fate mapping, and lineage-specific retroviral barcode labeling, we find that clonally related interneurons can be widely dispersed while unrelated interneurons can be closely clustered. These data suggest that migratory mechanisms related to the clustering of interneurons occur largely independent of their clonal origin. PMID:26299474

  18. The Stochastic Search Dynamics of Interneuron Migration

    PubMed Central

    Britto, Joanne M.; Johnston, Leigh A.; Tan, Seong-Seng

    2009-01-01

    Abstract Migration is a dynamic process in which a cell searches the environment and translates acquired information into somal advancement. In particular, interneuron migration during development is accomplished by two distinct processes: the extension of neurites tipped with growth cones; and nucleus translocation, termed nucleokinesis. The primary purpose of our study is to investigate neurite branching and nucleokinesis using high-resolution time-lapse confocal microscopy and computational modeling. We demonstrate that nucleokinesis is accurately modeled by a spring-dashpot system and that neurite branching is independent of the nucleokinesis event, and displays the dynamics of a stochastic birth-death process. This is in contrast to traditional biological descriptions, which suggest a closer relationship between the two migratory mechanisms. Our models are validated on independent data sets acquired using two different imaging protocols, and are shown to be robust to alterations in guidance cues and cellular migratory mechanisms, through treatment with brain-derived neurotrophic factor, neurotrophin-4, and blebbistatin. We postulate that the stochastic branch dynamics exhibited by interneurons undergoing guidance-directed migration permit efficient exploration of the environment. PMID:19651028

  19. The organization of two novel cortical interneuronal circuits

    PubMed Central

    Jiang, Xiaolong; Wang, Guangfu; Lee, Alice J.; Stornetta, Ruth L.; Zhu, J. Julius

    2013-01-01

    Deciphering interneuronal circuitry is central to understanding brain functions yet remains as a challenging task in neurobiology. Using simultaneous quadruple-octuple in vitro and dual in vivo whole-cell recordings, we found two previously unknown interneuronal circuits that link cortical layer 1–3 (L1-3) interneurons and L5 pyramidal neurons in the rat neocortex. L1 single-bouquet cells (SBCs) preferentially form unidirectional inhibitory connections on L2/3 interneurons that inhibit the entire dendritic-somato-axonal axis of ~1% of L5 pyramidal neurons located within the same column. In contrast, L1 elongated neurogliaform cells (ENGCs) frequently form mutual inhibitory and electric connections with L2/3 interneurons, and these L1-3 interneurons inhibit the distal apical dendrite of >60% of L5 pyramidal neurons across multiple columns. Functionally, SBC→L2/3 interneuron→L5 pyramidal neuronal circuits disinhibit and ENGC↔L2/3 interneuron→L5 pyramidal neuronal circuits inhibit the initiation of dendritic complex spikes in L5 pyramidal neurons. As dendritic complex spikes can serve coincidence detection, these cortical interneuronal circuits may be essential for salience selection. PMID:23313910

  20. Genetics and Function of Neocortical GABAergic Interneurons in Neurodevelopmental Disorders

    PubMed Central

    Rossignol, E.

    2011-01-01

    A dysfunction of cortical and limbic GABAergic circuits has been postulated to contribute to multiple neurodevelopmental disorders in humans, including schizophrenia, autism, and epilepsy. In the current paper, I summarize the characteristics that underlie the great diversity of cortical GABAergic interneurons and explore how the multiple roles of these cells in developing and mature circuits might contribute to the aforementioned disorders. Furthermore, I review the tightly controlled genetic cascades that determine the fate of cortical interneurons and summarize how the dysfunction of genes important for the generation, specification, maturation, and function of cortical interneurons might contribute to these disorders. PMID:21876820

  1. Interneurons from Embryonic Development to Cell-Based Therapy

    PubMed Central

    Southwell, Derek G.; Nicholas, Cory R.; Basbaum, Allan I.; Stryker, Michael P.; Kriegstein, Arnold R.; Rubenstein, John L.; Alvarez-Buylla, Arturo

    2014-01-01

    Many neurologic and psychiatric disorders are marked by imbalances between neural excitation and inhibition. In the cerebral cortex, inhibition is mediated largely by GABAergic (γ-aminobutyric acid–secreting) interneurons, a cell type that originates in the embryonic ventral telencephalon and populates the cortex through long-distance tangential migration. Remarkably, when transplanted from embryos or in vitro culture preparations, immature interneurons disperse and integrate into host brain circuits, both in the cerebral cortex and in other regions of the central nervous system. These features make interneuron transplantation a powerful tool for the study of neurodevelopmental processes such as cell specification, cell death, and cortical plasticity. Moreover, interneuron transplantation provides a novel strategy for modifying neural circuits in rodent models of epilepsy, Parkinson’s disease, mood disorders, and chronic pain. PMID:24723614

  2. Apical versus Basal Neurogenesis Directs Cortical Interneuron Subclass Fate.

    PubMed

    Petros, Timothy J; Bultje, Ronald S; Ross, M Elizabeth; Fishell, Gord; Anderson, Stewart A

    2015-11-10

    Fate determination in the mammalian telencephalon, with its diversity of neuronal subtypes and relevance to neuropsychiatric disease, remains a critical area of study in neuroscience. Most studies investigating this topic focus on the diversity of neural progenitors within spatial and temporal domains along the lateral ventricles. Often overlooked is whether the location of neurogenesis within a fate-restricted domain is associated with, or instructive for, distinct neuronal fates. Here, we use in vivo fate mapping and the manipulation of neurogenic location to demonstrate that apical versus basal neurogenesis influences the fate determination of major subgroups of cortical interneurons derived from the subcortical telencephalon. Somatostatin-expressing interneurons arise mainly from apical divisions along the ventricular surface, whereas parvalbumin-expressing interneurons originate predominantly from basal divisions in the subventricular zone. As manipulations that shift neurogenic location alter interneuron subclass fate, these results add an additional dimension to the spatial-temporal determinants of neuronal fate determination. PMID:26526999

  3. Striatal cholinergic interneurons drive GABA release from dopamine terminals

    PubMed Central

    Nelson, Alexandra B.; Hammack, Nora; Yang, Cindy F.; Shah, Nirao M.; Seal, Rebecca P.; Kreitzer, Anatol C.

    2014-01-01

    Summary Striatal cholinergic interneurons are implicated in motor control, associative plasticity, and reward-dependent learning. Synchronous activation of cholinergic interneurons triggers large inhibitory synaptic currents in dorsal striatal projection neurons, providing one potential substrate for control of striatal output, but the mechanism for these GABAergic currents is not fully understood. Using optogenetics and whole-cell recordings in brain slices, we find that a large component of these inhibitory responses derive from action-potential-independent disynaptic neurotransmission mediated by nicotinic receptors. Cholinergically-driven IPSCs were not affected by ablation of striatal fast-spiking interneurons, but were greatly reduced after acute treatment with vesicular monoamine transport inhibitors or selective destruction of dopamine terminals with 6-hydroxydopamine, indicating that GABA release originated from dopamine terminals. These results delineate a mechanism in which striatal cholinergic interneurons can co-opt dopamine terminals to drive GABA release and rapidly inhibit striatal output neurons. PMID:24613418

  4. Tasks for inhibitory interneurons in intact brain circuits

    PubMed Central

    Roux, Lisa; Buzsáki, György

    2014-01-01

    Synaptic inhibition, brought about by a rich variety of interneuron types that target different domains of principal cells and other interneurons, counters excitation, modulates the gain, timing, tuning, bursting properties of principal cell firing, and exerts selective filtering of synaptic excitation. At the network level, it allows for coordinating transient interactions among the principal cells to form cooperative assemblies for efficient transmission of information and routing of excitatory activity across networks, typically in the form of brain oscillations. Targeted expression of neuronal activity modulators, such as optogenetics, allow physiological identification and perturbation of specific interneuron subtypes. Combined with large-scale recordings or imaging techniques, these approaches facilitate our understanding of the multiple roles of inhibitory interneurons in shaping circuit functions. PMID:25239808

  5. A dynamic zone defines interneuron remodeling in the adult neocortex

    PubMed Central

    Lee, Wei-Chung Allen; Chen, Jerry L.; Huang, Hayden; Leslie, Jennifer H.; Amitai, Yael; So, Peter T.; Nedivi, Elly

    2008-01-01

    The contribution of structural remodeling to long-term adult brain plasticity is unclear. Here, we investigate features of GABAergic interneuron dendrite dynamics and extract clues regarding its potential role in cortical function and circuit plasticity. We show that remodeling interneurons are contained within a “dynamic zone” corresponding to a superficial strip of layers 2/3, and remodeling dendrites respect the lower border of this zone. Remodeling occurs primarily at the periphery of dendritic fields with addition and retraction of new branch tips. We further show that dendrite remodeling is not intrinsic to a specific interneuron class. These data suggest that interneuron remodeling is not a feature predetermined by genetic lineage, but rather, it is imposed by cortical laminar circuitry. Our findings are consistent with dynamic GABAergic modulation of feedforward and recurrent connections in response to top-down feedback and suggest a structural component to functional plasticity of supragranular neocortical laminae. PMID:19066223

  6. Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders.

    PubMed

    Zhang, Wen; Zhang, Lifeng; Liang, Bo; Schroeder, David; Zhang, Zhong-Wei; Cox, Gregory A; Li, Yun; Lin, Da-Ting

    2016-04-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative disorders whose pathogenesis remains largely unknown. Using TDP-43(A315T) mice, an ALS and FTD model with marked cortical pathology, we found that hyperactive somatostatin interneurons disinhibited layer 5 pyramidal neurons (L5-PNs) and contributed to their excitotoxicity. Focal ablation of somatostatin interneurons efficiently restored normal excitability of L5-PNs and alleviated neurodegeneration, suggesting a new therapeutic target for ALS and FTD. PMID:26900927

  7. Early Somatostatin Interneuron Connectivity Mediates the Maturation of Deep Layer Cortical Circuits.

    PubMed

    Tuncdemir, Sebnem N; Wamsley, Brie; Stam, Floor J; Osakada, Fumitaka; Goulding, Martyn; Callaway, Edward M; Rudy, Bernardo; Fishell, Gord

    2016-02-01

    The precise connectivity of somatostatin and parvalbumin cortical interneurons is generated during development. An understanding of how these interneuron classes incorporate into cortical circuitry is incomplete but essential to elucidate the roles they play during maturation. Here, we report that somatostatin interneurons in infragranular layers receive dense but transient innervation from thalamocortical afferents during the first postnatal week. During this period, parvalbumin interneurons and pyramidal neurons within the same layers receive weaker thalamocortical inputs, yet are strongly innervated by somatostatin interneurons. Further, upon disruption of the early (but not late) somatostatin interneuron network, the synaptic maturation of thalamocortical inputs onto parvalbumin interneurons is perturbed. These results suggest that infragranular somatostatin interneurons exhibit a transient early synaptic connectivity that is essential for the establishment of thalamic feedforward inhibition mediated by parvalbumin interneurons. PMID:26844832

  8. An interneuron progenitor maintains neurogenic potential in vivo and differentiates into GABAergic interneurons after transplantation in the postnatal rat brain.

    PubMed

    Wang, Qi; Hong, Peiwei; Gao, Hui; Chen, Yuntian; Yang, Qi; Jiang, Mei; Li, Hedong

    2016-01-01

    Dysfunction of cortical GABAergic interneurons are involved in numerous neurological disorders including epilepsy, schizophrenia and autism; and replenishment of these cells by transplantation strategy has proven to be a feasible and effective method to help revert the symptoms in several animal models. To develop methodology of generating transplantable GABAergic interneurons for therapy, we previously reported the isolation of a v-myc-induced GABAergic interneuron progenitor clone GE6 from embryonic ganglionic eminence (GE). These cells can proliferate and form functional inhibitory synapses in culture. Here, we tested their differentiation behavior in vivo by transplanting them into the postnatal rat forebrain. We found that GE6 cells migrate extensively in the neonatal forebrain and differentiate into both neurons and glia, but preferentially into neurons when compared with a sister progenitor clone CTX8. The neurogenic potential of GE6 cells is also maintained after transplantation into a non-permissive environment such as adult cortex or when treated with inflammatory cytokine in culture. The GE6-derived neurons were able to mature in vivo as GABAergic interneurons expressing GABAergic, not glutamatergic, presynaptic puncta. Finally, we propose that v-myc-induced human interneuron progenitor clones could be an alternative cell source of transplantable GABAergic interneurons for treating related neurological diseases in future clinic. PMID:26750620

  9. Classification of neocortical interneurons using affinity propagation

    PubMed Central

    Santana, Roberto; McGarry, Laura M.; Bielza, Concha; Larrañaga, Pedro; Yuste, Rafael

    2013-01-01

    In spite of over a century of research on cortical circuits, it is still unknown how many classes of cortical neurons exist. In fact, neuronal classification is a difficult problem because it is unclear how to designate a neuronal cell class and what are the best characteristics to define them. Recently, unsupervised classifications using cluster analysis based on morphological, physiological, or molecular characteristics, have provided quantitative and unbiased identification of distinct neuronal subtypes, when applied to selected datasets. However, better and more robust classification methods are needed for increasingly complex and larger datasets. Here, we explored the use of affinity propagation, a recently developed unsupervised classification algorithm imported from machine learning, which gives a representative example or exemplar for each cluster. As a case study, we applied affinity propagation to a test dataset of 337 interneurons belonging to four subtypes, previously identified based on morphological and physiological characteristics. We found that affinity propagation correctly classified most of the neurons in a blind, non-supervised manner. Affinity propagation outperformed Ward's method, a current standard clustering approach, in classifying the neurons into 4 subtypes. Affinity propagation could therefore be used in future studies to validly classify neurons, as a first step to help reverse engineer neural circuits. PMID:24348339

  10. Classification of neocortical interneurons using affinity propagation.

    PubMed

    Santana, Roberto; McGarry, Laura M; Bielza, Concha; Larrañaga, Pedro; Yuste, Rafael

    2013-01-01

    In spite of over a century of research on cortical circuits, it is still unknown how many classes of cortical neurons exist. In fact, neuronal classification is a difficult problem because it is unclear how to designate a neuronal cell class and what are the best characteristics to define them. Recently, unsupervised classifications using cluster analysis based on morphological, physiological, or molecular characteristics, have provided quantitative and unbiased identification of distinct neuronal subtypes, when applied to selected datasets. However, better and more robust classification methods are needed for increasingly complex and larger datasets. Here, we explored the use of affinity propagation, a recently developed unsupervised classification algorithm imported from machine learning, which gives a representative example or exemplar for each cluster. As a case study, we applied affinity propagation to a test dataset of 337 interneurons belonging to four subtypes, previously identified based on morphological and physiological characteristics. We found that affinity propagation correctly classified most of the neurons in a blind, non-supervised manner. Affinity propagation outperformed Ward's method, a current standard clustering approach, in classifying the neurons into 4 subtypes. Affinity propagation could therefore be used in future studies to validly classify neurons, as a first step to help reverse engineer neural circuits. PMID:24348339

  11. Striatal cholinergic interneuron regulation and circuit effects

    PubMed Central

    Lim, Sean Austin O.; Kang, Un Jung; McGehee, Daniel S.

    2014-01-01

    The striatum plays a central role in motor control and motor learning. Appropriate responses to environmental stimuli, including pursuit of reward or avoidance of aversive experience all require functional striatal circuits. These pathways integrate synaptic inputs from limbic and cortical regions including sensory, motor and motivational information to ultimately connect intention to action. Although many neurotransmitters participate in striatal circuitry, one critically important player is acetylcholine (ACh). Relative to other brain areas, the striatum contains exceptionally high levels of ACh, the enzymes that catalyze its synthesis and breakdown, as well as both nicotinic and muscarinic receptor types that mediate its postsynaptic effects. The principal source of striatal ACh is the cholinergic interneuron (ChI), which comprises only about 1–2% of all striatal cells yet sends dense arbors of projections throughout the striatum. This review summarizes recent advances in our understanding of the factors affecting the excitability of these neurons through acute effects and long term changes in their synaptic inputs. In addition, we discuss the physiological effects of ACh in the striatum, and how changes in ACh levels may contribute to disease states during striatal dysfunction. PMID:25374536

  12. The interneuron energy hypothesis: Implications for brain disease.

    PubMed

    Kann, Oliver

    2016-06-01

    Fast-spiking, inhibitory interneurons - prototype is the parvalbumin-positive (PV+) basket cell - generate action potentials at high frequency and synchronize the activity of numerous excitatory principal neurons, such as pyramidal cells, during fast network oscillations by rhythmic inhibition. For this purpose, fast-spiking, PV+ interneurons have unique electrophysiological characteristics regarding action potential kinetics and ion conductances, which are associated with high energy expenditure. This is reflected in the neural ultrastructure by enrichment with mitochondria and cytochrome c oxidase, indicating the dependence on oxidative phosphorylation for adenosine-5'-triphosphate (ATP) generation. The high energy expenditure is most likely required for membrane ion transport in dendrites and the extensive axon arbor as well as for presynaptic release of neurotransmitter, gamma-aminobutyric acid (GABA). Fast-spiking, PV+ interneurons are central for the emergence of gamma oscillations (30-100Hz) that provide a fundamental mechanism of complex information processing during sensory perception, motor behavior and memory formation in networks of the hippocampus and the neocortex. Conversely, shortage in glucose and oxygen supply (metabolic stress) and/or excessive formation of reactive oxygen and nitrogen species (oxidative stress) may render these interneurons to be a vulnerable target. Dysfunction in fast-spiking, PV+ interneurons might set a low threshold for impairment of fast network oscillations and thus higher brain functions. This pathophysiological mechanism might be highly relevant for cerebral aging as well as various acute and chronic brain diseases, such as stroke, vascular cognitive impairment, epilepsy, Alzheimer's disease and schizophrenia. PMID:26284893

  13. Serotonin Attenuates Feedback Excitation onto O-LM Interneurons

    PubMed Central

    Böhm, Claudia; Pangalos, Maria; Schmitz, Dietmar; Winterer, Jochen

    2015-01-01

    The serotonergic system is a subcortical neuromodulatory center that controls cortical information processing in a state-dependent manner. In the hippocampus, serotonin (5-HT) is released by ascending serotonergic fibers from the midbrain raphe nuclei, thereby mediating numerous modulatory functions on various neuronal subtypes. Here, we focus on the neuromodulatory effects of 5-HT on GABAergic inhibitory oriens lacunosum-moleculare (O-LM) cells in the hippocampal area CA1 of the rat. These interneurons are thought to receive primarily local excitatory input and are, via their axonal projections to stratum lacunosum-moleculare, ideally suited to control entorhinal cortex input. We show that 5-HT reduces excitatory glutamatergic transmission onto O-LM interneurons. By means of paired recordings from synaptically connected CA1 pyramidal cells and O-LM interneurons we reveal that this synapse is modulated by 5-HT. Furthermore, we demonstrate that the reduction of glutamatergic transmission by serotonin is likely to be mediated via a decrease of calcium influx into presynaptic terminals of CA1 pyramidal cells. This modulation of excitatory synaptic transmission onto O-LM interneurons by 5-HT might be a mechanism to vary the activation of O-LM interneurons during ongoing network activity and serve as a brain state-dependent switch gating the efficiency of entorhinal cortex input to CA1 pyramidal neurons. PMID:26021702

  14. Behavior-dependent specialization of identified hippocampal interneurons

    PubMed Central

    Lapray, Damien; Lasztoczi, Balint; Lagler, Michael; Viney, Tim James; Katona, Linda; Valenti, Ornella; Hartwich, Katja; Borhegyi, Zsolt; Somogyi, Peter; Klausberger, Thomas

    2012-01-01

    A large variety of GABAergic interneurons control information processing in hippocampal circuits governing the formation of neuronal representations. Whether distinct hippocampal interneuron types contribute differentially to information-processing during behavior is not known. We employed a novel technique for recording and labeling interneurons and pyramidal cells in drug-free, freely-moving rats. Recorded parvalbumin-expressing basket interneurons innervate somata and proximal pyramidal cell dendrites, whereas nitric-oxide-synthase- and neuropeptide-Y-expressing ivy cells provide synaptic and extrasynaptic dendritic modulation. Basket and ivy cells showed distinct spike timing dynamics, firing at different rates and times during theta and ripple oscillations. Basket but not ivy cells changed their firing rates during movement, sleep and quiet wakefulness, suggesting that basket cells coordinate cell assemblies in a behavioral state-contingent manner, whereas persistently-firing ivy cells might control network excitability and homeostasis. Different interneuron types provide GABA to specific subcellular domains at defined times and rates, thus differentially controlling network activity during behavior. PMID:22864613

  15. Electrical coupling regulates layer 1 interneuron microcircuit formation in the neocortex.

    PubMed

    Yao, Xing-Hua; Wang, Min; He, Xiang-Nan; He, Fei; Zhang, Shu-Qing; Lu, Wenlian; Qiu, Zi-Long; Yu, Yong-Chun

    2016-01-01

    The coexistence of electrical and chemical synapses among interneurons is essential for interneuron function in the neocortex. However, it remains largely unclear whether electrical coupling between interneurons influences chemical synapse formation and microcircuit assembly during development. Here, we show that electrical and GABAergic chemical connections robustly develop between interneurons in neocortical layer 1 over a similar time course. Electrical coupling promotes action potential generation and synchronous firing between layer 1 interneurons. Furthermore, electrically coupled interneurons exhibit strong GABA-A receptor-mediated synchronous synaptic activity. Disruption of electrical coupling leads to a loss of bidirectional, but not unidirectional, GABAergic connections. Moreover, a reduction in electrical coupling induces an increase in excitatory synaptic inputs to layer 1 interneurons. Together, these findings strongly suggest that electrical coupling between neocortical interneurons plays a critical role in regulating chemical synapse development and precise formation of circuits. PMID:27510304

  16. Optogenetic mapping of cerebellar inhibitory circuitry reveals spatially biased coordination of interneurons via electrical synapses.

    PubMed

    Kim, Jinsook; Lee, Soojung; Tsuda, Sachiko; Zhang, Xuying; Asrican, Brent; Gloss, Bernd; Feng, Guoping; Augustine, George J

    2014-06-12

    We used high-speed optogenetic mapping technology to examine the spatial organization of local inhibitory circuits formed by cerebellar interneurons. Transgenic mice expressing channelrhodopsin-2 exclusively in molecular layer interneurons allowed us to focally photostimulate these neurons, while measuring resulting responses in postsynaptic Purkinje cells. This approach revealed that interneurons converge upon Purkinje cells over a broad area and that at least seven interneurons form functional synapses with a single Purkinje cell. The number of converging interneurons was reduced by treatment with gap junction blockers, revealing that electrical synapses between interneurons contribute substantially to the spatial convergence. Remarkably, gap junction blockers affected convergence in sagittal slices, but not in coronal slices, indicating a sagittal bias in electrical coupling between interneurons. We conclude that electrical synapse networks spatially coordinate interneurons in the cerebellum and may also serve this function in other brain regions. PMID:24857665

  17. Electrical coupling regulates layer 1 interneuron microcircuit formation in the neocortex

    PubMed Central

    Yao, Xing-Hua; Wang, Min; He, Xiang-Nan; He, Fei; Zhang, Shu-Qing; Lu, Wenlian; Qiu, Zi-Long; Yu, Yong-Chun

    2016-01-01

    The coexistence of electrical and chemical synapses among interneurons is essential for interneuron function in the neocortex. However, it remains largely unclear whether electrical coupling between interneurons influences chemical synapse formation and microcircuit assembly during development. Here, we show that electrical and GABAergic chemical connections robustly develop between interneurons in neocortical layer 1 over a similar time course. Electrical coupling promotes action potential generation and synchronous firing between layer 1 interneurons. Furthermore, electrically coupled interneurons exhibit strong GABA-A receptor-mediated synchronous synaptic activity. Disruption of electrical coupling leads to a loss of bidirectional, but not unidirectional, GABAergic connections. Moreover, a reduction in electrical coupling induces an increase in excitatory synaptic inputs to layer 1 interneurons. Together, these findings strongly suggest that electrical coupling between neocortical interneurons plays a critical role in regulating chemical synapse development and precise formation of circuits. PMID:27510304

  18. Striatal cholinergic interneurons: birthdates predict compartmental localization.

    PubMed

    van Vulpen, E H; van der Kooy, D

    1998-07-01

    The striatal patch and matrix compartment neurons are born at different times during rat development. The majority of the early born neurons preferentially end up in the patch compartment, while the majority of the later born neurons end up in the matrix compartment. Although the cholinergic interneurons are all born early in neurogenesis (between embryonic day E12 and E17), and we would therefore expect them to be located mainly in the patches, they are relatively homogeneously distributed in the adult, with a preference for the matrix area just outside the patches (the intermediate zone). To ask if birthdate can predict the compartmental localization of cholinergic neurons in the striatum, we marked new postmitotic neurons in the embryo with a maternal injection of bromodeoxyuridine (BrdU) on E13, E15 or E17 and labeled the patch compartment with an injection of the retrograde tracer True Blue into the substantia nigra on postnatal day (P) 1. The pups were sacrificed at P40 and the tissue was processed for BrdU, choline acetyltransferase, and True Blue triple labeling. Cholinergic neurons that became postmitotic at E13, had a higher chance of ending up in the patch compartment compared to either the intermediate zone or the rest of the matrix compartment. On the other hand cholinergic neurons that became postmitotic at E17 had a higher chance of ending up in the matrix compartment (including the intermediate zone). We conclude that birthdate can predict compartmental localization, with the cholinergic neurons in the intermediate zone following the same pattern as the cholinergic neurons in the rest of the matrix compartment. Cholinergic neurons show the same relative birthdate/compartment relationship as do other striatal neurons, although the absolute birthdates of cholinergic neurons are shifted earlier in neurogenesis. PMID:9706390

  19. Pyramidal Cell-Interneuron Interactions Underlie Hippocampal Ripple Oscillations

    PubMed Central

    Stark, Eran; Roux, Lisa; Eichler, Ronny; Senzai, Yuta; Royer, Sebastien; Buzsáki, György

    2015-01-01

    SUMMARY High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation, frequency control, and spatial coherence of the rhythm are poorly understood. Using multisite optogenetic manipulations in freely behaving rodents, we found that depolarization of a small group of nearby pyramidal cells was sufficient to induce high-frequency oscillations, whereas closed-loop silencing of pyramidal cells or activation of parvalbumin-(PV) or somatostatin-immunoreactive interneurons aborted spontaneously occurring ripples. Focal pharmacological blockade of GABAA receptors abolished ripples. Localized PV inter-neuron activation paced ensemble spiking, and simultaneous induction of high-frequency oscillations at multiple locations resulted in a temporally coherent pattern mediated by phase-locked inter-neuron spiking. These results constrain competing models of ripple generation and indicate that temporally precise local interactions between excitatory and inhibitory neurons support ripple generation in the intact hippocampus. PMID:25033186

  20. GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits.

    PubMed

    Tremblay, Robin; Lee, Soohyun; Rudy, Bernardo

    2016-07-20

    Cortical networks are composed of glutamatergic excitatory projection neurons and local GABAergic inhibitory interneurons that gate signal flow and sculpt network dynamics. Although they represent a minority of the total neocortical neuronal population, GABAergic interneurons are highly heterogeneous, forming functional classes based on their morphological, electrophysiological, and molecular features, as well as connectivity and in vivo patterns of activity. Here we review our current understanding of neocortical interneuron diversity and the properties that distinguish cell types. We then discuss how the involvement of multiple cell types, each with a specific set of cellular properties, plays a crucial role in diversifying and increasing the computational power of a relatively small number of simple circuit motifs forming cortical networks. We illustrate how recent advances in the field have shed light onto the mechanisms by which GABAergic inhibition contributes to network operations. PMID:27477017

  1. Neuregulin 1 promotes excitatory synapse development specifically in GABAergic interneurons

    PubMed Central

    Ting, Annie K.; Chen, Yongjun; Wen, Lei; Yin, Dong-Min; Shen, Chengyong; Tao, Yanmei; Liu, Xihui; Xiong, Wen-Cheng; Mei, Lin

    2011-01-01

    Neuregulin 1 (NRG1) and its receptor ErbB4 are both susceptibility genes of schizophrenia. However, little is known about the underlying mechanisms of their malfunction. Although ErbB4 is enriched in GABAergic interneurons, the role of NRG1 in excitatory synapse formation in these neurons remains poorly understood. We showed that NRG1 increased both the number and size of PSD-95 puncta and the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in GABAergic interneurons, indicating that NRG1 stimulates the formation of new synapses and strengthens existing synapses. In contrast, NRG1 treatment had no effect on either the number or size of excitatory synapses in glutamatergic neurons, suggesting its synaptogenic effect is specific to GABAergic interneurons. Ecto-ErbB4 treatment diminished both the number and size of excitatory synapses, suggesting that endogenous NRG1 may be critical for basal synapse formation. NRG1 could stimulate the stability of PSD-95 in the manner that requires tyrosine kinase activity of ErbB4. Finally, deletion of ErbB4 in parvalbumin-positive interneurons led to reduced frequency and amplitude of mEPSCs, providing in vivo evidence that ErbB4 is important in excitatory synaptogenesis in interneurons. Taken together, our findings suggested a novel synaptogenic role of NRG1 in excitatory synapse development, possibly via stabilizing PSD-95, and this effect is specific to GABAergic interneurons. In light of the association of the genes of both NRG1 and ErbB4 with schizophrenia and dysfunction of GABAergic system in this disorder, these results provide insight into its potential pathological mechanism. PMID:21209185

  2. Bayesian network classifiers for categorizing cortical GABAergic interneurons.

    PubMed

    Mihaljević, Bojan; Benavides-Piccione, Ruth; Bielza, Concha; DeFelipe, Javier; Larrañaga, Pedro

    2015-04-01

    An accepted classification of GABAergic interneurons of the cerebral cortex is a major goal in neuroscience. A recently proposed taxonomy based on patterns of axonal arborization promises to be a pragmatic method for achieving this goal. It involves characterizing interneurons according to five axonal arborization features, called F1-F5, and classifying them into a set of predefined types, most of which are established in the literature. Unfortunately, there is little consensus among expert neuroscientists regarding the morphological definitions of some of the proposed types. While supervised classifiers were able to categorize the interneurons in accordance with experts' assignments, their accuracy was limited because they were trained with disputed labels. Thus, here we automatically classify interneuron subsets with different label reliability thresholds (i.e., such that every cell's label is backed by at least a certain (threshold) number of experts). We quantify the cells with parameters of axonal and dendritic morphologies and, in order to predict the type, also with axonal features F1-F4 provided by the experts. Using Bayesian network classifiers, we accurately characterize and classify the interneurons and identify useful predictor variables. In particular, we discriminate among reliable examples of common basket, horse-tail, large basket, and Martinotti cells with up to 89.52% accuracy, and single out the number of branches at 180 μm from the soma, the convex hull 2D area, and the axonal features F1-F4 as especially useful predictors for distinguishing among these types. These results open up new possibilities for an objective and pragmatic classification of interneurons. PMID:25420745

  3. Interneuronal mechanism for Tinbergen's hierarchical model of behavioral choice.

    PubMed

    Pirger, Zsolt; Crossley, Michael; László, Zita; Naskar, Souvik; Kemenes, György; O'Shea, Michael; Benjamin, Paul R; Kemenes, Ildikó

    2014-09-01

    Recent studies of behavioral choice support the notion that the decision to carry out one behavior rather than another depends on the reconfiguration of shared interneuronal networks [1]. We investigated another decision-making strategy, derived from the classical ethological literature [2, 3], which proposes that behavioral choice depends on competition between autonomous networks. According to this model, behavioral choice depends on inhibitory interactions between incompatible hierarchically organized behaviors. We provide evidence for this by investigating the interneuronal mechanisms mediating behavioral choice between two autonomous circuits that underlie whole-body withdrawal [4, 5] and feeding [6] in the pond snail Lymnaea. Whole-body withdrawal is a defensive reflex that is initiated by tactile contact with predators. As predicted by the hierarchical model, tactile stimuli that evoke whole-body withdrawal responses also inhibit ongoing feeding in the presence of feeding stimuli. By recording neurons from the feeding and withdrawal networks, we found no direct synaptic connections between the interneuronal and motoneuronal elements that generate the two behaviors. Instead, we discovered that behavioral choice depends on the interaction between two unique types of interneurons with asymmetrical synaptic connectivity that allows withdrawal to override feeding. One type of interneuron, the Pleuro-Buccal (PlB), is an extrinsic modulatory neuron of the feeding network that completely inhibits feeding when excited by touch-induced monosynaptic input from the second type of interneuron, Pedal-Dorsal12 (PeD12). PeD12 plays a critical role in behavioral choice by providing a synaptic pathway joining the two behavioral networks that underlies the competitive dominance of whole-body withdrawal over feeding. PMID:25155505

  4. Interneurons in the human olfactory system in Alzheimer's disease.

    PubMed

    Saiz-Sanchez, Daniel; Flores-Cuadrado, Alicia; Ubeda-Bañon, Isabel; de la Rosa-Prieto, Carlos; Martinez-Marcos, Alino

    2016-02-01

    The principal olfactory structures display Alzheimer's disease (AD) related pathology at early stages of the disease. Consequently, olfactory deficits are among the earliest symptoms. Reliable olfactory tests for accurate clinical diagnosis are rarely made. In addition, neuropathological analysis postmortem of olfactory structures is often not made. Therefore, the relationship between the clinical features and the underlying pathology is poorly defined. Traditionally, research into Alzheimer's disease has focused on the degeneration of cortical temporal projection neurons and cholinergic neurons. Recent evidence has demonstrated the neurodegeneration of interneuron populations in AD. This review provides an updated overview of the pathological involvement of interneuron populations in the human olfactory system in Alzheimer's disease. PMID:26616239

  5. The early fetal development of human neocortical GABAergic interneurons.

    PubMed

    Al-Jaberi, Nahidh; Lindsay, Susan; Sarma, Subrot; Bayatti, Nadhim; Clowry, Gavin J

    2015-03-01

    GABAergic interneurons are crucial to controlling the excitability and responsiveness of cortical circuitry. Their developmental origin may differ between rodents and human. We have demonstrated the expression of 12 GABAergic interneuron-associated genes in samples from human neocortex by quantitative rtPCR from 8 to 12 postconceptional weeks (PCW) and shown a significant anterior to posterior expression gradient, confirmed by in situ hybridization or immunohistochemistry for GAD1 and 2, DLX1, 2, and 5, ASCL1, OLIG2, and CALB2. Following cortical plate (CP) formation from 8 to 9 PCW, a proportion of cells were strongly stained for all these markers in the CP and presubplate. ASCL1 and DLX2 maintained high expression in the proliferative zones and showed extensive immunofluorescent double-labeling with the cell division marker Ki-67. CALB2-positive cells increased steadily in the SVZ/VZ from 10 PCW but were not double-labeled with Ki-67. Expression of GABAergic genes was generally higher in the dorsal pallium than in the ganglionic eminences, with lower expression in the intervening ventral pallium. It is widely accepted that the cortical proliferative zones may generate CALB2-positive interneurons from mid-gestation; we now show that the anterior neocortical proliferative layers especially may be a rich source of interneurons in the early neocortex. PMID:24047602

  6. Mutual Control of Cholinergic and Low-Threshold Spike Interneurons in the Striatum

    PubMed Central

    Elghaba, Rasha; Vautrelle, Nicolas; Bracci, Enrico

    2016-01-01

    The striatum is the largest nucleus of the basal ganglia and is crucially involved in action selection and reward processing. Cortical and thalamic inputs to the striatum are processed by local networks in which several classes of interneurons play an important, but still poorly understood role. Here we investigated the interactions between cholinergic and low-threshold spike (LTS) interneurons. LTS interneurons were hyperpolarized by co-application of muscarinic and nicotinic receptor antagonists (atropine and mecamylamine, respectively). Mecamylamine alone also caused hyperpolarizations, while atropine alone caused depolarizations and increased firing. LTS interneurons were also under control of tonic GABA, as application of the GABAA receptor antagonist picrotoxin caused depolarizations and increased firing. Frequency of spontaneous GABAergic events in LTS interneurons was increased by co-application of atropine and mecamylamine or by atropine alone, but reduced by mecamylamine alone. In the presence of picrotoxin and tetrodotoxin (TTX), atropine and mecamylamine depolarized the LTS interneurons. We concluded that part of the excitatory effects of tonic acetylcholine (ACh) on LTS interneurons were due to cholinergic modulation of tonic GABA. We then studied the influence of LTS interneurons on cholinergic interneurons. Application of antagonists of somatostatin or neuropeptide Y (NPY) receptors or of an inhibitor of nitric oxide synthase (L-NAME) did not cause detectable effects in cholinergic interneurons. However, prolonged synchronized depolarizations of LTS interneurons (elicited with optogenetics tools) caused slow-onset depolarizations in cholinergic interneurons, which were often accompanied by strong action potential firing and were fully abolished by L-NAME. Thus, a mutual excitatory influence exists between LTS and cholinergic interneurons in the striatum, providing an opportunity for sustained activation of the two cell types. This activation may

  7. Respiratory interneurones in the thoracic spinal cord of the cat.

    PubMed Central

    Kirkwood, P A; Munson, J B; Sears, T A; Westgaard, R H

    1988-01-01

    1. The discharges of spontaneously firing neurones, whose activity was modulated in phase with the central respiratory cycle, were recorded in the thoracic ventral horn (T3-T9) of anaesthetized, paralysed cats. 2. Out of 310 neurones, forty-six were positively identified as motoneurones by antidromic activation or spike-triggered averaging, fifty-four were positively identified as interneurones by antidromic activation from other spinal cord segments and ninety were indirectly identified as interneurones by virtue of their positions or firing rates as compared to the motoneurones. 3. Units were classified as inspiratory (64%), expiratory (25%) or post-inspiratory (7%) according to the times of their maximum firing rates. The remaining 4% consisted of units whose discharges were either strongly locked to the respiratory pump cycle or did not fit into the other categories. All but one of the motoneurones were classified as inspiratory or expiratory. 4. Inspiratory and expiratory units were further classified as early, late or tonic according to the starting times of their discharges in the respiratory cycle. The interneurones (both positively and indirectly identified) included more of the early and tonic categories and more fast-firing units than did the motoneurones in both the inspiratory and expiratory groups. 5. The locations of the motoneurones corresponded to the known positions of the intercostal and interchondral motor nuclei, including clear segregation of inspiratory and expiratory populations. The locations of neither the interneurones nor the unidentified units were segregated according to their firing patterns. These neurones were concentrated in the medial half of the ventral horn and were found generally more dorsally than the positions of the motoneurones, though their positions overlapped considerably with this group. 6. The axons of the positively identified interneurones were identified from one to five segments caudally and mostly contralaterally

  8. Resonant Interneurons Can Increase Robustness of Gamma Oscillations

    PubMed Central

    Tikidji-Hamburyan, Ruben A.; Martínez, Joan José; White, John A.

    2015-01-01

    Gamma oscillations are believed to play a critical role in in information processing, encoding, and retrieval. Inhibitory interneuronal network gamma (ING) oscillations may arise from a coupled oscillator mechanism in which individual neurons oscillate or from a population oscillator in which individual neurons fire sparsely and stochastically. All ING mechanisms, including the one proposed herein, rely on alternating waves of inhibition and windows of opportunity for spiking. The coupled oscillator model implemented with Wang–Buzsáki model neurons is not sufficiently robust to heterogeneity in excitatory drive, and therefore intrinsic frequency, to account for in vitro models of ING. Similarly, in a tightly synchronized regime, the stochastic population oscillator model is often characterized by sparse firing, whereas interneurons both in vivo and in vitro do not fire sparsely during gamma, but rather on average every other cycle. We substituted so-called resonator neural models, which exhibit class 2 excitability and postinhibitory rebound (PIR), for the integrators that are typically used. This results in much greater robustness to heterogeneity that actually increases as the average participation in spikes per cycle approximates physiological levels. Moreover, dynamic clamp experiments that show autapse-induced firing in entorhinal cortical interneurons support the idea that PIR can serve as a network gamma mechanism. Furthermore, parvalbumin-positive (PV+) cells were much more likely to display both PIR and autapse-induced firing than GAD2+ cells, supporting the view that PV+ fast-firing basket cells are more likely to exhibit class 2 excitability than other types of inhibitory interneurons. SIGNIFICANCE STATEMENT Gamma oscillations are believed to play a critical role in information processing, encoding, and retrieval. Networks of inhibitory interneurons are thought to be essential for these oscillations. We show that one class of interneurons with an

  9. Target-Specific Effects of Somatostatin-Expressing Interneurons on Neocortical Visual Processing

    PubMed Central

    Cottam, James C. H.

    2013-01-01

    A diverse array of interneuron types regulates activity in the mammalian neocortex. Two of the most abundant are the fast-spiking, parvalbumin-positive (PV+) interneurons, which target the axosomatic region of pyramidal cells, and the somatostatin-positive (SOM+) interneurons, which target the dendrites. Recent work has focused on the influence of PV+ and SOM+ interneurons on pyramidal cells. However, the connections among PV+ and SOM+ interneurons are poorly understood and could play an important role in cortical circuitry, since their interactions may alter the net influence on pyramidal cell output. We used an optogenetic approach to investigate the effect of SOM+ interneurons on pyramidal cells and PV+ interneurons during visual stimulation in mouse primary visual cortex. We find that SOM+ interneuron activation suppresses PV+ cell spiking at least twice as potently as pyramidal cell spiking during visual stimulation. This differential effect of SOM+ cell stimulation is detectable even when only two to three SOM+ cells are activated. Importantly, the remaining responses to oriented gratings in PV+ cells are more orientation tuned and temporally modulated, suggesting that SOM+ activity unmasks this tuning by suppressing untuned input. Our results highlight the importance of SOM+ inhibition of PV+ interneurons during sensory processing. This prominent competitive inhibition between interneuron types leads to a reconfiguration of inhibition along the somatodendritic axis of pyramidal cells, and enhances the orientation selectivity of PV+ cells. PMID:24336721

  10. Postnatal subventricular zone progenitors give rise not only to granular and periglomerular interneurons but also to interneurons in the external plexiform layer of the rat olfactory bulb.

    PubMed

    Yang, Zhengang

    2008-01-10

    Interneurons in the granule cell layer (GCL) and glomerular layer (GL) of the olfactory bulb (OB) are generated from progenitors in the subventricular zone (SVZ) of the lateral ventricle. However, little is known about the origin of interneurons in the external plexiform layer (EPL) of the OB. On the basis of the concept of corticogenesis, I hypothesized that interneurons in the EPL of the rodent OB also originate in the SVZ. In the present study, replication-incompetent retroviruses encoding a marker gene, human placental alkaline phosphatase (AP), were injected into the lateral ventricles of postnatal day 4 Wistar rats to label dividing cells in the SVZ. Two days after injection, some of the AP-labeled cells had migrated into the OB. Five weeks after injection, AP/NeuN double-labeled cells were found not only in the GCL and GL but also in the EPL of the OB. In the EPL, most AP-labeled cells were calcium-binding protein parvalbumin (PV)-immunoreactive (+) interneurons. A subset of these cells was made up of calcium-binding protein calretinin (CR)(+) interneurons. According to their structural features, AP-labeled cells in the EPL were Van Gehuchten cells, multipolar cells, and superficial short-axon cells. Thus, postnatal SVZ progenitors give rise not only to granular and periglomerular interneurons but also to interneurons in the EPL of the OB. Furthermore, these results suggest that SVZ progenitors give rise to virtually all subpopulations of interneurons in the OB. PMID:18022946

  11. [Interneuronal functional connections in the canine sensomotor cortex].

    PubMed

    Dolbakian, E E; Tarakanova, T A

    1993-01-01

    Multiple unit activity (MUA) of the sensomotor cortex was recorded from chronically implanted semimicroelectrodes in dogs. The spike trains of 6-8 neural units were selected from MUA. The character and temporal parameters of interneuronal functional connections were examined by the method of computerized cross-interval analysis. For this purpose the autocorrelation and cross-interval histograms were constructed. One of the main results was complete absence of symmetrical central peaks (shared input). The functional interrelations of selected neurons were characterized by unilateral and bilateral nonsymmetrical excitatory connections with short (1-10 ms), middle (10-80 ms) and late (80-2000 vs) delays. The peculiarities of these interneuronal connections are discussed. PMID:8485189

  12. Mechanisms of retroaxonal barrage firing in hippocampal interneurons.

    PubMed

    Sheffield, Mark E J; Edgerton, Gabrielle B; Heuermann, Robert J; Deemyad, Tara; Mensh, Brett D; Spruston, Nelson

    2013-10-01

    We recently described a new form of neural integration and firing in a subset of interneurons, in which evoking hundreds of action potentials over tens of seconds to minutes produces a sudden barrage of action potentials lasting about a minute beyond the inciting stimulation. During this persistent firing, action potentials are generated in the distal axon and propagate retrogradely to the soma. To distinguish this from other forms of persistent firing, we refer to it here as 'retroaxonal barrage firing', or 'barrage firing' for short. Its induction is blocked by chemical inhibitors of gap junctions and curiously, stimulation of one interneuron in some cases triggers barrage firing in a nearby, unstimulated interneuron. Beyond these clues, the mechanisms of barrage firing are unknown. Here we report new results related to these mechanisms. Induction of barrage firing was blocked by lowering extracellular calcium, as long as normal action potential threshold was maintained, and it was inhibited by blocking L-type voltage-gated calcium channels. Despite its calcium dependence, barrage firing was not prevented by inhibiting chemical synaptic transmission. Furthermore, loading the stimulated/recorded interneuron with BAPTA did not block barrage firing, suggesting that the required calcium entry occurs in other cells. Finally, barrage firing was normal in mice with deletion of the primary gene for neuronal gap junctions (connexin36), suggesting that non-neuronal gap junctions may be involved. Together, these findings suggest that barrage firing is probably triggered by a multicellular mechanism involving calcium signalling and gap junctions, but operating independently of chemical synaptic transmission. PMID:23878372

  13. Estimating functional connectivity in an electrically coupled interneuron network

    PubMed Central

    Alcami, Pepe; Marty, Alain

    2013-01-01

    Even though it has been known for some time that in many mammalian brain areas interneurons are electrically coupled, a quantitative description of the network electrical connectivity and its impact on cellular passive properties is still lacking. Approaches used so far to solve this problem are limited because they do not readily distinguish junctions among direct neighbors from indirect junctions involving intermediary, multiply connected cells. In the cerebellar cortex, anatomical and functional evidence indicates electrical coupling between molecular layer interneurons (basket and stellate cells). An analysis of the capacitive currents obtained under voltage clamp in molecular layer interneurons of juvenile rats or mice reveals an exponential component with a time constant of ∼20 ms, which represents capacitive loading of neighboring cells through gap junctions. These results, taken together with dual cell recording of electrical synapses, have led us to estimate the number of direct neighbors to be ∼4 for rat basket cells and ∼1 for rat stellate cells. The weighted number of neighbors (number of neighbors, both direct and indirect, weighted with the percentage of voltage deflection at steady state) was 1.69 in basket cells and 0.23 in stellate cells. The last numbers indicate the spread of potential changes in the network and serve to estimate the contribution of gap junctions to cellular input conductance. In conclusion the present work offers effective tools to analyze the connectivity of electrically connected interneuron networks, and it indicates that in juvenile rodents, electrical communication is stronger among basket cells than among stellate cells. PMID:24248377

  14. The role of cannabinoid 1 receptor expressing interneurons in behavior

    PubMed Central

    Brown, Jacquelyn A.; Horváth, Szatmár; Garbett, Krassimira; Schmidt, Martin J.; Everheart, Monika; Gellért, Levente; Ebert, Philip; Mirnics, Károly

    2013-01-01

    Schizophrenia is a devastating neurodevelopmental disorder that affects approximately 1% of the population. Reduced expression of the 67-kD a protein isoform of glutamic acid decarboxylase (GAD67), is a hallmark of the disease, and is encoded by the GAD1 gene. In schizophrenia, GAD67 downregulation occurs in multiple interneuronal subpopulations, including the cannabinoid receptor type 1 positive (CNR1+) cells, but the functional consequences of these disturbances are not well understood. To investigate the role of the CNR1-positive GABA-ergic interneurons in behavioral and molecular processes, we employed a novel, miRNA-mediated transgenic mouse approach. We silenced the Gad1 transcript using a miRNA engineered to specifically target Gad1 mRNA under the control of Cnr1 bacterial artificial chromosome. Behavioral characterization of our transgenic mice showed elevated and persistent conditioned fear associated with an auditory cue and a significantly altered response to an amphetamine challenge. These deficits could not be attributed to sensory deficits or changes in baseline learning and memory. Furthermore, HPLC analyses revealed that Cnr1/Gad1 mice have enhanced serotonin levels, but not dopamine levels in response to amphetamine. Our findings demonstrate that dysfunction of a small subset of interneurons can have a profound effect on behavior and that the GABA-ergic, monoamine, and cannabinoid systems are functionally interconnected. The results also suggest that understanding the function of various interneuronal subclasses might be essential to develop knowledge-based treatment strategies for various mental disorders including schizophrenia and substance abuse. PMID:24239560

  15. Hippocampal gamma-frequency oscillations: from interneurones to pyramidal cells, and back.

    PubMed

    Mann, Edward O; Radcliffe, Catrin A; Paulsen, Ole

    2005-01-01

    GABAergic interneurones are necessary for the emergence of hippocampal gamma-frequency network oscillations, during which they play a key role in the synchronization of pyramidal cell firing. However, it remains to be resolved how distinct interneurone subtypes contribute to gamma-frequency oscillations, in what way the spatiotemporal pattern of interneuronal input affects principal cell activity, and by which mechanisms the interneurones themselves are synchronized. Here we summarize recent evidence from cholinergically induced gamma-frequency network oscillations in vitro, showing that perisomatic-targeting GABAergic interneurones provide prominent rhythmic inhibition in pyramidal cells, and that these interneurones are synchronized by recurrent excitation. We conclude by presenting a minimal integrate-and-fire network model which demonstrates that this excitatory-inhibitory feedback loop is sufficient to explain the generation of intrahippocampal gamma-frequency oscillations. PMID:15539391

  16. Hindbrain interneurons and axon guidance signaling critical for breathing.

    PubMed

    Bouvier, Julien; Thoby-Brisson, Muriel; Renier, Nicolas; Dubreuil, Véronique; Ericson, Johan; Champagnat, Jean; Pierani, Alessandra; Chédotal, Alain; Fortin, Gilles

    2010-09-01

    Breathing is a bilaterally synchronous behavior that relies on a respiratory rhythm generator located in the brainstem. An essential component of this generator is the preBötzinger complex (preBötC), which paces inspirations. Little is known about the developmental origin of the interneuronal populations forming the preBötC oscillator network. We found that the homeobox gene Dbx1 controls the fate of glutamatergic interneurons required for preBötC rhythm generation in the mouse embryo. We also found that a conditional inactivation in Dbx1-derived cells of the roundabout homolog 3 (Robo3) gene, which is necessary for axonal midline crossing, resulted in left-right de-synchronization of the preBötC oscillator. Together, these findings identify Dbx1-derived interneurons as the core rhythmogenic elements of the preBötC oscillator and indicate that Robo3-dependent guidance signaling in these cells is required for bilaterally synchronous activity. PMID:20680010

  17. Modeling Inhibitory Interneurons in Efficient Sensory Coding Models

    PubMed Central

    Zhu, Mengchen; Rozell, Christopher J.

    2015-01-01

    There is still much unknown regarding the computational role of inhibitory cells in the sensory cortex. While modeling studies could potentially shed light on the critical role played by inhibition in cortical computation, there is a gap between the simplicity of many models of sensory coding and the biological complexity of the inhibitory subpopulation. In particular, many models do not respect that inhibition must be implemented in a separate subpopulation, with those inhibitory interneurons having a diversity of tuning properties and characteristic E/I cell ratios. In this study we demonstrate a computational framework for implementing inhibition in dynamical systems models that better respects these biophysical observations about inhibitory interneurons. The main approach leverages recent work related to decomposing matrices into low-rank and sparse components via convex optimization, and explicitly exploits the fact that models and input statistics often have low-dimensional structure that can be exploited for efficient implementations. While this approach is applicable to a wide range of sensory coding models (including a family of models based on Bayesian inference in a linear generative model), for concreteness we demonstrate the approach on a network implementing sparse coding. We show that the resulting implementation stays faithful to the original coding goals while using inhibitory interneurons that are much more biophysically plausible. PMID:26172289

  18. Muscarinic and dopaminergic receptor subtypes on striatal cholinergic interneurons

    SciTech Connect

    Dawson, V.L.; Dawson, T.M.; Wamsley, J.K. )

    1990-12-01

    Unilateral stereotaxic injection of small amounts of the cholinotoxin, AF64A, caused minimal nonselective tissue damage and resulted in a significant loss of the presynaptic cholinergic markers (3H)hemicholinium-3 (45% reduction) and choline acetyltransferase (27% reduction). No significant change from control was observed in tyrosine hydroxylase or tryptophan hydroxylase activity; presynaptic neuronal markers for dopamine- and serotonin-containing neurons, respectively. The AF64A lesion resulted in a significant reduction of dopamine D2 receptors as evidenced by a decrease in (3H)sulpiride binding (42% reduction) and decrease of muscarinic non-M1 receptors as shown by a reduction in (3H)QNB binding in the presence of 100 nM pirenzepine (36% reduction). Saturation studies revealed that the change in (3H)sulpiride and (3H)QNB binding was due to a change in Bmax not Kd. Intrastriatal injection of AF64A failed to alter dopamine D1 or muscarinic M1 receptors labeled with (3H)SCH23390 and (3H)pirenzepine, respectively. In addition, no change in (3H)forskolin-labeled adenylate cyclase was observed. These results demonstrate that a subpopulation of muscarinic receptors (non-M1) are presynaptic on cholinergic interneurons (hence, autoreceptors), and a subpopulation of dopamine D2 receptors are postsynaptic on cholinergic interneurons. Furthermore, dopamine D1, muscarinic M1 and (3H)forskolin-labeled adenylate cyclase are not localized to striatal cholinergic interneurons.

  19. Hierarchical spike clustering analysis for investigation of interneuron heterogeneity.

    PubMed

    Boehlen, Anne; Heinemann, Uwe; Henneberger, Christian

    2016-04-21

    Action potentials represent the output of a neuron. Especially interneurons display a variety of discharge patterns ranging from regular action potential firing to prominent spike clustering or stuttering. The mechanisms underlying this heterogeneity remain incompletely understood. We established hierarchical cluster analysis of spike trains as a measure of spike clustering. A clustering index was calculated from action potential trains recorded in the whole-cell patch clamp configuration from hippocampal (CA1, stratum radiatum) and entorhinal (medial entorhinal cortex, layer 2) interneurons in acute slices and simulated data. Prominent, region-dependent, but also variable spike clustering was detected using this measure. Further analysis revealed a strong positive correlation between spike clustering and membrane potentials oscillations but an inverse correlation with neuronal resonance. Furthermore, clustering was more pronounced when the balance between fast-activating K(+) currents, assessed by the spike repolarisation time, and hyperpolarization-activated currents, gauged by the size of the sag potential, was shifted in favour of fast K(+) currents. Simulations of spike clustering confirmed that variable ratios of fast K(+) and hyperpolarization-activated currents could underlie different degrees of spike clustering and could thus be crucial for temporally structuring interneuron spike output. PMID:26987719

  20. Differential gene expression in migratory streams of cortical interneurons

    PubMed Central

    Antypa, Mary; Faux, Clare; Eichele, Gregor; Parnavelas, John G; Andrews, William D

    2011-01-01

    Cortical interneurons originate in the ganglionic eminences of the subpallium and migrate into the cortex in well-defined tangential streams. At the start of corticogenesis, two streams of migrating neurons are evident: a superficial one at the level of the preplate (PPL), and a deeper one at the level of the intermediate zone (IZ). Currently, little is known about the signalling mechanisms that regulate interneuron migration, and almost nothing is known about the molecules that may be involved in their choice of migratory stream. Here, we performed a microarray analysis, comparing the changes in gene expression between cells migrating in the PPL and those migrating in the IZ at embryonic day 13.5. This analysis identified genes, many of them novel, that were upregulated in one of the two streams. Moreover, polymerase chain reaction, in situ hybridization experiments and immunohistochemistry showed the expression of these genes in interneurons migrating within the PPL or IZ, suggesting that they play a role in their migration and choice of stream. PMID:22103416

  1. Modeling Inhibitory Interneurons in Efficient Sensory Coding Models.

    PubMed

    Zhu, Mengchen; Rozell, Christopher J

    2015-07-01

    There is still much unknown regarding the computational role of inhibitory cells in the sensory cortex. While modeling studies could potentially shed light on the critical role played by inhibition in cortical computation, there is a gap between the simplicity of many models of sensory coding and the biological complexity of the inhibitory subpopulation. In particular, many models do not respect that inhibition must be implemented in a separate subpopulation, with those inhibitory interneurons having a diversity of tuning properties and characteristic E/I cell ratios. In this study we demonstrate a computational framework for implementing inhibition in dynamical systems models that better respects these biophysical observations about inhibitory interneurons. The main approach leverages recent work related to decomposing matrices into low-rank and sparse components via convex optimization, and explicitly exploits the fact that models and input statistics often have low-dimensional structure that can be exploited for efficient implementations. While this approach is applicable to a wide range of sensory coding models (including a family of models based on Bayesian inference in a linear generative model), for concreteness we demonstrate the approach on a network implementing sparse coding. We show that the resulting implementation stays faithful to the original coding goals while using inhibitory interneurons that are much more biophysically plausible. PMID:26172289

  2. Emergent gamma synchrony in all-to-all interneuronal networks

    PubMed Central

    Ratnadurai-Giridharan, Shivakeshavan; Khargonekar, Pramod P.; Talathi, Sachin S.

    2015-01-01

    We investigate the emergence of in-phase synchronization in a heterogeneous network of coupled inhibitory interneurons in the presence of spike timing dependent plasticity (STDP). Using a simple network of two mutually coupled interneurons (2-MCI), we first study the effects of STDP on in-phase synchronization. We demonstrate that, with STDP, the 2-MCI network can evolve to either a state of stable 1:1 in-phase synchronization or exhibit multiple regimes of higher order synchronization states. We show that the emergence of synchronization induces a structural asymmetry in the 2-MCI network such that the synapses onto the high frequency firing neurons are potentiated, while those onto the low frequency firing neurons are de-potentiated, resulting in the directed flow of information from low frequency firing neurons to high frequency firing neurons. Finally, we demonstrate that the principal findings from our analysis of the 2-MCI network contribute to the emergence of robust synchronization in the Wang-Buzsaki network (Wang and Buzsáki, 1996) of all-to-all coupled inhibitory interneurons (100-MCI) for a significantly larger range of heterogeneity in the intrinsic firing rate of the neurons in the network. We conclude that STDP of inhibitory synapses provide a viable mechanism for robust neural synchronization. PMID:26528174

  3. Controlling interneuron activity in Caenorhabditis elegans to evoke chemotactic behaviour.

    PubMed

    Kocabas, Askin; Shen, Ching-Han; Guo, Zengcai V; Ramanathan, Sharad

    2012-10-11

    Animals locate and track chemoattractive gradients in the environment to find food. With its small nervous system, Caenorhabditis elegans is a good model system in which to understand how the dynamics of neural activity control this search behaviour. Extensive work on the nematode has identified the neurons that are necessary for the different locomotory behaviours underlying chemotaxis through the use of laser ablation, activity recording in immobilized animals and the study of mutants. However, we do not know the neural activity patterns in C. elegans that are sufficient to control its complex chemotactic behaviour. To understand how the activity in its interneurons coordinate different motor programs to lead the animal to food, here we used optogenetics and new optical tools to manipulate neural activity directly in freely moving animals to evoke chemotactic behaviour. By deducing the classes of activity patterns triggered during chemotaxis and exciting individual neurons with these patterns, we identified interneurons that control the essential locomotory programs for this behaviour. Notably, we discovered that controlling the dynamics of activity in just one interneuron pair (AIY) was sufficient to force the animal to locate, turn towards and track virtual light gradients. Two distinct activity patterns triggered in AIY as the animal moved through the gradient controlled reversals and gradual turns to drive chemotactic behaviour. Because AIY neurons are post-synaptic to most chemosensory and thermosensory neurons, it is probable that these activity patterns in AIY have an important role in controlling and coordinating different taxis behaviours of the animal. PMID:23000898

  4. Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus

    PubMed Central

    Song, Juan; Sun, Jiaqi; Moss, Jonathan; Wen, Zhexing; Sun, Gerald J.; Hsu, Derek; Zhong, Chun; Davoudi, Heydar; Christian, Kimberly M.; Toni, Nicolas; Ming, Guo-li; Song, Hongjun

    2014-01-01

    Using immunohistology, electron microscopy, electrophysiology and optogenetics, we show that proliferating adult hippocampal neural precursors receive immature GABAergic synaptic inputs from parvalbumin-expressing interneurons. Recently shown to suppress quiescent neural stem cell activation, parvalbumin interneuron activation promotes newborn neuronal progeny survival and development. Our study suggests a niche mechanism involving parvalbumin interneurons that couples local circuit activity to diametric regulation of two critical initial phases of adult hippocampal neurogenesis. PMID:24212671

  5. The control of sets of motoneurones by local interneurones in the locust.

    PubMed Central

    Burrows, M

    1980-01-01

    1. A motoneurone innervating a muscle in a hind leg of a locust is controlled in a graded manner by many non-spiking, local interneurones. There is overlap and fractionation of control between these interneurones. Some interneurones depolarize the motoneurone over part of its range, others hyperpolarize it, whilst some do both. 2. The interneurones organize the small number of motoneurones that innervate one muscle into overlapping sets of various sizes. A motoneurone can therefore be activated individually or in particular combinations with its fellow motoneurones. 3. The motoneurones innervating two muscles of a joint are also organized into overlapping sets by many local interneurones. This permits the motoneurones to the two muscles to be activated reciprocally, together, or independently. 4. One interneurone can elicit a co-ordinated movement of one, two or even three joints in a hind leg that are components of the normal behaviour of the locust. 5. A single interneurone acting alone does not usually elicit the maximum output from one motoneurone, nor a complete piece of behaviour. A stronger contraction of a muscle and a more complete movement results from the action of groups of interneurones. 6. It is suggested that local interneurones, exerting graded control over motoneurones are a major element in the organization of motor patterns in the locust. PMID:7359394

  6. Excitatory connections of nonspiking interneurones in the terminal abdominal ganglion of the crayfish.

    PubMed

    Namba, Hisaaki; Nagayama, Toshiki

    2015-08-01

    The output effects of the nonspiking interneurones in the crayfish terminal abdominal ganglion upon the uropod motor neurones were characterized using simultaneous intracellular recordings. Inhibitory interactions from nonspiking interneurones to the uropod motor neurones were one-way and chemically mediated. The depolarization of the motor neurones with current injection increased the amplitude of the nonspiking interneurone-mediated hyperpolarization, while hyperpolarization of the motor neurone decreased it. By contrast, excitatory interactions from the nonspiking interneurones to the motor neurones were not mediated via chemical synaptic transmissions. These excitatory connections with the slow motor neurones were one-way while connections with fast motor neurones were bidirectional. Nonspiking interneurone-mediated membrane depolarization of the motor neurones was not affected by the passage of hyperpolarizing current. Each motor neurone spike elicited a time-locked EPSP in the nonspiking interneurones with very short delay (0.2 ms) that suggested electrical coupling between nonspiking interneurones and motor neurones. Nonspiking interneurones directly control the organization of slow motor neurone activity, while they appear to regulate the background activity of the fast motor neurones. A single nonspiking interneurone is possible to inhibit some inter and/or motor neurones via direct chemical synapses and simultaneously excite other neurones via electrical synapses. PMID:26038269

  7. Multi-dimensional classification of GABAergic interneurons with Bayesian network-modeled label uncertainty.

    PubMed

    Mihaljević, Bojan; Bielza, Concha; Benavides-Piccione, Ruth; DeFelipe, Javier; Larrañaga, Pedro

    2014-01-01

    Interneuron classification is an important and long-debated topic in neuroscience. A recent study provided a data set of digitally reconstructed interneurons classified by 42 leading neuroscientists according to a pragmatic classification scheme composed of five categorical variables, namely, of the interneuron type and four features of axonal morphology. From this data set we now learned a model which can classify interneurons, on the basis of their axonal morphometric parameters, into these five descriptive variables simultaneously. Because of differences in opinion among the neuroscientists, especially regarding neuronal type, for many interneurons we lacked a unique, agreed-upon classification, which we could use to guide model learning. Instead, we guided model learning with a probability distribution over the neuronal type and the axonal features, obtained, for each interneuron, from the neuroscientists' classification choices. We conveniently encoded such probability distributions with Bayesian networks, calling them label Bayesian networks (LBNs), and developed a method to predict them. This method predicts an LBN by forming a probabilistic consensus among the LBNs of the interneurons most similar to the one being classified. We used 18 axonal morphometric parameters as predictor variables, 13 of which we introduce in this paper as quantitative counterparts to the categorical axonal features. We were able to accurately predict interneuronal LBNs. Furthermore, when extracting crisp (i.e., non-probabilistic) predictions from the predicted LBNs, our method outperformed related work on interneuron classification. Our results indicate that our method is adequate for multi-dimensional classification of interneurons with probabilistic labels. Moreover, the introduced morphometric parameters are good predictors of interneuron type and the four features of axonal morphology and thus may serve as objective counterparts to the subjective, categorical axonal features

  8. Multi-dimensional classification of GABAergic interneurons with Bayesian network-modeled label uncertainty

    PubMed Central

    Mihaljević, Bojan; Bielza, Concha; Benavides-Piccione, Ruth; DeFelipe, Javier; Larrañaga, Pedro

    2014-01-01

    Interneuron classification is an important and long-debated topic in neuroscience. A recent study provided a data set of digitally reconstructed interneurons classified by 42 leading neuroscientists according to a pragmatic classification scheme composed of five categorical variables, namely, of the interneuron type and four features of axonal morphology. From this data set we now learned a model which can classify interneurons, on the basis of their axonal morphometric parameters, into these five descriptive variables simultaneously. Because of differences in opinion among the neuroscientists, especially regarding neuronal type, for many interneurons we lacked a unique, agreed-upon classification, which we could use to guide model learning. Instead, we guided model learning with a probability distribution over the neuronal type and the axonal features, obtained, for each interneuron, from the neuroscientists' classification choices. We conveniently encoded such probability distributions with Bayesian networks, calling them label Bayesian networks (LBNs), and developed a method to predict them. This method predicts an LBN by forming a probabilistic consensus among the LBNs of the interneurons most similar to the one being classified. We used 18 axonal morphometric parameters as predictor variables, 13 of which we introduce in this paper as quantitative counterparts to the categorical axonal features. We were able to accurately predict interneuronal LBNs. Furthermore, when extracting crisp (i.e., non-probabilistic) predictions from the predicted LBNs, our method outperformed related work on interneuron classification. Our results indicate that our method is adequate for multi-dimensional classification of interneurons with probabilistic labels. Moreover, the introduced morphometric parameters are good predictors of interneuron type and the four features of axonal morphology and thus may serve as objective counterparts to the subjective, categorical axonal features

  9. Postnatal development of GABAergic interneurons in the neocortical subplate of mice.

    PubMed

    Qu, G-J; Ma, J; Yu, Y-C; Fu, Y

    2016-05-13

    The subplate (SP) plays important roles in developmental and functional events in the neocortex, such as thalamocortical and corticofugal projection, cortical oscillation generation and corticocortical connectivity. Although accumulated evidence indicates that SP interneurons are crucial for SP function, the molecular composition of SP interneurons as well as their developmental profile and distribution remain largely unclear. In this study, we systematically investigated dynamic development of SP thickness and chemical marker expression in SP interneurons in distinct cortical regions during the first postnatal month. We found that, although the relative area of the SP in the cerebral cortex significantly declined with postnatal development, the absolute thickness did not change markedly. We also found that somatostatin (SOM), the ionotropic serotonin receptor 3A (5HT3AR), and parvalbumin (PV) reliably identify three distinct non-overlapping subpopulations of SP interneurons. The SOM group, which represents ∼30% of total SP interneurons, expresses neuronal nitric oxide synthase (nNOS) and calbindin (CB) and colocalizes entirely with neuropeptide Y (NPY). The 5HT3AR group, which accounts for ∼60% of the total interneuronal population, expresses calretinin (CR) and GABA-A receptor subunit delta (GABAARδ). The PV group accounts for ∼10% of total SP interneurons and coexpressed GABAARδ. Moreover, distinct interneuron subtypes show characteristic temporal and spatial distribution in the SP. nNOS(+) interneurons in the SP increase from the anterior motor cortex to posterior visual cortex, while CR(+) and CB(+) interneurons the opposite. Interestedly, the majority of GABAARδ(+) neurons in SP are non-GABAergic neurons in contrast to other cortical layers. These findings clarify and extend our understanding of SP interneurons in the developing cerebral cortex and will underpin further study of SP function. PMID:26892297

  10. Cortical interneurons from human pluripotent stem cells: prospects for neurological and psychiatric disease

    PubMed Central

    Arber, Charles; Li, Meng

    2012-01-01

    Cortical interneurons represent 20% of the cells in the cortex. These cells are local inhibitory neurons whose function is to modulate the firing activities of the excitatory projection neurons. Cortical interneuron dysfunction is believed to lead to runaway excitation underlying (or implicated in) seizure-based diseases, such as epilepsy, autism, and schizophrenia. The complex development of this cell type and the intricacies involved in defining the relative subtypes are being increasingly well defined. This has led to exciting experimental cell therapy in model organisms, whereby fetal-derived interneuron precursors can reverse seizure severity and reduce mortality in adult epileptic rodents. These proof-of-principle studies raise hope for potential interneuron-based transplantation therapies for treating epilepsy. On the other hand, cortical neurons generated from patient iPSCs serve as a valuable tool to explore genetic influences of interneuron development and function. This is a fundamental step in enhancing our understanding of the molecular basis of neuropsychiatric illnesses and the development of targeted treatments. Protocols are currently being developed for inducing cortical interneuron subtypes from mouse and human pluripotent stem cells. This review sets out to summarize the progress made in cortical interneuron development, fetal tissue transplantation and the recent advance in stem cell differentiation toward interneurons. PMID:23493959

  11. Cervical Pre-Phrenic Interneurons in the Normal and Lesioned Spinal Cord of the Adult Rat

    PubMed Central

    Lane, Michael A.; White, Todd E.; Coutts, Marcella A.; Jones, Alex L.; Sandhu, Milapjit S.; Bloom, David C.; Bolser, Donald C.; Yates, Bill J.; Fuller, David D.; Reier, Paul J.

    2008-01-01

    While monosynaptic bulbospinal projections to phrenic motoneurons have been extensively described, little is known about the organization of phrenic premotor neurons in the adult rat spinal cord. As interneurons may play an important role in normal breathing and recovery following spinal cord injury, the present study has used anterograde and transneuronal retrograde tracing to study their distribution and synaptic relations. Exclusive unilateral, first-order labeling of the phrenic motoneuron pool with pseudorabies virus demonstrated a substantial number of second-order, bilaterally-distributed cervical interneurons predominantly in the dorsal horn and around the central canal. Combined transneuronal and anterograde tracing revealed ventral respiratory column projections to pre-phrenic interneurons suggesting some propriospinal relays exist between medullary neurons and the phrenic nucleus. Dual-labeling studies with pseudorabies virus recombinants also showed pre-phrenic interneurons integrated with either contralateral phrenic or intercostal motoneuron pools. The stability of interneuronal pseudorabies virus labeling patterns following lateral cervical hemisection was then addressed. Except for fewer infected contralateral interneurons at the level of the central canal, the number and distribution of phrenic-associated interneurons was not significantly altered two weeks post-hemisection (i.e. when the earliest post-injury recovery of phrenic activity has been reported). These results demonstrate a heterogeneous population of phrenic-related interneurons. Their connectivity and relative stability after cervical hemisection raises speculation for potentially diverse roles in modulating phrenic function normally and post-injury. PMID:18924146

  12. Postnatal development of the electrophysiological properties of somatostatin interneurons in the anterior cingulate cortex of mice.

    PubMed

    Pan, Geng; Yang, Jian-Ming; Hu, Xing-Yue; Li, Xiao-Ming

    2016-01-01

    Somatostatin (SST)-positive interneurons in the anterior cingulate cortex (ACC) play important roles in neuronal diseases, memory and cognitive functions. However, their development in the ACC remains unclear. Using postnatal day 3 (P3) to P45 GIN mice, we found that most of the intrinsic membrane properties of SST interneurons in the ACC were developmentally mature after the second postnatal week and that the development of these neurons differed from that of parvalbumin (PV) interneurons in the prefrontal cortex. In addition, electrical coupling between SST interneurons appeared primarily between P12-14. The coupling probability plateaued at approximately P21-30, with a non-age-dependent development of coupling strength. The development of excitatory chemical afferents to SST interneurons occurred earlier than the development of inhibitory chemical afferents. Furthermore, eye closure attenuated the development of electrical coupling probability at P21-30 but had no effect on coupling strength. Eye closure also delayed the development of inhibitory chemical afferent frequency but had no effect on the excitatory chemical afferent amplitude, frequency or rise time. Our data suggest that SST interneurons in the ACC exhibit inherent developmental characteristics distinct from other interneuron subtypes, such as PV interneurons, and that some of these characteristics are subject to environmental regulation. PMID:27319800

  13. Coding Characteristics of Spiking Local Interneurons During Imposed Limb Movements in the Locust

    PubMed Central

    Vidal-Gadea, A. G.; Jing, X. J.; Simpson, D.; Dewhirst, O. P.; Kondoh, Y.; Allen, R.

    2010-01-01

    The performance of adaptive behavior relies on continuous sensory feedback to produce relevant modifications to central motor patterns. The femoral chordotonal organ (FeCO) of the legs of the desert locust monitors the movements of the tibia about the femoro-tibial joint. A ventral midline population of spiking local interneurons in the metathoracic ganglia integrates inputs from the FeCO. We used a Wiener kernel cross-correlation method combined with a Gaussian white noise stimulation of the FeCO to completely characterize and model the output dynamics of the ventral midline population of interneurons. A wide range of responses were observed, and interneurons could be classified into three broad groups that received excitatory and inhibitory or principally inhibitory or excitatory synaptic inputs from the FeCO. Interneurons that received mixed inputs also had the greatest linear responses but primarily responded to extension of the tibia and were mostly sensitive to stimulus velocity. Interneurons that received principally inhibitory inputs were sensitive to extension and to joint position. A small group of interneurons received purely excitatory synaptic inputs and were also sensitive to tibial extension. In addition to capturing the linear and nonlinear dynamics of this population of interneurons, first- and second-order Wiener kernels revealed that the dynamics of the interneurons in the population were graded and formed a spectrum of responses whereby the activity of many cells appeared to be required to adequately describe a particular stimulus characteristic, typical of population coding. PMID:19955290

  14. GABAergic interneurons form transient layer-specific circuits in early postnatal neocortex

    PubMed Central

    Anastasiades, Paul G.; Marques-Smith, Andre; Lyngholm, Daniel; Lickiss, Tom; Raffiq, Sayda; Kätzel, Dennis; Miesenböck, Gero; Butt, Simon J. B.

    2016-01-01

    GABAergic interneurons play key roles in cortical circuits, yet little is known about their early connectivity. Here we use glutamate uncaging and a novel optogenetic strategy to track changes in the afferent and efferent synaptic connections of developing neocortical interneuron subtypes. We find that Nkx2-1-derived interneurons possess functional synaptic connections before emerging pyramidal cell networks. Subsequent interneuron circuit maturation is both subtype and layer dependent. Glutamatergic input onto fast spiking (FS), but not somatostatin-positive, non-FS interneurons increases over development. Interneurons of both subtype located in layers (L) 4 and 5b engage in transient circuits that disappear after the somatosensory critical period. These include a pathway mediated by L5b somatostatin-positive interneurons that specifically targets L4 during the first postnatal week. The innervation patterns of immature cortical interneuron circuits are thus neither static nor progressively strengthened but follow a layer-specific choreography of transient connections that differ from those of the adult brain. PMID:26843463

  15. Two functional inhibitory circuits are comprised of a heterogeneous population of fast spiking cortical interneurons

    PubMed Central

    Li, Peijun; Huntsman, Molly M.

    2014-01-01

    Cortical fast spiking (FS) interneurons possess autaptic, synaptic, and electrical synapses that serve to mediate a fast, coordinated response to their postsynaptic targets. While FS interneurons are known to participate in numerous and diverse actions, functional subgroupings within this multi-functional interneuron class remain to be identified. In the present study, we examined parvalbumin positive FS interneurons in layer 4 of the primary somatosensory (barrel) cortex - a brain region well-known for specialized inhibitory function. Here we show that FS interneurons fall into two broad categories identified by the onset of the first action potential in a depolarizing train as: “Delayed Firing FS interneurons (FSD) and Early Onset Firing FS interneurons (FSE). Subtle variations in action potential firing reveal 6 subtypes within these two categories: delayed non-accommodating (FSD-NAC), delayed stuttering (FSD-STUT), early onset stuttering (FSE-STUT), early onset-late spiking (FSE-LS), early onset early-spiking (FSE-ES), and early onset accommodating (FSE-AC). Using biophysical criteria previously employed to distinguish neuronal cell types, the FSD and FSE categories exhibit several shared biophysical and synaptic properties that coincide with the notion of specificity of inhibitory function within the cortical FS interneuron class. PMID:24480365

  16. Selective Depletion of Molecularly Defined Cortical Interneurons in Human Holoprosencephaly with Severe Striatal Hypoplasia

    PubMed Central

    Fertuzinhos, Sofia; Krsnik, Željka; Kawasawa, Yuka Imamura; Rašin, Mladen-Roko; Kwan, Kenneth Y.; Chen, Jie-Guang; Judaš, Miloš; Hayashi, Masaharu; Šestan, Nenad

    2009-01-01

    Cortical excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons follow substantially different developmental programs. In rodents, projection neurons originate from progenitors within the dorsal forebrain, whereas interneurons arise from progenitors in the ventral forebrain. In contrast, it has been proposed that in humans, the majority of cortical interneurons arise from progenitors within the dorsal forebrain, suggesting that their origin and migration is complex and evolutionarily divergent. However, whether molecularly defined human cortical interneuron subtypes originate from distinct progenitors, including those in the ventral forebrain, remains unknown. Furthermore, abnormalities in cortical interneurons have been linked to human disorders, yet no distinct cell population selective loss has been reported. Here we show that cortical interneurons expressing nitric oxide synthase 1, neuropeptide Y, and somatostatin, are either absent or substantially reduced in fetal and infant cases of human holoprosencephaly (HPE) with severe ventral forebrain hypoplasia. Notably, another interneuron subtype normally abundant from the early fetal period, marked by calretinin expression, and different subtypes of projection neuron were present in the cortex of control and HPE brains. These findings have important implications for the understanding of neuronal pathogenesis underlying the clinical manifestations associated with HPE and the developmental origins of human cortical interneuron diversity. PMID:19234067

  17. Postnatal development of the electrophysiological properties of somatostatin interneurons in the anterior cingulate cortex of mice

    PubMed Central

    Pan, Geng; Yang, Jian-Ming; Hu, Xing-Yue; Li, Xiao-Ming

    2016-01-01

    Somatostatin (SST)-positive interneurons in the anterior cingulate cortex (ACC) play important roles in neuronal diseases, memory and cognitive functions. However, their development in the ACC remains unclear. Using postnatal day 3 (P3) to P45 GIN mice, we found that most of the intrinsic membrane properties of SST interneurons in the ACC were developmentally mature after the second postnatal week and that the development of these neurons differed from that of parvalbumin (PV) interneurons in the prefrontal cortex. In addition, electrical coupling between SST interneurons appeared primarily between P12–14. The coupling probability plateaued at approximately P21–30, with a non-age-dependent development of coupling strength. The development of excitatory chemical afferents to SST interneurons occurred earlier than the development of inhibitory chemical afferents. Furthermore, eye closure attenuated the development of electrical coupling probability at P21–30 but had no effect on coupling strength. Eye closure also delayed the development of inhibitory chemical afferent frequency but had no effect on the excitatory chemical afferent amplitude, frequency or rise time. Our data suggest that SST interneurons in the ACC exhibit inherent developmental characteristics distinct from other interneuron subtypes, such as PV interneurons, and that some of these characteristics are subject to environmental regulation. PMID:27319800

  18. Hippocampal Somatostatin Interneurons Control the Size of Neuronal Memory Ensembles.

    PubMed

    Stefanelli, Thomas; Bertollini, Cristina; Lüscher, Christian; Muller, Dominique; Mendez, Pablo

    2016-03-01

    Hippocampal neurons activated during encoding drive the recall of contextual fear memory. Little is known about how such ensembles emerge during acquisition and eventually form the cellular engram. Manipulating the activity of granule cells (GCs) of the dentate gyrus (DG), we reveal a mechanism of lateral inhibition that modulates the size of the cellular engram. GCs engage somatostatin-positive interneurons that inhibit the dendrites of surrounding GCs. Our findings reveal a microcircuit within the DG that controls the size of the cellular engram and the stability of contextual fear memory. PMID:26875623

  19. Inhibition of Inhibition in Visual Cortex: The Logic of Connections Between Molecularly Distinct Interneurons

    PubMed Central

    Pfeffer, Carsten K.; Xue, Mingshan; He, Miao; Huang, Z. Josh; Scanziani, Massimo

    2013-01-01

    Cortical inhibitory neurons contact each other to form a network of inhibitory synaptic connections. Our knowledge of the connectivity pattern underlying this inhibitory network is, however, still incomplete. Here we discover a simple and complementary interaction scheme between three large molecularly distinct interneuron populations in mouse visual cortex: Parvalbumin expressing interneurons strongly inhibit one another but, surprisingly, provide little inhibition to other populations. In contrast, somatostatin expressing interneurons avoid inhibiting one another, yet strongly inhibit all other populations. Finally, vasoactive intestinal peptide expressing interneurons preferentially inhibit somatostatin interneurons. This scheme occurs in supra- and infra-granular layers, suggesting that inhibitory networks operate similarly at the input and output of visual cortex. Thus, as the specificity of connections between excitatory neurons forms the basis for the cortical canonical circuit, the scheme described here outlines a standard connectivity pattern among cortical inhibitory neurons. PMID:23817549

  20. Linking Cholinergic Interneurons, Synaptic Plasticity, and Behavior during the Extinction of a Cocaine-Context Association.

    PubMed

    Lee, Junuk; Finkelstein, Joel; Choi, Jung Yoon; Witten, Ilana B

    2016-06-01

    Despite the fact that cholinergic interneurons are a key cell type within the nucleus accumbens, a relationship between synaptic plasticity and the in vivo activity of cholinergic interneurons remains to be established. Here, we identify a three-way link between the activity of cholinergic interneurons, synaptic plasticity, and learning in mice undergoing the extinction of a cocaine-context association. We found that activity of cholinergic interneurons regulates extinction learning for a cocaine-context association and generates a sustained reduction in glutamatergic presynaptic strength onto medium spiny neurons. Interestingly, activation of cholinergic interneurons does not support reinforcement learning or plasticity by itself, suggesting that these neurons have a modulatory rather than a reinforcing function. PMID:27210555

  1. Cortical Interneurons Require Jnk1 to Enter and Navigate the Developing Cerebral Cortex

    PubMed Central

    Myers, Abigail K.; Meechan, Daniel W.; Adney, Danielle R.

    2014-01-01

    Proper assembly of cortical circuitry relies on the correct migration of cortical interneurons from their place of birth in the ganglionic eminences to their place of terminal differentiation in the cerebral cortex. Although molecular mechanisms mediating cortical interneuron migration have been well studied, intracellular signals directing their migration are largely unknown. Here we illustrate a novel and essential role for c-Jun N-terminal kinase (JNK) signaling in guiding the pioneering population of cortical interneurons into the mouse cerebral cortex. Migrating cortical interneurons express Jnk proteins at the entrance to the cortical rudiment and have enriched expression of Jnk1 relative to noninterneuronal cortical cells. Pharmacological blockade of JNK signaling in ex vivo slice cultures resulted in dose-dependent and highly specific disruption of interneuron migration into the nascent cortex. Time-lapse imaging revealed that JNK-inhibited cortical interneurons advanced slowly and assumed aberrant migratory trajectories while traversing the cortical entry zone. In vivo analyses of JNK-deficient embryos supported our ex vivo pharmacological data. Deficits in interneuron migration were observed in Jnk1 but not Jnk2 single nulls, and those migratory deficits were further exacerbated when homozygous loss of Jnk1 was combined with heterozygous reduction of Jnk2. Finally, genetic ablation of Jnk1 and Jnk2 from cortical interneurons significantly perturbed migration in vivo, but not in vitro, suggesting JNK activity functions to direct their guidance rather than enhance their motility. These data suggest JNK signaling, predominantly mediated by interneuron expressed Jnk1, is required for guiding migration of cortical interneurons into and within the developing cerebral cortex. PMID:24899703

  2. CBP regulates the differentiation of interneurons from ventral forebrain neural precursors during murine development.

    PubMed

    Tsui, David; Voronova, Anastassia; Gallagher, Denis; Kaplan, David R; Miller, Freda D; Wang, Jing

    2014-01-15

    The mechanisms that regulate appropriate genesis and differentiation of interneurons in the developing mammalian brain are of significant interest not only because interneurons play key roles in the establishment of neural circuitry, but also because when they are deficient, this can cause epilepsy. In this regard, one genetic syndrome that is associated with deficits in neural development and epilepsy is Rubinstein-Taybi Syndrome (RTS), where the transcriptional activator and histone acetyltransferase CBP is mutated and haploinsufficient. Here, we have asked whether CBP is necessary for the appropriate genesis and differentiation of interneurons in the murine forebrain, since this could provide an explanation for the epilepsy that is associated with RTS. We show that CBP is expressed in neural precursors within the embryonic medial ganglionic eminence (MGE), an area that generates the vast majority of interneurons for the cortex. Using primary cultures of MGE precursors, we show that knockdown of CBP causes deficits in differentiation of these precursors into interneurons and oligodendrocytes, and that overexpression of CBP is by itself sufficient to enhance interneuron genesis. Moreover, we show that levels of the neurotransmitter synthesis enzyme GAD67, which is expressed in inhibitory interneurons, are decreased in the dorsal and ventral forebrain of neonatal CBP(+/-) mice, indicating that CBP plays a role in regulating interneuron development in vivo. Thus, CBP normally acts to ensure the differentiation of appropriate numbers of forebrain interneurons, and when its levels are decreased, this causes deficits in interneuron development, providing a potential explanation for the epilepsy seen in individuals with RTS. PMID:24247009

  3. Dopaminergic and Cholinergic Modulation of Striatal Tyrosine Hydroxylase Interneurons

    PubMed Central

    Ibáñez-Sandoval, Osvaldo; Xenias, Harry S.; Tepper, James M.; Koós, Tibor

    2015-01-01

    The recent electrophysiological characterization of TH-expressing GABAergic interneurons (THINs) in the neostriatum revealed an unexpected degree of diversity of interneurons in this brain area (Ibáñez-Sandoval et al., 2010, Unal et al., 2011, 2013). Despite being relatively few in number, THINs may play a significant role in transmitting and distributing extra- and intrastriatal neuromodulatory signals in the striatal circuitry. Here we investigated the dopaminergic and cholinergic regulation of THINs in vitro. We found that the dominant effect of dopamine was a dramatic enhancement of the ability of THINs to generate long-lasting depolarizing plateau potentials (PPs). Interestingly, the same effect could also be elicited by amphetamine-induced release of endogenous dopamine suggesting that THINs may exhibit similar responses to changes in extracellular dopamine concentration in vivo. The enhancement of PPs in THINs is perhaps the most pronounced effect of dopamine on the intrinsic excitability of neostriatal neurons described to date. Further, we demonstrate that all subtypes of THINSs tested also express nicotinic cholinergic receptors. All THIS responded, albeit differentially, with depolarization, PPs and spiking to brief application of nicotinic agonists. Powerful modulation of the nonlinear integrative properties of THINs by dopamine and the direct depolarization of these neurons by acetylcholine may play important roles in mediating the effects of these neuromodulators in the neostriatum with potentially important implications for understanding the mechanisms of neuropsychiatric disorders affecting the basal ganglia. PMID:25908399

  4. Dopaminergic and cholinergic modulation of striatal tyrosine hydroxylase interneurons.

    PubMed

    Ibáñez-Sandoval, Osvaldo; Xenias, Harry S; Tepper, James M; Koós, Tibor

    2015-08-01

    The recent electrophysiological characterization of TH-expressing GABAergic interneurons (THINs) in the neostriatum revealed an unexpected degree of diversity of interneurons in this brain area (Ibáñez-Sandoval et al., 2010, Unal et al., 2011, 2015). Despite being relatively few in number, THINs may play a significant role in transmitting and distributing extra- and intrastriatal neuromodulatory signals in the striatal circuitry. Here we investigated the dopaminergic and cholinergic regulation of THINs in vitro. We found that the dominant effect of dopamine was a dramatic enhancement of the ability of THINs to generate long-lasting depolarizing plateau potentials (PPs). Interestingly, the same effect could also be elicited by amphetamine-induced release of endogenous dopamine suggesting that THINs may exhibit similar responses to changes in extracellular dopamine concentration in vivo. The enhancement of PPs in THINs is perhaps the most pronounced effect of dopamine on the intrinsic excitability of neostriatal neurons described to date. Further, we demonstrate that all subtypes of THINSs tested also express nicotinic cholinergic receptors. All THIS responded, albeit differentially, with depolarization, PPs and spiking to brief application of nicotinic agonists. Powerful modulation of the nonlinear integrative properties of THINs by dopamine and the direct depolarization of these neurons by acetylcholine may play important roles in mediating the effects of these neuromodulators in the neostriatum with potentially important implications for understanding the mechanisms of neuropsychiatric disorders affecting the basal ganglia. PMID:25908399

  5. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression.

    PubMed

    Courtin, Julien; Chaudun, Fabrice; Rozeske, Robert R; Karalis, Nikolaos; Gonzalez-Campo, Cecilia; Wurtz, Hélène; Abdi, Azzedine; Baufreton, Jerome; Bienvenu, Thomas C M; Herry, Cyril

    2014-01-01

    Synchronization of spiking activity in neuronal networks is a fundamental process that enables the precise transmission of information to drive behavioural responses. In cortical areas, synchronization of principal-neuron spiking activity is an effective mechanism for information coding that is regulated by GABA (γ-aminobutyric acid)-ergic interneurons through the generation of neuronal oscillations. Although neuronal synchrony has been demonstrated to be crucial for sensory, motor and cognitive processing, it has not been investigated at the level of defined circuits involved in the control of emotional behaviour. Converging evidence indicates that fear behaviour is regulated by the dorsomedial prefrontal cortex (dmPFC). This control over fear behaviour relies on the activation of specific prefrontal projections to the basolateral complex of the amygdala (BLA), a structure that encodes associative fear memories. However, it remains to be established how the precise temporal control of fear behaviour is achieved at the level of prefrontal circuits. Here we use single-unit recordings and optogenetic manipulations in behaving mice to show that fear expression is causally related to the phasic inhibition of prefrontal parvalbumin interneurons (PVINs). Inhibition of PVIN activity disinhibits prefrontal projection neurons and synchronizes their firing by resetting local theta oscillations, leading to fear expression. Our results identify two complementary neuronal mechanisms mediated by PVINs that precisely coordinate and enhance the neuronal activity of prefrontal projection neurons to drive fear expression. PMID:24256726

  6. Molecular layer interneurons of the cerebellum: developmental and morphological aspects.

    PubMed

    Sotelo, Constantino

    2015-10-01

    During the past 25 years, our knowledge on the development of basket and stellate cells (molecular layer interneurons [MLIs]) has completely changed, not only regarding their origin from the ventricular zone, corresponding to the primitive cerebellar neuroepithelium, instead of the external granular layer, but above all by providing an almost complete account of the genetic regulations (transcription factors and other genes) involved in their differentiation and synaptogenesis. Moreover, it has been shown that MLIs' precursors (dividing neuroblasts) and not young postmitotic neurons, as in other germinal neuroepithelia, leave the germinative zone and migrate all along a complex and lengthy path throughout the presumptive cerebellar white matter, which provides suitable niches exerting epigenetic influences on their ultimate neuronal identities. Recent studies carried out on the anatomical-functional properties of adult MLIs emphasize the importance of these interneurons in regulating PC inhibition, and point out the crucial role played by electrical synaptic transmission between MLIs as well as ephaptic interactions between them and Purkinje cells at the pinceaux level, in the regulation of this inhibition. PMID:25599913

  7. Dendritic and Axonal Wiring Optimization of Cortical GABAergic Interneurons.

    PubMed

    Anton-Sanchez, Laura; Bielza, Concha; Benavides-Piccione, Ruth; DeFelipe, Javier; Larrañaga, Pedro

    2016-10-01

    The way in which a neuronal tree expands plays an important role in its functional and computational characteristics. We aimed to study the existence of an optimal neuronal design for different types of cortical GABAergic neurons. To do this, we hypothesized that both the axonal and dendritic trees of individual neurons optimize brain connectivity in terms of wiring length. We took the branching points of real three-dimensional neuronal reconstructions of the axonal and dendritic trees of different types of cortical interneurons and searched for the minimal wiring arborization structure that respects the branching points. We compared the minimal wiring arborization with real axonal and dendritic trees. We tested this optimization problem using a new approach based on graph theory and evolutionary computation techniques. We concluded that neuronal wiring is near-optimal in most of the tested neurons, although the wiring length of dendritic trees is generally nearer to the optimum. Therefore, wiring economy is related to the way in which neuronal arborizations grow irrespective of the marked differences in the morphology of the examined interneurons. PMID:27345531

  8. The Current Status of Somatostatin-Interneurons in Inhibitory Control of Brain Function and Plasticity

    PubMed Central

    2016-01-01

    The mammalian neocortex contains many distinct inhibitory neuronal populations to balance excitatory neurotransmission. A correct excitation/inhibition equilibrium is crucial for normal brain development, functioning, and controlling lifelong cortical plasticity. Knowledge about how the inhibitory network contributes to brain plasticity however remains incomplete. Somatostatin- (SST-) interneurons constitute a large neocortical subpopulation of interneurons, next to parvalbumin- (PV-) and vasoactive intestinal peptide- (VIP-) interneurons. Unlike the extensively studied PV-interneurons, acknowledged as key components in guiding ocular dominance plasticity, the contribution of SST-interneurons is less understood. Nevertheless, SST-interneurons are ideally situated within cortical networks to integrate unimodal or cross-modal sensory information processing and therefore likely to be important mediators of experience-dependent plasticity. The lack of knowledge on SST-interneurons partially relates to the wide variety of distinct subpopulations present in the sensory neocortex. This review informs on those SST-subpopulations hitherto described based on anatomical, molecular, or electrophysiological characteristics and whose functional roles can be attributed based on specific cortical wiring patterns. A possible role for these subpopulations in experience-dependent plasticity will be discussed, emphasizing on learning-induced plasticity and on unimodal and cross-modal plasticity upon sensory loss. This knowledge will ultimately contribute to guide brain plasticity into well-defined directions to restore sensory function and promote lifelong learning. PMID:27403348

  9. Exogenous Sonic hedgehog modulates the pool of GABAergic interneurons during cerebellar development.

    PubMed

    De Luca, A; Parmigiani, E; Tosatto, G; Martire, S; Hoshino, M; Buffo, A; Leto, K; Rossi, F

    2015-04-01

    All cerebellar GABAergic interneurons were derived from a common pool of precursor cells residing in the embryonic ventricular zone (VZ) and migrating in the prospective white matter (PWM) after birth, where both intrinsic and extrinsic factors contribute to regulate their amplification. Among the environmental factors, we focused on Sonic hedgehog (Shh), a morphogen well known to regulate neural progenitor cell proliferation. We asked if and how exogenous Shh treatment affects the lineage of cerebellar GABAergic interneurons. To address these issues, exogenous Shh was administered to embryonic and postnatal organotypic slices. We found that Shh is able to expand the pool of interneuron progenitors residing in the embryonic epithelium and in the postnatal PWM. In particular, Shh signalling pathway was highly mitogenic at early developmental stages of interneuron production, whereas its effect decreased after the first postnatal week. Gene expression analysis of sorted cells and in situ hybridization further showed that immature interneurons express both the Shh receptor patched and the Shh target gene Gli1. Thus, within the interneuron lineage, Shh might exert regulatory functions also in postmitotic cells. On the whole, our data enlighten the role of Shh during cerebellar maturation and further broaden our knowledge on the amplification mechanisms of the interneuron progenitor pool. PMID:25245619

  10. Crosstalk between intracellular and extracellular signals regulating interneuron production, migration and integration into the cortex

    PubMed Central

    Peyre, Elise; Silva, Carla G.; Nguyen, Laurent

    2015-01-01

    During embryogenesis, cortical interneurons are generated by ventral progenitors located in the ganglionic eminences of the telencephalon. They travel along multiple tangential paths to populate the cortical wall. As they reach this structure they undergo intracortical dispersion to settle in their final destination. At the cellular level, migrating interneurons are highly polarized cells that extend and retract processes using dynamic remodeling of microtubule and actin cytoskeleton. Different levels of molecular regulation contribute to interneuron migration. These include: (1) Extrinsic guidance cues distributed along migratory streams that are sensed and integrated by migrating interneurons; (2) Intrinsic genetic programs driven by specific transcription factors that grant specification and set the timing of migration for different subtypes of interneurons; (3) Adhesion molecules and cytoskeletal elements/regulators that transduce molecular signalings into coherent movement. These levels of molecular regulation must be properly integrated by interneurons to allow their migration in the cortex. The aim of this review is to summarize our current knowledge of the interplay between microenvironmental signals and cell autonomous programs that drive cortical interneuron porduction, tangential migration, and intergration in the developing cerebral cortex. PMID:25926769

  11. The Current Status of Somatostatin-Interneurons in Inhibitory Control of Brain Function and Plasticity.

    PubMed

    Scheyltjens, Isabelle; Arckens, Lutgarde

    2016-01-01

    The mammalian neocortex contains many distinct inhibitory neuronal populations to balance excitatory neurotransmission. A correct excitation/inhibition equilibrium is crucial for normal brain development, functioning, and controlling lifelong cortical plasticity. Knowledge about how the inhibitory network contributes to brain plasticity however remains incomplete. Somatostatin- (SST-) interneurons constitute a large neocortical subpopulation of interneurons, next to parvalbumin- (PV-) and vasoactive intestinal peptide- (VIP-) interneurons. Unlike the extensively studied PV-interneurons, acknowledged as key components in guiding ocular dominance plasticity, the contribution of SST-interneurons is less understood. Nevertheless, SST-interneurons are ideally situated within cortical networks to integrate unimodal or cross-modal sensory information processing and therefore likely to be important mediators of experience-dependent plasticity. The lack of knowledge on SST-interneurons partially relates to the wide variety of distinct subpopulations present in the sensory neocortex. This review informs on those SST-subpopulations hitherto described based on anatomical, molecular, or electrophysiological characteristics and whose functional roles can be attributed based on specific cortical wiring patterns. A possible role for these subpopulations in experience-dependent plasticity will be discussed, emphasizing on learning-induced plasticity and on unimodal and cross-modal plasticity upon sensory loss. This knowledge will ultimately contribute to guide brain plasticity into well-defined directions to restore sensory function and promote lifelong learning. PMID:27403348

  12. Serotonin excites hippocampal CA1 GABAergic interneurons at the stratum radiatum-stratum lacunosum moleculare border.

    PubMed

    Wyskiel, Daniel R; Andrade, Rodrigo

    2016-09-01

    The hippocampus receives robust serotonergic innervation that is thought to control the excitability of both pyramidal cells and GABAergic interneurons. Previous work has addressed serotonergic regulation of pyramidal cells but considerable gaps remain in our understanding of how serotonin regulates different interneuron subclasses. 5-HT2A receptors (5-HT2A Rs) appear to localize predominantly, if not solely, on interneurons in the hippocampus and have been implicated in the regulation of hippocampal function including mnemonic and novelty recognition processes. Interneurons are functionally diverse. Therefore in the current work, we have used a BAC transgenic mouse line expressing EGFP under the control of the 5-HT2A R promoter to identify the interneuron subtype(s) regulated by serotonin via 5-HT2A Rs. We find that EGFP expression in this mouse identifies a group of interneurons that resides predominantly along the border of the stratum radiatum (SR) and stratum lacunosum moleculare (SLM) of the CA1 region. We then show that these cells are depolarized and excited by serotonin acting through 5-HT2A Rs and appear to belong predominantly to the perforant pathway-associated and Schaffer collateral/commissural pathway-associated subtypes. These results indicate that serotonin interneurons expressing 5-HT2A Rs are localized primarily along the SR-SLM border of the CA1 region and represent a newly identified target for serotonin regulation in the hippocampus. © 2016 Wiley Periodicals, Inc. PMID:27328460

  13. GABA interneurons mediate the rapid antidepressant-like effects of scopolamine.

    PubMed

    Wohleb, Eric S; Wu, Min; Gerhard, Danielle M; Taylor, Seth R; Picciotto, Marina R; Alreja, Meenakshi; Duman, Ronald S

    2016-07-01

    Major depressive disorder (MDD) is a recurring psychiatric illness that causes substantial health and socioeconomic burdens. Clinical reports have revealed that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in individuals with MDD. Preclinical models suggest that these rapid antidepressant effects can be recapitulated with blockade of M1-type muscarinic acetylcholine receptors (M1-AChR); however, the cellular mechanisms underlying activity-dependent synaptic and behavioral responses to scopolamine have not been determined. Here, we demonstrate that the antidepressant-like effects of scopolamine are mediated by GABA interneurons in the medial prefrontal cortex (mPFC). Both GABAergic (GAD67+) interneurons and glutamatergic (CaMKII+) interneurons in the mPFC expressed M1-AChR. In mice, viral-mediated knockdown of M1-AChR specifically in GABAergic neurons, but not glutamatergic neurons, in the mPFC attenuated the antidepressant-like effects of scopolamine. Immunohistology and electrophysiology showed that somatostatin (SST) interneurons in the mPFC express M1-AChR at higher levels than parvalbumin interneurons. Moreover, knockdown of M1-AChR in SST interneurons in the mPFC demonstrated that M1-AChR expression in these neurons is required for the rapid antidepressant-like effects of scopolamine. These data indicate that SST interneurons in the mPFC are a promising pharmacological target for developing rapid-acting antidepressant therapies. PMID:27270172

  14. Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity

    PubMed Central

    Matta, Jose A; Pelkey, Kenneth A; Craig, Michael T; Chittajallu, Ramesh; Jeffries, Brian W; McBain, Chris J

    2014-01-01

    Disrupted excitatory synapse maturation in GABAergic interneurons may promote neuropsychiatric disorders such as schizophrenia. However, establishing developmental programs for nascent synapses in GABAergic cells is confounded by their sparsity, heterogeneity and late acquisition of subtype-defining characteristics. We investigated synaptic development in mouse interneurons targeting cells by lineage from medial ganglionic eminence (MGE) or caudal ganglionic eminence (CGE) progenitors. MGE-derived interneuron synapses were dominated by GluA2-lacking AMPA-type glutamate receptors (AMPARs), with little contribution from NMDA-type receptors (NMDARs) throughout development. In contrast, CGE-derived cell synapses had large NMDAR components and used GluA2-containing AMPARs. In neonates, both MGE- and CGE-derived interneurons expressed primarily GluN2B subunit–containing NMDARs, which most CGE-derived interneurons retained into adulthood. However, MGE-derived interneuron NMDARs underwent a GluN2B-to-GluN2A switch that could be triggered acutely with repetitive synaptic activity. Our findings establish ganglionic eminence–dependent rules for early synaptic integration programs of distinct interneuron cohorts, including parvalbumin- and cholecystokinin-expressing basket cells. PMID:23852113

  15. Adenosine-mediated modulation of ventral horn interneurons and spinal motoneurons in neonatal mice.

    PubMed

    Witts, Emily C; Nascimento, Filipe; Miles, Gareth B

    2015-10-01

    Neuromodulation allows neural networks to adapt to varying environmental and biomechanical demands. Purinergic signaling is known to be an important modulatory system in many parts of the CNS, including motor control circuitry. We have recently shown that adenosine modulates the output of mammalian spinal locomotor control circuitry (Witts EC, Panetta KM, Miles GB. J Neurophysiol 107: 1925-1934, 2012). Here we investigated the cellular mechanisms underlying this adenosine-mediated modulation. Whole cell patch-clamp recordings were performed on ventral horn interneurons and motoneurons within in vitro mouse spinal cord slice preparations. We found that adenosine hyperpolarized interneurons and reduced the frequency and amplitude of synaptic inputs to interneurons. Both effects were blocked by the A1-type adenosine receptor antagonist DPCPX. Analysis of miniature postsynaptic currents recorded from interneurons revealed that adenosine reduced their frequency but not amplitude, suggesting that adenosine acts on presynaptic receptors to modulate synaptic transmission. In contrast to interneurons, recordings from motoneurons revealed an adenosine-mediated depolarization. The frequency and amplitude of synaptic inputs to motoneurons were again reduced by adenosine, but we saw no effect on miniature postsynaptic currents. Again these effects on motoneurons were blocked by DPCPX. Taken together, these results demonstrate differential effects of adenosine, acting via A1 receptors, in the mouse spinal cord. Adenosine has a general inhibitory action on ventral horn interneurons while potentially maintaining motoneuron excitability. This may allow for adaptation of the locomotor pattern generated by interneuronal networks while helping to ensure the maintenance of overall motor output. PMID:26311185

  16. Cell-type Specific Development of NMDA Receptors in the Interneurons of Rat Prefrontal Cortex

    PubMed Central

    Wang, Huai-Xing; Gao, Wen-Jun

    2009-01-01

    In the prefrontal cortex, N-methyl-D-aspartic acid (NMDA) receptors are critical not only for normal prefrontal functions but also for the pathological processes of schizophrenia. Little is known, however, about the developmental properties of NMDA receptors in the functionally diverse subpopulations of interneurons. We investigated the developmental changes of NMDA receptors in rat prefrontal interneurons using patch clamp recording in cortical slices. We found that fast-spiking (FS) interneurons exhibited properties of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA currents distinct from those in regular spiking (RS) and low-threshold spiking (LTS) interneurons, particularly during the adolescent period. In juvenile animals, most (73%) of the FS cells demonstrated both AMPA and NMDA currents. The NMDA currents, however, gradually became undetectable during cortical development, with most (74%) of the FS cells exhibiting no NMDA current in adults. In contrast, AMPA and NMDA currents in RS and LTS interneurons were relatively stable, without significant changes from juveniles to adults. Moreover, even in FS cells with NMDA currents, the NMDA/AMPA ratio dramatically decreased during the adolescent period but returned to juvenile level in adults, compared to the relatively stable ratios in RS and LTS interneurons. These data suggest that FS interneurons in the PFC undergo dramatic changes in glutamatergic receptors during the adolescent period. These properties may make FS cells particularly sensitive and vulnerable to epigenetic stimulation, thus contributing to the onset of many psychiatric disorders, including schizophrenia. PMID:19242405

  17. Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome

    PubMed Central

    Xu, Meiyu; Kobets, Andrew; Du, Jung-Chieh; Lennington, Jessica; Li, Lina; Banasr, Mounira; Duman, Ronald S.; Vaccarino, Flora M.; DiLeone, Ralph J.; Pittenger, Christopher

    2015-01-01

    Gilles de la Tourette syndrome (TS) is characterized by tics, which are transiently worsened by stress, acute administration of dopaminergic drugs, and by subtle deficits in motor coordination and sensorimotor gating. It represents the most severe end of a spectrum of tic disorders that, in aggregate, affect ∼5% of the population. Available treatments are frequently inadequate, and the pathophysiology is poorly understood. Postmortem studies have revealed a reduction in specific striatal interneurons, including the large cholinergic interneurons, in severe disease. We tested the hypothesis that this deficit is sufficient to produce aspects of the phenomenology of TS, using a strategy for targeted, specific cell ablation in mice. We achieved ∼50% ablation of the cholinergic interneurons of the striatum, recapitulating the deficit observed in patients postmortem, without any effect on GABAergic markers or on parvalbumin-expressing fast-spiking interneurons. Interneuron ablation in the dorsolateral striatum (DLS), corresponding roughly to the human putamen, led to tic-like stereotypies after either acute stress or d-amphetamine challenge; ablation in the dorsomedial striatum, in contrast, did not. DLS interneuron ablation also led to a deficit in coordination on the rotorod, but not to any abnormalities in prepulse inhibition, a measure of sensorimotor gating. These results support the causal sufficiency of cholinergic interneuron deficits in the DLS to produce some, but not all, of the characteristic symptoms of TS. PMID:25561540

  18. DREADD in Parvalbumin Interneurons of the Dentate Gyrus Modulates Anxiety, Social Interaction and Memory Extinction

    PubMed Central

    Zou, D.; Chen, L.; Deng, D.; Jiang, D.; Dong, F.; McSweeney, C.; Zhou, Y.; Liu, L.; Chen, G.; Wu, Y.; Mao, Y.

    2016-01-01

    Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PV-positive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3D-Gq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.

  19. The vulnerability of calretinin-containing hippocampal interneurons to temporal lobe epilepsy

    PubMed Central

    Tóth, Kinga; Maglóczky, Zsófia

    2014-01-01

    This review focuses on the vulnerability of a special interneuron type—the calretinin (CR)-containing interneurons—in temporal lobe epilepsy (TLE). CR is a calcium-binding protein expressed mainly by GABAergic interneurons in the hippocampus. Despite their morphological heterogeneity, CR-containing interneurons form a distinct subpopulation of inhibitory cells, innervating other interneurons in rodents and to some extent principal cells in the human. Their dendrites are strongly connected by zona adherentiae and presumably by gap junctions both in rats and humans. CR-containing interneurons are suggested to play a key role in the hippocampal inhibitory network, since they can effectively synchronize dendritic inhibitory interneurons. The sensitivity of CR-expressing interneurons to epilepsy was discussed in several reports, both in animal models and in humans. In the sclerotic hippocampus the density of CR-immunopositive cells is decreased significantly. In the non-sclerotic hippocampus, the CR-containing interneurons are preserved, but their dendritic tree is varicose, segmented, and zona-adherentia-type contacts can be less frequently observed among dendrites. Therefore, the dendritic inhibition of pyramidal cells may be less effective in TLE. This can be partially explained by the impairment of the CR-containing interneuron ensemble in the epileptic hippocampus, which may result in an asynchronous and thus less effective dendritic inhibition of the principal cells. This phenomenon, together with the sprouting of excitatory pathway axons and enhanced innervation of principal cells, may be involved in seizure generation. Preventing the loss of CR-positive cells and preserving the integrity of CR-positive dendrite gap junctions may have antiepileptic effects, maintaining proper inhibitory function and helping to protect principal cells in epilepsy. PMID:25324731

  20. Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease

    PubMed Central

    Lax, Nichola Z.; Grady, John; Laude, Alex; Chan, Felix; Hepplewhite, Philippa D.; Gorman, Grainne; Whittaker, Roger G.; Ng, Yi; Cunningham, Mark O.

    2015-01-01

    Aims Mitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA. Currently, we do not understand the specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest γ‐aminobutyric acid (GABA)‐ergic interneurones are particularly susceptible to respiratory chain dysfunction. In this neuropathological study, we assess the impact of mitochondrial DNA defects on inhibitory interneurones in patients with mitochondrial disease. Methods Histochemical, immunohistochemical and immunofluorescent assays were performed on post‐mortem brain tissue from 10 patients and 10 age‐matched control individuals. We applied a quantitative immunofluorescent method to interrogate complex I and IV protein expression in mitochondria within GABAergic interneurone populations in the frontal, temporal and occipital cortices. We also evaluated the density of inhibitory interneurones in serial sections to determine if cell loss was occurring. Results We observed significant, global reductions in complex I expression within GABAergic interneurones in frontal, temporal and occipital cortices in the majority of patients. While complex IV expression is more variable, there is reduced expression in patients harbouring m.8344A>G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABAergic cell density showed a dramatic reduction in cell density suggesting interneurone loss. Conclusions We propose that the combined loss of interneurones and severe respiratory deficiency in remaining interneurones contributes to impaired neuronal network oscillations and could underlie development of neurological deficits, such as cognitive impairment and epilepsy, in mitochondrial disease. PMID:25786813

  1. In vivo properties of cerebellar interneurons in the macaque caudal vestibular vermis

    PubMed Central

    Meng, Hui; Laurens, Jean; Blázquez, Pablo M; Angelaki, Dora E

    2015-01-01

    The cerebellar cortex is among the brain’s most well-studied circuits and includes distinct classes of excitatory and inhibitory interneurons. Several studies have attempted to characterize the in vivo properties of cerebellar interneurons, yet little is currently known about their stimulus-driven properties. Here we quantify both spontaneous and stimulus-driven responses of interneurons in lobules X (nodulus) and IXc,d (ventral uvula) of the macaque caudal vermis during vestibular stimulation. Interneurons were identified as cells located >100 μm from the Purkinje cell layer that did not exhibit complex spikes. Based on baseline firing, three types of interneurons could be distinguished. First, there was a group of very regular firing interneurons with high mean discharge rates, which consistently encoded tilt, rather than translational head movements. Second, there was a group of low firing interneurons with a range of discharge regularity. This group had more diverse vestibular properties, where most were translation-selective and a few tilt- or gravitoinertial acceleration-selective. Third, we also encountered interneurons that were similar to Purkinje cells in terms of discharge regularity and mean firing rate. This group also encoded mixtures of tilt and translation signals. A few mossy fibres showed unprocessed, otolith afferent-like properties, encoding the gravitoinertial acceleration. We conclude that tilt- and translation-selective signals, which reflect neural computations transforming vestibular afferent information, are not only encountered in Purkinje cell responses. Instead, upstream interneurons within the cerebellar cortex are also characterized by similar properties, thus implying a widespread network computation. PMID:25556803

  2. Interneurons Differentially Contribute to Spontaneous Network Activity in the Developing Hippocampus Dependent on Their Embryonic Lineage

    PubMed Central

    Wester, Jason C.

    2016-01-01

    Spontaneously generated network activity is a hallmark of developing neural circuits, and plays an important role in the formation of synaptic connections. In the rodent hippocampus, this activity is observed in vitro as giant depolarizing potentials (GDPs) during the first postnatal week. Interneurons importantly contribute to GDPs, due to the depolarizing actions of GABA early in development. While they are highly diverse, cortical interneurons can be segregated into two distinct groups based on their embryonic lineage from either the medial or caudal ganglionic eminences (MGE and CGE). There is evidence suggesting CGE-derived interneurons are important for GDP generation; however, their contribution relative to those from the MGE has never been directly tested. Here, we optogenetically inhibited either MGE- or CGE-derived interneurons in a region-specific manner in mouse neonatal hippocampus in vitro. In CA1, where interneurons are the primary source of recurrent excitation, we found that those from the MGE strongly and preferentially contributed to GDP generation. Furthermore, in dual whole-cell patch recordings in neonatal CA1, MGE interneurons formed synaptic connections to and from neighboring pyramidal cells at a much higher rate than those from the CGE. These MGE interneurons were commonly perisomatic targeting, in contrast to those from the CGE, which were dendrite targeting. Finally, inhibiting MGE interneurons in CA1 suppressed GDPs in CA3 and vice versa; conversely, they could also trigger GDPs in CA1 that propagated to CA3 and vice versa. Our data demonstrate a key role for MGE-derived interneurons in both generating and coordinating GDPs across the hippocampus. SIGNIFICANCE STATEMENT During nervous system development, immature circuits internally generate rhythmic patterns of electrical activity that promote the establishment of synaptic connections. Immature interneurons are excitatory rather than inhibitory and actively contribute to the generation

  3. Spillover-mediated feedforward-inhibition functionally segregates interneuron activity

    PubMed Central

    Coddington, Luke T.; Rudolph, Stephanie; Lune, Patrick Vande; Overstreet-Wadiche, Linda; Wadiche, Jacques I.

    2013-01-01

    Summary Neurotransmitter spillover represents a form of neural transmission not restricted to morphologically defined synaptic connections. Communication between climbing fibers (CFs) and molecular layer interneurons (MLIs) in the cerebellum is mediated exclusively by glutamate spillover. Here, we show how CF stimulation functionally segregates MLIs based on their location relative to glutamate release. Excitation of MLIs that reside within the domain of spillover diffusion coordinates inhibition of MLIs outside the diffusion limit. CF excitation of MLIs is dependent on extrasynaptic NMDA receptors that enhance the spatial and temporal spread of CF signaling. Activity mediated by functionally segregated MLIs converges onto neighboring Purkinje cells (PCs) to generate a long-lasting biphasic change in inhibition. These data demonstrate how glutamate release from single CFs modulates excitability of neighboring PCs, thus expanding the influence of CFs on cerebellar cortical activity in a manner not predicted by anatomical connectivity. PMID:23707614

  4. Four GABAergic interneurons impose feeding restraint in Drosophila

    PubMed Central

    Pool, Allan-Hermann; Kvello, Pal; Mann, Kevin; Cheung, Samantha K.; Gordon, Michael D.; Wang, Liming; Scott, Kristin

    2014-01-01

    Summary Feeding is dynamically regulated by the palatability of the food source and the physiological needs of the animal. How consumption is controlled by external sensory cues and internal metabolic state remains under intense investigation. Here, we identify four GABAergic interneurons in the Drosophila brain that establish a central feeding threshold which is required to inhibit consumption. Inactivation of these cells results in indiscriminate and excessive intake of all compounds, independent of taste quality or nutritional state. Conversely, acute activation of these neurons suppresses consumption of water and nutrients. The output from these neurons is required to gate activity in motor neurons that control meal initiation and consumption. Thus, our study reveals a new layer of inhibitory control in feeding circuits that is required to suppress a latent state of unrestricted and non-selective consumption. PMID:24991960

  5. Parvalbumin-expressing interneurons linearly control olfactory bulb output.

    PubMed

    Kato, Hiroyuki K; Gillet, Shea N; Peters, Andrew J; Isaacson, Jeffry S; Komiyama, Takaki

    2013-12-01

    In the olfactory bulb, odor representations by principal mitral cells are modulated by local inhibitory circuits. While dendrodendritic synapses between mitral and granule cells are typically thought to be a major source of this modulation, the contributions of other inhibitory neurons remain unclear. Here we demonstrate the functional properties of olfactory bulb parvalbumin-expressing interneurons (PV cells) and identify their important role in odor coding. Using paired recordings, we find that PV cells form reciprocal connections with the majority of nearby mitral cells, in contrast to the sparse connectivity between mitral and granule cells. In vivo calcium imaging in awake mice reveals that PV cells are broadly tuned to odors. Furthermore, selective PV cell inactivation enhances mitral cell responses in a linear fashion while maintaining mitral cell odor preferences. Thus, dense connections between mitral and PV cells underlie an inhibitory circuit poised to modulate the gain of olfactory bulb output. PMID:24239124

  6. Adult Born Olfactory Bulb Dopaminergic Interneurons: Molecular Determinants and Experience-Dependent Plasticity.

    PubMed

    Bonzano, Sara; Bovetti, Serena; Gendusa, Claudio; Peretto, Paolo; De Marchis, Silvia

    2016-01-01

    The olfactory bulb (OB) is a highly plastic brain region involved in the early processing of olfactory information. A remarkably feature of the OB circuits in rodents is the constitutive integration of new neurons that takes place during adulthood. Newborn cells in the adult OB are mostly inhibitory interneurons belonging to chemically, morphologically and functionally heterogeneous types. Although there is general agreement that adult neurogenesis in the OB plays a key role in sensory information processing and olfaction-related plasticity, the contribution of each interneuron subtype to such functions is far to be elucidated. Here, we focus on the dopaminergic (DA) interneurons: we highlight recent findings about their morphological features and then describe the molecular factors required for the specification/differentiation and maintenance of the DA phenotype in adult born neurons. We also discuss dynamic changes of the DA interneuron population related to age, environmental stimuli and lesions, and their possible functional implications. PMID:27199651

  7. Adult Born Olfactory Bulb Dopaminergic Interneurons: Molecular Determinants and Experience-Dependent Plasticity

    PubMed Central

    Bonzano, Sara; Bovetti, Serena; Gendusa, Claudio; Peretto, Paolo; De Marchis, Silvia

    2016-01-01

    The olfactory bulb (OB) is a highly plastic brain region involved in the early processing of olfactory information. A remarkably feature of the OB circuits in rodents is the constitutive integration of new neurons that takes place during adulthood. Newborn cells in the adult OB are mostly inhibitory interneurons belonging to chemically, morphologically and functionally heterogeneous types. Although there is general agreement that adult neurogenesis in the OB plays a key role in sensory information processing and olfaction-related plasticity, the contribution of each interneuron subtype to such functions is far to be elucidated. Here, we focus on the dopaminergic (DA) interneurons: we highlight recent findings about their morphological features and then describe the molecular factors required for the specification/differentiation and maintenance of the DA phenotype in adult born neurons. We also discuss dynamic changes of the DA interneuron population related to age, environmental stimuli and lesions, and their possible functional implications. PMID:27199651

  8. Transient Suppression of Dbx1 PreBötzinger Interneurons Disrupts Breathing in Adult Mice.

    PubMed

    Vann, Nikolas C; Pham, Francis D; Hayes, John A; Kottick, Andrew; Del Negro, Christopher A

    2016-01-01

    Interneurons derived from Dbx1-expressing precursors located in the brainstem preBötzinger complex (preBötC) putatively form the core oscillator for inspiratory breathing movements. We tested this Dbx1 core hypothesis by expressing archaerhodopsin in Dbx1-derived interneurons and then transiently hyperpolarizing these neurons while measuring respiratory rhythm in vitro or breathing in vagus-intact adult mice. Transient illumination of the preBötC interrupted inspiratory rhythm in both slice preparations and sedated mice. In awake mice, light application reduced breathing frequency and prolonged the inspiratory duration. Support for the Dbx1 core hypothesis previously came from embryonic and perinatal mouse experiments, but these data suggest that Dbx1-derived preBötC interneurons are rhythmogenic in adult mice too. The neural origins of breathing behavior can be attributed to a localized and genetically well-defined interneuron population. PMID:27611210

  9. A Comparative Perspective on Minicolumns and Inhibitory GABAergic Interneurons in the Neocortex

    PubMed Central

    Raghanti, Mary Ann; Spocter, Muhammad A.; Butti, Camilla; Hof, Patrick R.; Sherwood, Chet C.

    2009-01-01

    Neocortical columns are functional and morphological units whose architecture may have been under selective evolutionary pressure in different mammalian lineages in response to encephalization and specializations of cognitive abilities. Inhibitory interneurons make a substantial contribution to the morphology and distribution of minicolumns within the cortex. In this context, we review differences in minicolumns and GABAergic interneurons among species and discuss possible implications for signaling among and within minicolumns. Furthermore, we discuss how abnormalities of both minicolumn disposition and inhibitory interneurons might be associated with neuropathological processes, such as Alzheimer's disease, autism, and schizophrenia. Specifically, we explore the possibility that phylogenetic variability in calcium-binding protein-expressing interneuron subtypes is directly related to differences in minicolumn morphology among species and might contribute to neuropathological susceptibility in humans. PMID:20161991

  10. Topochemistry of Internuclear and Intranuclear Interneurons of the Vasomotor Area in the Medulla Oblongata of Hypertensive Rats.

    PubMed

    Chertok, V M; Kotsyuba, A E; Startseva, M S

    2016-01-01

    Immunohistochemical examination with the antiserum against neuronal NO synthase and cystathionine β-synthase was used to study the following two pools of interneurons in Wistar rats at various periods after the development of renovascular hypertension: intranuclear interneurons (lying in the projection of the solitary nucleus, reticular gigantocellular nucleus, and parvocellular nucleus) and 2 groups of internuclear interneurons (small interneurons, area 50-300 μ(2); and large interneurons, area above 350 μ(2)). Intranuclear and internuclear interneurons probably play a role in the central mechanisms of hemodynamics regulation. These interneurons differ by not only in topochemical parameters, but also functional properties (different resistances to BP changes). Intranuclear interneurons are characterized by high sensitivity of the gas transmitter systems to a continuous increase in BP, which results in remodeling and dysfunction of the bulbar part of the cardiovascular center. Large internuclear interneurons demonstrate a strong reaction to BP rise, which confirms their involvement into hemodynamics regulation. By contrast, small internuclear interneurons retain their characteristics in arterial hypertension and probably perform an integrative function. PMID:26746841

  11. Whole-Brain Mapping of Inputs to Projection Neurons and Cholinergic Interneurons in the Dorsal Striatum

    PubMed Central

    Guo, Qingchun; Wang, Daqing; He, Xiaobin; Feng, Qiru; Lin, Rui; Xu, Fuqiang; Fu, Ling; Luo, Minmin

    2015-01-01

    The dorsal striatum integrates inputs from multiple brain areas to coordinate voluntary movements, associative plasticity, and reinforcement learning. Its projection neurons consist of the GABAergic medium spiny neurons (MSNs) that express dopamine receptor type 1 (D1) or dopamine receptor type 2 (D2). Cholinergic interneurons account for a small portion of striatal neuron populations, but they play important roles in striatal functions by synapsing onto the MSNs and other local interneurons. By combining the modified rabies virus with specific Cre- mouse lines, a recent study mapped the monosynaptic input patterns to MSNs. Because only a small number of extrastriatal neurons were labeled in the prior study, it is important to reexamine the input patterns of MSNs with higher labeling efficiency. Additionally, the whole-brain innervation pattern of cholinergic interneurons remains unknown. Using the rabies virus-based transsynaptic tracing method in this study, we comprehensively charted the brain areas that provide direct inputs to D1-MSNs, D2-MSNs, and cholinergic interneurons in the dorsal striatum. We found that both types of projection neurons and the cholinergic interneurons receive extensive inputs from discrete brain areas in the cortex, thalamus, amygdala, and other subcortical areas, several of which were not reported in the previous study. The MSNs and cholinergic interneurons share largely common inputs from areas outside the striatum. However, innervations within the dorsal striatum represent a significantly larger proportion of total inputs for cholinergic interneurons than for the MSNs. The comprehensive maps of direct inputs to striatal MSNs and cholinergic interneurons shall assist future functional dissection of the striatal circuits. PMID:25830919

  12. Prefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons.

    PubMed

    Bissonette, Gregory B; Bae, Mihyun H; Suresh, Tejas; Jaffe, David E; Powell, Elizabeth M

    2014-02-01

    Alterations of inhibitory GABAergic neurons are implicated in multiple psychiatric and neurological disorders, including schizophrenia, autism and epilepsy. In particular, interneuron deficits in prefrontal areas, along with presumed decreased inhibition, have been reported in several human patients. The majority of forebrain GABAergic interneurons arise from a single subcortical source before migrating to their final regional destination. Factors that govern the interneuron populations have been identified, demonstrating that a single gene mutation may globally affect forebrain structures or a single area. In particular, mice lacking the urokinase plasminogen activator receptor (Plaur) gene have decreased GABAergic interneurons in frontal and parietal, but not caudal, cortical regions. Plaur assists in the activation of hepatocyte growth factor/scatter factor (HGF/SF), and several of the interneuron deficits are correlated with decreased levels of HGF/SF. In some cortical regions, the interneuron deficit can be remediated by endogenous overexpression of HGF/SF. In this study, we demonstrate decreased parvalbumin-expressing interneurons in the medial frontal cortex, but not in the hippocampus or basal lateral amygdala in the Plaur null mouse. The Plaur null mouse demonstrates impaired medial frontal cortical function in extinction of cued fear conditioning and the inability to form attentional sets. Endogenous HGF/SF overexpression increased the number of PV-expressing cells in medial frontal cortical areas to levels greater than found in wildtype mice, but did not remediate the behavioral deficits. These data suggest that proper medial frontal cortical function is dependent upon optimum levels of inhibition and that a deficit or excess of interneuron numbers impairs normal cognition. PMID:24211452

  13. Whole-brain mapping of inputs to projection neurons and cholinergic interneurons in the dorsal striatum.

    PubMed

    Guo, Qingchun; Wang, Daqing; He, Xiaobin; Feng, Qiru; Lin, Rui; Xu, Fuqiang; Fu, Ling; Luo, Minmin

    2015-01-01

    The dorsal striatum integrates inputs from multiple brain areas to coordinate voluntary movements, associative plasticity, and reinforcement learning. Its projection neurons consist of the GABAergic medium spiny neurons (MSNs) that express dopamine receptor type 1 (D1) or dopamine receptor type 2 (D2). Cholinergic interneurons account for a small portion of striatal neuron populations, but they play important roles in striatal functions by synapsing onto the MSNs and other local interneurons. By combining the modified rabies virus with specific Cre- mouse lines, a recent study mapped the monosynaptic input patterns to MSNs. Because only a small number of extrastriatal neurons were labeled in the prior study, it is important to reexamine the input patterns of MSNs with higher labeling efficiency. Additionally, the whole-brain innervation pattern of cholinergic interneurons remains unknown. Using the rabies virus-based transsynaptic tracing method in this study, we comprehensively charted the brain areas that provide direct inputs to D1-MSNs, D2-MSNs, and cholinergic interneurons in the dorsal striatum. We found that both types of projection neurons and the cholinergic interneurons receive extensive inputs from discrete brain areas in the cortex, thalamus, amygdala, and other subcortical areas, several of which were not reported in the previous study. The MSNs and cholinergic interneurons share largely common inputs from areas outside the striatum. However, innervations within the dorsal striatum represent a significantly larger proportion of total inputs for cholinergic interneurons than for the MSNs. The comprehensive maps of direct inputs to striatal MSNs and cholinergic interneurons shall assist future functional dissection of the striatal circuits. PMID:25830919

  14. Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility

    PubMed Central

    Dutton, Stacey B.; Makinson, Christopher D.; Papale, Ligia A.; Shankar, Anupama; Balakrishnan, Bindu; Nakazawa, Kazu; Escayg, Andrew

    2012-01-01

    Voltage-gated sodium channels (VGSCs) are essential for the generation and propagation of action potentials in electrically excitable cells. Dominant mutations in SCN1A, which encodes the Nav1.1 VGSC α-subunit, underlie several forms of epilepsy, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Electrophysiological analyses of DS and GEFS+ mouse models have led to the hypothesis that SCN1A mutations reduce the excitability of inhibitory cortical and hippocampal interneurons. To more directly examine the relative contribution of inhibitory interneurons and excitatory pyramidal cells to SCN1A-derived epilepsy, we first compared the expression of Nav1.1 in inhibitory parvalbumin (PV) interneurons and excitatory neurons from P22 mice using fluorescent immunohistochemistry. In the hippocampus and neocortex, 69% of Nav1.1 immunoreactive neurons were also positive for PV. In contrast, 13% and 5% of Nav1.1 positive cells in the hippocampus and neocortex, respectively, were found to co-localize with excitatory cells identified by CaMK2α immunoreactivity. Next, we reduced the expression of Scn1a in either a subset of interneurons (mainly PV interneurons) or excitatory cells by crossing mice heterozygous for a floxed Scn1a allele to either the Ppp1r2-Cre or EMX1-Cre transgenic lines, respectively. The inactivation of one Scn1a allele in interneurons of the neocortex and hippocampus was sufficient to reduce thresholds to flurothyl- and hyperthermia-induced seizures, whereas thresholds were unaltered following inactivation in excitatory cells. Reduced interneuron Scn1a expression also resulted in the generation of spontaneous seizures. These findings provide direct evidence for an important role of PV interneurons in the pathogenesis of Scn1a-derived epilepsies. PMID:22926190

  15. Concerted GABAergic actions of Aplysia feeding interneurons in motor program specification.

    PubMed

    Jing, Jian; Vilim, Ferdinand S; Wu, Jin-Sheng; Park, Ji-Ho; Weiss, Klaudiusz R

    2003-06-15

    GABAergic inhibitory interneurons regulate the activity of diverse types of neural networks, but the specific roles of these interneurons in motor control are poorly understood. In the Aplysia feeding motor network, three interneurons, cerebral-buccal interneuron-3 (CBI-3) and buccal interneurons B40 and B34, are GABA-immunoreactive and evoke fast IPSPs in their postsynaptic followers. Using a combination of pharmacological experiments with GABA antagonists, agonists, and uptake inhibitors, we found that these fast IPSPs are likely mediated by GABA. Functionally, these fast IPSPs specify two parameters for ingestive motor programs elicited by the command-like interneuron CBI-2: (1) the appropriate phasing of activity of the radula closer motor neuron B8 relative to protraction-retraction, and (2) protraction duration. First, in ingestive programs, B8 activity is phased such that it fires minimally during protraction. CBI-3 and B40 exert fast inhibition to minimize B8 activity during protraction, by either acting directly on B8 (B40) or indirectly on B8 (CBI-3). Second, these ingestive programs are characterized by long protraction duration, which is promoted by B40 and B34 because hyperpolarization of either cell shortens protraction. Such effects of B40 and B34 are attributable, at least partly, to their inhibitory effects on the retraction-phase interneuron B64 whose activation terminates protraction. Consistent with a GABAergic contribution to both B8 phasing and protraction duration, blockade of GABAergic inhibition by picrotoxin increases B8 activity during protraction and shortens protraction, without disrupting the integrity of motor programs. Thus, the concerted actions of GABAergic inhibition from three Aplysia feeding interneurons contribute to the specification of multiple features that define the motor program as an ingestive one. PMID:12832553

  16. Prefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons

    PubMed Central

    Bissonette, Gregory B.; Bae, Mihyun H.; Suresh, Tejas; Jaffe, David E.; Powell, Elizabeth M.

    2013-01-01

    Alterations of inhibitory GABAergic neurons are implicated in multiple psychiatric and neurological disorders, including schizophrenia, autism and epilepsy. In particular, interneuron deficits in prefrontal areas, along with presumed decreased inhibition, have been reported in several human patients. The majority of forebrain GABAergic interneurons arise from a single subcortical source before migrating to their final regional destination. Factors that govern the interneuron populations have been identified, demonstrating that a single gene mutation may globally affect forebrain structures or a single area. In particular, mice lacking the urokinase plasminogen activator receptor (Plaur) gene have decreased GABAergic interneurons in frontal and parietal, but not caudal, cortical regions. Plaur assists in the activation of hepatocyte growth factor/scatter factor (HGF/SF), and several of the interneuron deficits are correlated with decreased levels of HGF/SF. In some cortical regions, the interneuron deficit can be remediated by endogenous overexpression of HGF/SF. In this study, we demonstrate decreased parvalbumin-expressing interneurons in the medial frontal cortex, but not in the hippocampus or basal lateral amygdala in the Plaur null mouse. The Plaur null mouse demonstrates impaired medial frontal cortical function in extinction of cued fear conditioning and the inability to form attentional sets. Endogenous HGF/SF overexpression increased the number of PV-expressing cells in medial frontal cortical areas to levels greater than found in wildtype mice, but did not remediate the behavioral deficits. These data suggest that proper medial frontal cortical function is dependent upon optimum levels of inhibition and that a deficit or excess of interneuron numbers impairs normal cognition. PMID:24211452

  17. Motor command for precision grip in the macaque monkey can be mediated by spinal interneurons.

    PubMed

    Alstermark, B; Pettersson, L G; Nishimura, Y; Yoshino-Saito, K; Tsuboi, F; Takahashi, M; Isa, T

    2011-07-01

    In motor control, the general view is still that spinal interneurons mainly contribute to reflexes and automatic movements. The question raised here is whether spinal interneurons can mediate the cortical command for independent finger movements, like a precision grip between the thumb and index finger in the macaque monkey, or if this function depends exclusively on a direct corticomotoneuronal pathway. This study is a followup of a previous report (Sasaki et al. J Neurophysiol 92: 3142-3147, 2004) in which we trained macaque monkeys to pick a small piece of sweet potato from a cylinder by a precision grip between the index finger and thumb. We have now isolated one spinal interneuronal system, the C3-C4 propriospinal interneurons with projection to hand and arm motoneurons. In the previous study, the lateral corticospinal tract (CST) was interrupted in C4/C5 (input intact to the C3-C4 propriospinal interneurons), and in this study, the CST was interrupted in C2 (input abolished). The precision grip could be performed within the first 15 days after a CST lesion in C4/C5 but not in C2. We conclude that C3-C4 propriospinal interneurons also can carry the command for precision grip. PMID:21511706

  18. Circuits for grasping: spinal dI3 interneurons mediate cutaneous control of motor behavior.

    PubMed

    Bui, Tuan V; Akay, Turgay; Loubani, Osama; Hnasko, Thomas S; Jessell, Thomas M; Brownstone, Robert M

    2013-04-10

    Accurate motor performance depends on the integration in spinal microcircuits of sensory feedback information. Hand grasp is a skilled motor behavior known to require cutaneous sensory feedback, but spinal microcircuits that process and relay this feedback to the motor system have not been defined. We sought to define classes of spinal interneurons involved in the cutaneous control of hand grasp in mice and to show that dI3 interneurons, a class of dorsal spinal interneurons marked by the expression of Isl1, convey input from low threshold cutaneous afferents to motoneurons. Mice in which the output of dI3 interneurons has been inactivated exhibit deficits in motor tasks that rely on cutaneous afferent input. Most strikingly, the ability to maintain grip strength in response to increasing load is lost following genetic silencing of dI3 interneuron output. Thus, spinal microcircuits that integrate cutaneous feedback crucial for paw grip rely on the intermediary role of dI3 interneurons. PMID:23583114

  19. Interneurons and oligodendrocyte progenitors form a structured synaptic network in the developing neocortex

    PubMed Central

    Orduz, David; Maldonado, Paloma P; Balia, Maddalena; Vélez-Fort, Mateo; de Sars, Vincent; Yanagawa, Yuchio; Emiliani, Valentina; Angulo, Maria Cecilia

    2015-01-01

    NG2 cells, oligodendrocyte progenitors, receive a major synaptic input from interneurons in the developing neocortex. It is presumed that these precursors integrate cortical networks where they act as sensors of neuronal activity. We show that NG2 cells of the developing somatosensory cortex form a transient and structured synaptic network with interneurons that follows its own rules of connectivity. Fast-spiking interneurons, highly connected to NG2 cells, target proximal subcellular domains containing GABAA receptors with γ2 subunits. Conversely, non-fast-spiking interneurons, poorly connected with these progenitors, target distal sites lacking this subunit. In the network, interneuron-NG2 cell connectivity maps exhibit a local spatial arrangement reflecting innervation only by the nearest interneurons. This microcircuit architecture shows a connectivity peak at PN10, coinciding with a switch to massive oligodendrocyte differentiation. Hence, GABAergic innervation of NG2 cells is temporally and spatially regulated from the subcellular to the network level in coordination with the onset of oligodendrogenesis. DOI: http://dx.doi.org/10.7554/eLife.06953.001 PMID:25902404

  20. Highly energized inhibitory interneurons are a central element for information processing in cortical networks

    PubMed Central

    Kann, Oliver; Papageorgiou, Ismini E; Draguhn, Andreas

    2014-01-01

    Gamma oscillations (∼30 to 100 Hz) provide a fundamental mechanism of information processing during sensory perception, motor behavior, and memory formation by coordination of neuronal activity in networks of the hippocampus and neocortex. We review the cellular mechanisms of gamma oscillations about the underlying neuroenergetics, i.e., high oxygen consumption rate and exquisite sensitivity to metabolic stress during hypoxia or poisoning of mitochondrial oxidative phosphorylation. Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory GABAergic interneurons. In particular, specialized interneurons such as parvalbumin-positive basket cells generate action potentials at high frequency (‘fast-spiking') and synchronize the activity of numerous pyramidal cells by rhythmic inhibition (‘clockwork'). As prerequisites, fast-spiking interneurons have unique electrophysiological properties and particularly high energy utilization, which is reflected in the ultrastructure by enrichment with mitochondria and cytochrome c oxidase, most likely needed for extensive membrane ion transport and γ-aminobutyric acid metabolism. This supports the hypothesis that highly energized fast-spiking interneurons are a central element for cortical information processing and may be critical for cognitive decline when energy supply becomes limited (‘interneuron energy hypothesis'). As a clinical perspective, we discuss the functional consequences of metabolic and oxidative stress in fast-spiking interneurons in aging, ischemia, Alzheimer's disease, and schizophrenia. PMID:24896567

  1. Loss of dopamine D2 receptors increases parvalbumin-positive interneurons in the anterior cingulate cortex.

    PubMed

    Graham, Devon L; Durai, Heather H; Garden, Jamie D; Cohen, Evan L; Echevarria, Franklin D; Stanwood, Gregg D

    2015-02-18

    Disruption to dopamine homeostasis during brain development has been implicated in a variety of neuropsychiatric disorders, including depression and schizophrenia. Inappropriate expression or activity of GABAergic interneurons are common features of many of these disorders. We discovered a persistent upregulation of GAD67+ and parvalbumin+ neurons within the anterior cingulate cortex of dopamine D2 receptor knockout mice, while other GABAergic interneuron markers were unaffected. Interneuron distribution and number were not altered in the striatum or in the dopamine-poor somatosensory cortex. The changes were already present by postnatal day 14, indicating a developmental etiology. D2eGFP BAC transgenic mice demonstrated the presence of D2 receptor expression within a subset of parvalbumin-expressing cortical interneurons, suggesting the possibility of a direct cellular mechanism through which D2 receptor stimulation regulates interneuron differentiation or survival. D2 receptor knockout mice also exhibited decreased depressive-like behavior compared with wild-type controls in the tail suspension test. These data indicate that dopamine signaling modulates interneuron number and emotional behavior and that developmental D2 receptor loss or blockade could reveal a potential mechanism for the prodromal basis of neuropsychiatric disorders. PMID:25393953

  2. Loss of Dopamine D2 Receptors Increases Parvalbumin-Positive Interneurons in the Anterior Cingulate Cortex

    PubMed Central

    2015-01-01

    Disruption to dopamine homeostasis during brain development has been implicated in a variety of neuropsychiatric disorders, including depression and schizophrenia. Inappropriate expression or activity of GABAergic interneurons are common features of many of these disorders. We discovered a persistent upregulation of GAD67+ and parvalbumin+ neurons within the anterior cingulate cortex of dopamine D2 receptor knockout mice, while other GABAergic interneuron markers were unaffected. Interneuron distribution and number were not altered in the striatum or in the dopamine-poor somatosensory cortex. The changes were already present by postnatal day 14, indicating a developmental etiology. D2eGFP BAC transgenic mice demonstrated the presence of D2 receptor expression within a subset of parvalbumin-expressing cortical interneurons, suggesting the possibility of a direct cellular mechanism through which D2 receptor stimulation regulates interneuron differentiation or survival. D2 receptor knockout mice also exhibited decreased depressive-like behavior compared with wild-type controls in the tail suspension test. These data indicate that dopamine signaling modulates interneuron number and emotional behavior and that developmental D2 receptor loss or blockade could reveal a potential mechanism for the prodromal basis of neuropsychiatric disorders. PMID:25393953

  3. Distinct Roles of SOM and VIP Interneurons during Cortical Up States

    PubMed Central

    Neske, Garrett T.; Connors, Barry W.

    2016-01-01

    During cortical network activity, recurrent synaptic excitation among pyramidal neurons is approximately balanced by synaptic inhibition, which is provided by a vast diversity of inhibitory interneurons. The relative contributions of different interneuron subtypes to inhibitory tone during cortical network activity is not well-understood. We previously showed that many of the major interneuron subtypes in mouse barrel cortex are highly active during Up states (Neske et al., 2015); while fast-spiking (FS), parvalbumin (PV)-positive cells were the most active interneuron subtype, many non-fast-spiking (NFS), PV-negative interneurons were as active or more active than neighboring pyramidal cells. This suggests that the NFS cells could play a role in maintaining or modulating Up states. Here, using optogenetic techniques, we further dissected the functional roles during Up states of two major NFS, PV-negative interneuron subtypes: somatostatin (SOM)-positive cells and vasoactive intestinal peptide (VIP)-positive cells. We found that while pyramidal cell excitability during Up states significantly increased when SOM cells were optogenetically silenced, VIP cells did not influence pyramidal cell excitability either upon optogenetic silencing or activation. VIP cells failed to contribute to Up states despite their ability to inhibit SOM cells strongly. We suggest that the contribution of VIP cells to the excitability of pyramidal cells may vary with cortical state. PMID:27507936

  4. Maternal Immune Activation Leads to Selective Functional Deficits in Offspring Parvalbumin Interneurons

    PubMed Central

    Canetta, Sarah; Bolkan, Scott; Padilla-Coreano, Nancy; Song, LouJin; Sahn, Ryan; Harrison, Neil; Gordon, Joshua A.; Brown, Alan; Kellendonk, Christoph

    2015-01-01

    Summary Abnormalities in prefrontal GABAergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to maternal immune activation, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders. PMID:26830140

  5. Excitatory interneurons dominate sensory processing in the spinal substantia gelatinosa of rat

    PubMed Central

    Santos, Sónia F A; Rebelo, Sandra; Derkach, Victor A; Safronov, Boris V

    2007-01-01

    Substantia gelatinosa (SG, lamina II) is a spinal cord region where most unmyelinated primary afferents terminate and the central nociceptive processing begins. It is formed by several distinct groups of interneurons whose functional properties and synaptic connections are poorly understood, in part, because recordings from synaptically coupled pairs of SG neurons are quite challenging due to a very low probability of finding connected cells. Here, we describe an efficient method for identifying synaptically coupled interneurons in rat spinal cord slices and characterizing their excitatory or inhibitory function. Using tight-seal whole-cell recordings and a cell-attached stimulation technique, we routinely tested about 1500 SG interneurons, classifying 102 of them as monosynaptically connected to neurons in lamina I–III. Surprisingly, the vast majority of SG interneurons (n = 87) were excitatory and glutamatergic, while only 15 neurons were inhibitory. According to their intrinsic firing properties, these 102 SG neurons were also classified as tonic (n = 49), adapting (n = 17) or delayed-firing neurons (n = 36). All but two tonic neurons and all adapting neurons were excitatory interneurons. Of 36 delayed-firing neurons, 23 were excitatory and 13 were inhibitory. We conclude that sensory integration in the intrinsic SG neuronal network is dominated by excitatory interneurons. Such organization of neuronal circuitries in the spinal SG can be important for nociceptive encoding. PMID:17331995

  6. Tonic GABAA conductance bidirectionally controls interneuron firing pattern and synchronization in the CA3 hippocampal network

    PubMed Central

    Pavlov, Ivan; Savtchenko, Leonid P.; Song, Inseon; Koo, Jaeyeon; Pimashkin, Alexey; Rusakov, Dmitri A.; Semyanov, Alexey

    2014-01-01

    The spiking output of interneurons is key for rhythm generation in the brain. However, what controls interneuronal firing remains incompletely understood. Here we combine dynamic clamp experiments with neural network simulations to understand how tonic GABAA conductance regulates the firing pattern of CA3 interneurons. In baseline conditions, tonic GABAA depolarizes these cells, thus exerting an excitatory action while also reducing the excitatory postsynaptic potential (EPSP) amplitude through shunting. As a result, the emergence of weak tonic GABAA conductance transforms the interneuron firing pattern driven by individual EPSPs into a more regular spiking mode determined by the cell intrinsic properties. The increased regularity of spiking parallels stronger synchronization of the local network. With further increases in tonic GABAA conductance the shunting inhibition starts to dominate over excitatory actions and thus moderates interneuronal firing. The remaining spikes tend to follow the timing of suprathreshold EPSPs and thus become less regular again. The latter parallels a weakening in network synchronization. Thus, our observations suggest that tonic GABAA conductance can bidirectionally control brain rhythms through changes in the excitability of interneurons and in the temporal structure of their firing patterns. PMID:24344272

  7. Presynaptic Kainate Receptor Activation Preserves Asynchronous GABA Release Despite the Reduction in Synchronous Release from Hippocampal CCK Interneurons

    PubMed Central

    Daw, Michael I.; Pelkey, Kenneth A.; Chittajallu, Ramesh; McBain, Chris J.

    2010-01-01

    Inhibitory synaptic transmission in the hippocampus in mediated by a wide variety of different interneuron classes which are assumed to play different roles in network activity. Activation of presynaptic kainate receptors (KARs) has been shown to reduce inhibitory transmission but the interneuron class(es) at which they act is only recently beginning to emerge. Using paired recordings we show that KAR activation causes a decrease in presynaptic release from CCK- but not PV-containing interneurons and that this decrease is observed when pyramidal cells, but not interneurons, are the postsynaptic target. We also show that although the synchronous release component is reduced, the barrage of asynchronous GABA release from CCK interneurons during sustained firing is unaffected by KAR activation. This indicates that presynaptic KARs preserve and act in concert with asynchronous release to switch CCK interneurons from a phasic inhibition mode to produce prolonged inhibition during periods of intense activity. PMID:20720128

  8. A Subpopulation of Olfactory Bulb GABAergic Interneurons Is Derived from Emx1- and Dlx5/6-Expressing Progenitors

    PubMed Central

    Kohwi, Minoree; Petryniak, Magdalena A.; Long, Jason E.; Ekker, Marc; Obata, Kunihiko; Yanagawa, Yuchio; Rubenstein, John L. R.; Alvarez-Buylla, Arturo

    2016-01-01

    The subventricular zone (SVZ) of the postnatal brain continuously generates olfactory bulb (OB) interneurons. We show that calretinin+, calbindin+, and dopaminergic (TH+) periglomerular OB interneurons correspond to distinct subtypes of GABAergic cells; all were produced in the postnatal mouse brain, but they matured and were eliminated at different rates. The embryonic lateral ganglionic eminence (LGE) is thought to be the site of origin of postnatal SVZ neural progenitors. Consistently, grafts of the embryonic LGE into the adult brain SVZ generated many OB interneurons, including TH+ and calbindin+ periglomerular interneurons. However, calretinin+ cells were not produced from these LGE grafts. Surprisingly, pallial and septal embryonic progenitors transplanted into the adult brain SVZ also resulted in the generation of OB interneurons, including calretinin+ cells. A subset of Dlx2+ OB interneurons was derived from cells expressing Emx1, a transcription factor largely restricted to the pallium during development. Emx1 lineage-derived cells contributed a substantial portion of GABAergic cells in the OB, including calretinin+ interneurons. This is in contrast to cortex, in which Emx1 lineage-derived cells do not differentiate into GABAergic neurons. Our results suggest that some OB interneurons are derived from progenitors outside the LGE and that precursors expressing what has classically been considered a pallial transcription factor generate GABAergic interneurons. PMID:17596436

  9. Spontaneous activity does not predict morphological type in cerebellar interneurons.

    PubMed

    Haar, Shlomi; Givon-Mayo, Ronit; Barmack, Neal H; Yakhnitsa, Vadim; Donchin, Opher

    2015-01-28

    The effort to determine morphological and anatomically defined neuronal characteristics from extracellularly recorded physiological signatures has been attempted with varying success in different brain areas. Recent studies have attempted such classification of cerebellar interneurons (CINs) based on statistical measures of spontaneous activity. Previously, such efforts in different brain areas have used supervised clustering methods based on standard parameterizations of spontaneous interspike interval (ISI) histograms. We worried that this might bias researchers toward positive identification results and decided to take a different approach. We recorded CINs from anesthetized cats. We used unsupervised clustering methods applied to a nonparametric representation of the ISI histograms to identify groups of CINs with similar spontaneous activity and then asked how these groups map onto different cell types. Our approach was a fuzzy C-means clustering algorithm applied to the Kullbach-Leibler distances between ISI histograms. We found that there is, in fact, a natural clustering of the spontaneous activity of CINs into six groups but that there was no relationship between this clustering and the standard morphologically defined cell types. These results proved robust when generalization was tested to completely new datasets, including datasets recorded under different anesthesia conditions and in different laboratories and different species (rats). Our results suggest the importance of an unsupervised approach in categorizing neurons according to their extracellular activity. Indeed, a reexamination of such categorization efforts throughout the brain may be necessary. One important open question is that of functional differences of our six spontaneously defined clusters during actual behavior. PMID:25632121

  10. Narp regulates homeostatic scaling of excitatory synapses on Parvalbumin interneurons

    PubMed Central

    Chang, Michael C.; Park, Joo Min; Pelkey, Kenneth A.; Grabenstatter, Heidi L.; Xu, Desheng; Linden, David J.; Sutula, Thomas P.; McBain, Chris J.; Worley, Paul F.

    2010-01-01

    Homeostatic synaptic scaling alters the strength of synapses to compensate for prolonged changes in network activity, and involves both excitatory and inhibitory neurons. The immediate-early gene termed Narp (Neuronal activity-regulated pentraxin) encodes a secreted synaptic protein that can bind and cluster AMPA receptors (AMPARs). Here, we report that Narp prominently accumulates at excitatory synapses on Parvalbumin-expressing interneurons (PV-INs). Increasing network activity results in a homeostatic increase of excitatory synaptic strength onto PV-INs that increases inhibitory drive, and this response is absent in neurons cultured from Narp knock-out (Narp−/−) mice. Activity-dependent changes in the strength of excitatory inputs on PV-INs in acute hippocampal slices are also dependent on Narp, and Narp−/− mice display increased sensitivity to kindling-induced seizures. We propose that Narp recruits AMPARs at excitatory synapses onto PV-INs to rebalance network excitation/inhibition dynamics following episodes of increased circuit activity. PMID:20729843

  11. [The interneuronal functional connections in the sensorimotor cortex of dogs].

    PubMed

    Dolbakian, E E; Tarakanova, T A; Fadeeva, M A

    1994-01-01

    Multiunit activity of sensorimotor cortex was recorded from chronically implanted semi-microelectrodes in two dogs. Functional interneuronal connections between neuronal spike trains of 6-8 neurons selected from background multiunit activity were studied by the method of cross-correlation analysis. Bin widths 0.5, 1, 2, 3 and further up to 40 ms by step of 1 ms were used. The cross-interval connections were characterized by complete absence of the shared input (central symmetrical peaks) and signs of inhibitory interrelations. The temporal interrelations between selected neurons were characterized by unilateral and bilateral non-symmetrical excitatory connections--ultra-narrow peaks with short (1-10 ms), middle (10-80 ms) and long (80-2000 ms) delays. The existence of such ultra-narrow peaks contradicts "classical" conceptions on the character of cross-interval connections based on model experiments on simple nervous systems. We suppose that special mechanism of synchronization with high temporal accuracy exists in the cortex. PMID:8171888

  12. Control of epileptiform bursting in the leech heart interneuron

    NASA Astrophysics Data System (ADS)

    Barnett, William; Anquez, Martin; Harris, Torrey; Cymbalyuk, Gennady

    2009-11-01

    The network controlling heartbeat in the medicinal leech contains leech heart interneurons (HNs). We modeled them under specific pharmacological conditions. The Ca^2+ currents were blocked by Co^2+. The K^+ currents, apart from the non-inactivating current, IK2, were blocked by 4AP. The hyperpolarization-activated current, Ih, was blocked by Cs^+. Under these conditions, epileptiform bursting characterized by long interburst intervals (IBI) has been shown. We considered three distinct cases. Model 1 included IK2, Ih, and the fast Na^+ current, INa. Model 2 was characterized by INa, IK2, and the persistent Na^+ current, INaP. Model 3 consisted of INa, IK2, Ih, and INaP. We also investigated the bi-stability of bursting and silence as the leak conductance, gleak, was varied. We showed that in 1 and 3, model HNs demonstrated bi-stability of silence and bursting. We analyzed how IBI and burst duration are controlled by the manipulation of Ih and INaP. In 1, as V1/2 of Ih decreased, IBI grew towards infinity one over the square root of the parameter difference. In 2, we showed that as gNaP decreased from 6.156 nS to 6.155 nS, IBI grew in accordance with the one over square root law. The system underwent a saddle-node bifurcation just below 6.155 nS. Supported by NSF PHY-0750456.

  13. Partial Conservation between Mice and Humans in Olfactory Bulb Interneuron Transcription Factor Codes

    PubMed Central

    Fujiwara, Nana; Cave, John W.

    2016-01-01

    The mammalian main olfactory bulb (OB) has a large population of GABAergic inhibitory interneurons that contains several subtypes defined by the co-expression other neurotransmitters and calcium binding proteins. The three most commonly studied OB interneuron subtypes co-express either Calretinin, Calbindin, or Tyrosine hydroxylase (Th). Combinations of transcription factors used to specify the phenotype of progenitors are referred to as transcription factor codes, and the current understanding of transcription factor codes that specify OB inhibitory neuron phenotypes are largely based on studies in mice. The conservation of these transcription factor codes in the human OB, however, has not been investigated. The aim of this study was to establish whether transcription factor codes in OB interneurons are conserved between mice and humans. This study compared the co-expression of Foxp2, Meis2, Pax6, and Sp8 transcription factors with Calretinin, Calbindin, or Th in human and mouse OB interneurons. This analysis found strong conservation of Calretinin co-expression with Sp8 and Meis2 as well as Th co-expression with Pax6 and Meis2. This analysis also showed that selective Foxp2 co-expression with Calbindin was conserved between mice and humans, which suggests Foxp2 is a novel determinant of the OB Calbindin interneuron phenotype. Together, the findings in this study provide insight into the conservation of transcription codes for OB interneuron phenotypes between humans and mice, as well as reveal some important differences between the species. This advance in our understanding of transcription factor codes in OB interneurons provides an important complement to the codes that have been established for other regions within the mammalian central nervous system, such as the cortex and spinal cord. PMID:27489533

  14. Partial Conservation between Mice and Humans in Olfactory Bulb Interneuron Transcription Factor Codes.

    PubMed

    Fujiwara, Nana; Cave, John W

    2016-01-01

    The mammalian main olfactory bulb (OB) has a large population of GABAergic inhibitory interneurons that contains several subtypes defined by the co-expression other neurotransmitters and calcium binding proteins. The three most commonly studied OB interneuron subtypes co-express either Calretinin, Calbindin, or Tyrosine hydroxylase (Th). Combinations of transcription factors used to specify the phenotype of progenitors are referred to as transcription factor codes, and the current understanding of transcription factor codes that specify OB inhibitory neuron phenotypes are largely based on studies in mice. The conservation of these transcription factor codes in the human OB, however, has not been investigated. The aim of this study was to establish whether transcription factor codes in OB interneurons are conserved between mice and humans. This study compared the co-expression of Foxp2, Meis2, Pax6, and Sp8 transcription factors with Calretinin, Calbindin, or Th in human and mouse OB interneurons. This analysis found strong conservation of Calretinin co-expression with Sp8 and Meis2 as well as Th co-expression with Pax6 and Meis2. This analysis also showed that selective Foxp2 co-expression with Calbindin was conserved between mice and humans, which suggests Foxp2 is a novel determinant of the OB Calbindin interneuron phenotype. Together, the findings in this study provide insight into the conservation of transcription codes for OB interneuron phenotypes between humans and mice, as well as reveal some important differences between the species. This advance in our understanding of transcription factor codes in OB interneurons provides an important complement to the codes that have been established for other regions within the mammalian central nervous system, such as the cortex and spinal cord. PMID:27489533

  15. Properties of precise firing synchrony between synaptically coupled cortical interneurons depend on their mode of coupling

    PubMed Central

    Hu, Hang

    2015-01-01

    Precise spike synchrony has been widely reported in the central nervous system, but its functional role in encoding, processing, and transmitting information is yet unresolved. Of particular interest is firing synchrony between inhibitory cortical interneurons, thought to drive various cortical rhythms such as gamma oscillations, the hallmark of cognitive states. Precise synchrony can arise between two interneurons connected electrically, through gap junctions, chemically, through fast inhibitory synapses, or dually, through both types of connections, but the properties of synchrony generated by these different modes of connectivity have never been compared in the same data set. In the present study we recorded in vitro from 152 homotypic pairs of two major subtypes of mouse neocortical interneurons: parvalbumin-containing, fast-spiking (FS) interneurons and somatostatin-containing (SOM) interneurons. We tested firing synchrony when the two neurons were driven to fire by long, depolarizing current steps and used a novel synchrony index to quantify the strength of synchrony, its temporal precision, and its dependence on firing rate. We found that SOM-SOM synchrony, driven solely by electrical coupling, was less precise than FS-FS synchrony, driven by inhibitory or dual coupling. Unlike SOM-SOM synchrony, FS-FS synchrony was strongly firing rate dependent and was not evident at the prototypical 40-Hz gamma frequency. Computer simulations reproduced these differences in synchrony without assuming any differences in intrinsic properties, suggesting that the mode of coupling is more important than the interneuron subtype. Our results provide novel insights into the mechanisms and properties of interneuron synchrony and point out important caveats in current models of cortical oscillations. PMID:25972585

  16. Neuronal activity is required for the development of specific cortical interneuron subtypes.

    PubMed

    De Marco García, Natalia V; Karayannis, Theofanis; Fishell, Gord

    2011-04-21

    Electrical activity has been shown to regulate development in a variety of species and in various structures, including the retina, spinal cord and cortex. Within the mammalian cortex specifically, the development of dendrites and commissural axons in pyramidal cells is activity-dependent. However, little is known about the developmental role of activity in the other major cortical population of neurons, the GABA-producing interneurons. These neurons are morphologically and functionally heterogeneous and efforts over the past decade have focused on determining the mechanisms that contribute to this diversity. It was recently discovered that 30% of all cortical interneurons arise from a relatively novel source within the ventral telencephalon, the caudal ganglionic eminence (CGE). Owing to their late birth date, these interneurons populate the cortex only after the majority of other interneurons and pyramidal cells are already in place and have started to functionally integrate. Here we demonstrate in mice that for CGE-derived reelin (Re)-positive and calretinin (Cr)-positive (but not vasoactive intestinal peptide (VIP)-positive) interneurons, activity is essential before postnatal day 3 for correct migration, and that after postnatal day 3, glutamate-mediated activity controls the development of their axons and dendrites. Furthermore, we show that the engulfment and cell motility 1 gene (Elmo1), a target of the transcription factor distal-less homeobox 1 (Dlx1), is selectively expressed in Re(+) and Cr(+) interneurons and is both necessary and sufficient for activity-dependent interneuron migration. Our findings reveal a selective requirement for activity in shaping the cortical integration of specific neuronal subtypes. PMID:21460837

  17. Impaired synaptic plasticity in the prefrontal cortex of mice with developmentally decreased number of interneurons.

    PubMed

    Konstantoudaki, X; Chalkiadaki, K; Tivodar, S; Karagogeos, D; Sidiropoulou, K

    2016-05-13

    Interneurons are inhibitory neurons, which protect neural tissue from excessive excitation. They are interconnected with glutamatergic pyramidal neurons in the cerebral cortex and regulate their function. Particularly in the prefrontal cortex (PFC), interneurons have been strongly implicated in regulating pathological states which display deficits in the PFC. The aim of this study is to investigate the adaptations in the adult glutamatergic system, when defects in interneuron development do not allow adequate numbers of interneurons to reach the cerebral cortex. To this end, we used a mouse model that displays ∼50% fewer cortical interneurons due to the Rac1 protein loss from Nkx2.1/Cre expressing cells (Rac1 conditional knockout (cKO) mice), to examine how the developmental loss of interneurons may affect basal synaptic transmission, synaptic plasticity and neuronal morphology in the adult PFC. Despite the decrease in the number of interneurons, basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks, is not altered in the PFC of Rac1 cKO mice. However, there is decreased paired-pulse ratio (PPR) and decreased long-term potentiation (LTP), in response to tetanic stimulation, in the layer II PFC synapses of Rac1 cKO mice. Furthermore, expression of N-methyl-d-aspartate (NMDA) subunits is decreased and dendritic morphology is altered, changes that could underlie the decrease in LTP in the Rac1 cKO mice. Finally, we find that treating Rac1 cKO mice with diazepam in early postnatal life can reverse changes in dendritic morphology observed in non-treated Rac1 cKO mice. Therefore, our data show that disruption in GABAergic inhibition alters glutamatergic function in the adult PFC, an effect that could be reversed by enhancement of GABAergic function during an early postnatal period. PMID:26926965

  18. Physiological Properties of Supragranular Cortical Inhibitory Interneurons Expressing Retrograde Persistent Firing

    PubMed Central

    Imbrosci, Barbara; Neitz, Angela; Mittmann, Thomas

    2015-01-01

    Neurons are polarized functional units. The somatodendritic compartment receives and integrates synaptic inputs while the axon relays relevant synaptic information in form of action potentials (APs) across long distance. Despite this well accepted notion, recent research has shown that, under certain circumstances, the axon can also generate APs independent of synaptic inputs at axonal sites distal from the soma. These ectopic APs travel both toward synaptic terminals and antidromically toward the soma. This unusual form of neuronal communication seems to preferentially occur in cortical inhibitory interneurons following a period of intense neuronal activity and might have profound implications for neuronal information processing. Here we show that trains of ectopically generated APs can be induced in a large portion of neocortical layer 2/3 GABAergic interneurons following a somatic depolarization inducing hundreds of APs. Sparsely occurring ectopic spikes were also observed in a large portion of layer 1 interneurons even in absence of prior somatic depolarization. Remarkably, we found that interneurons which produce ectopic APs display specific membrane and morphological properties significantly different from the remaining GABAergic cells and may therefore represent a functionally unique interneuronal subpopulation. PMID:25763283

  19. Spatiotemporal dynamics of rhythmic spinal interneurons measured with two-photon calcium imaging and coherence analysis.

    PubMed

    Kwan, Alex C; Dietz, Shelby B; Zhong, Guisheng; Harris-Warrick, Ronald M; Webb, Watt W

    2010-12-01

    In rhythmic neural circuits, a neuron often fires action potentials with a constant phase to the rhythm, a timing relationship that can be functionally significant. To characterize these phase preferences in a large-scale, cell type-specific manner, we adapted multitaper coherence analysis for two-photon calcium imaging. Analysis of simulated data showed that coherence is a simple and robust measure of rhythmicity for calcium imaging data. When applied to the neonatal mouse hindlimb spinal locomotor network, the phase relationships between peak activity of >1,000 ventral spinal interneurons and motor output were characterized. Most interneurons showed rhythmic activity that was coherent and in phase with the ipsilateral motor output during fictive locomotion. The phase distributions of two genetically identified classes of interneurons were distinct from the ensemble population and from each other. There was no obvious spatial clustering of interneurons with similar phase preferences. Together, these results suggest that cell type, not neighboring neuron activity, is a better indicator of an interneuron's response during fictive locomotion. The ability to measure the phase preferences of many neurons with cell type and spatial information should be widely applicable for studying other rhythmic neural circuits. PMID:20861442

  20. Identification of excitatory premotor interneurons which regulate local muscle contraction during Drosophila larval locomotion.

    PubMed

    Hasegawa, Eri; Truman, James W; Nose, Akinao

    2016-01-01

    We use Drosophila larval locomotion as a model to elucidate the working principles of motor circuits. Larval locomotion is generated by rhythmic and sequential contractions of body-wall muscles from the posterior to anterior segments, which in turn are regulated by motor neurons present in the corresponding neuromeres. Motor neurons are known to receive both excitatory and inhibitory inputs, combined action of which likely regulates patterned motor activity during locomotion. Although recent studies identified candidate inhibitory premotor interneurons, the identity of premotor interneurons that provide excitatory drive to motor neurons during locomotion remains unknown. In this study, we searched for and identified two putative excitatory premotor interneurons in this system, termed CLI1 and CLI2 (cholinergic lateral interneuron 1 and 2). These neurons were segmentally arrayed and activated sequentially from the posterior to anterior segments during peristalsis. Consistent with their being excitatory premotor interneurons, the CLIs formed GRASP- and ChAT-positive putative synapses with motoneurons and were active just prior to motoneuronal firing in each segment. Moreover, local activation of CLI1s induced contraction of muscles in the corresponding body segments. Taken together, our results suggest that the CLIs directly activate motoneurons sequentially along the segments during larval locomotion. PMID:27470675

  1. Identification of excitatory premotor interneurons which regulate local muscle contraction during Drosophila larval locomotion

    PubMed Central

    Hasegawa, Eri; Truman, James W.; Nose, Akinao

    2016-01-01

    We use Drosophila larval locomotion as a model to elucidate the working principles of motor circuits. Larval locomotion is generated by rhythmic and sequential contractions of body-wall muscles from the posterior to anterior segments, which in turn are regulated by motor neurons present in the corresponding neuromeres. Motor neurons are known to receive both excitatory and inhibitory inputs, combined action of which likely regulates patterned motor activity during locomotion. Although recent studies identified candidate inhibitory premotor interneurons, the identity of premotor interneurons that provide excitatory drive to motor neurons during locomotion remains unknown. In this study, we searched for and identified two putative excitatory premotor interneurons in this system, termed CLI1 and CLI2 (cholinergic lateral interneuron 1 and 2). These neurons were segmentally arrayed and activated sequentially from the posterior to anterior segments during peristalsis. Consistent with their being excitatory premotor interneurons, the CLIs formed GRASP- and ChAT-positive putative synapses with motoneurons and were active just prior to motoneuronal firing in each segment. Moreover, local activation of CLI1s induced contraction of muscles in the corresponding body segments. Taken together, our results suggest that the CLIs directly activate motoneurons sequentially along the segments during larval locomotion. PMID:27470675

  2. Extended Production of Cortical Interneurons into the Third Trimester of Human Gestation.

    PubMed

    Arshad, Arslan; Vose, Linnea R; Vinukonda, Govindaiah; Hu, Furong; Yoshikawa, Kazuaki; Csiszar, Anna; Brumberg, Joshua C; Ballabh, Praveen

    2016-05-01

    In humans, the developmental origins of interneurons in the third trimester of pregnancy and the timing of completion of interneuron neurogenesis have remained unknown. Here, we show that the total and cycling Nkx2.1(+)and Dlx2(+)interneuron progenitors as well as Sox2(+)precursor cells were higher in density in the medial ganglionic eminence (MGE) compared with the lateral ganglionic eminence and cortical ventricular/subventricular zone (VZ/SVZ) of 16-35 gw subjects. The proliferation of these progenitors reduced as a function of gestational age, almost terminating by 35 gw. Proliferating Dlx2(+)cells were higher in density in the caudal ganglionic eminence (CGE) compared with the MGE, and persisted beyond 35 gw. Consistent with these findings, Sox2, Nkx2.1, Dlx2, and Mash1 protein levels were higher in the ganglionic eminences relative to the cortical VZ/SVZ. The density of gamma-aminobutyric acid-positive (GABA(+)) interneurons was higher in the cortical VZ/SVZ relative to MGE, but Nkx2.1 or Dlx2-expressing GABA(+)cells were more dense in the MGE compared with the cortical VZ/SVZ. The data suggest that the MGE and CGE are the primary source of cortical interneurons. Moreover, their generation continues nearly to the end of pregnancy, which may predispose premature infants to neurobehavioral disorders. PMID:25882040

  3. Roller Coaster Scanning reveals spontaneous triggering of dendritic spikes in CA1 interneurons.

    PubMed

    Katona, Gergely; Kaszás, Attila; Turi, Gergely F; Hájos, Norbert; Tamás, Gábor; Vizi, E Sylvester; Rózsa, Balázs

    2011-02-01

    Inhibitory interneurons are considered to be the controlling units of neural networks, despite their sparse number and unique morphological characteristics compared with excitatory pyramidal cells. Although pyramidal cell dendrites have been shown to display local regenerative events--dendritic spikes (dSpikes)--evoked by artificially patterned stimulation of synaptic inputs, no such studies exist for interneurons or for spontaneous events. In addition, imaging techniques have yet to attain the required spatial and temporal resolution for the detection of spontaneously occurring events that trigger dSpikes. Here we describe a high-resolution 3D two-photon laser scanning method (Roller Coaster Scanning) capable of imaging long dendritic segments resolving individual spines and inputs with a temporal resolution of a few milliseconds. By using this technique, we found that local, NMDA receptor-dependent dSpikes can be observed in hippocampal CA1 stratum radiatum interneurons during spontaneous network activities in vitro. These NMDA spikes appear when approximately 10 spatially clustered inputs arrive synchronously and trigger supralinear integration in dynamic interaction zones. In contrast to the one-to-one relationship between computational subunits and dendritic branches described in pyramidal cells, here we show that interneurons have relatively small (∼14 μm) sliding interaction zones. Our data suggest a unique principle as to how interneurons integrate synaptic information by local dSpikes. PMID:21224413

  4. Mechanisms of Firing Patterns in Fast-Spiking Cortical Interneurons

    PubMed Central

    Golomb, David; Donner, Karnit; Shacham, Liron; Shlosberg, Dan; Amitai, Yael; Hansel, David

    2007-01-01

    Cortical fast-spiking (FS) interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequency tonic firing and rhythmic or irregular bursting (stuttering). What is the origin of this variability? In the present paper, we hypothesize that it emerges naturally if one assumes a continuous distribution of properties in a small set of active channels. To test this hypothesis, we construct a minimal, single-compartment conductance-based model of FS cells that includes transient Na+, delayed-rectifier K+, and slowly inactivating d-type K+ conductances. The model is analyzed using nonlinear dynamical system theory. For small Na+ window current, the neuron exhibits high-frequency tonic firing. At current threshold, the spike response is almost instantaneous for small d-current conductance, gd, and it is delayed for larger gd. As gd further increases, the neuron stutters. Noise substantially reduces the delay duration and induces subthreshold oscillations. In contrast, when the Na+ window current is large, the neuron always fires tonically. Near threshold, the firing rates are low, and the delay to firing is only weakly sensitive to noise; subthreshold oscillations are not observed. We propose that the variability in the response of cortical FS neurons is a consequence of heterogeneities in their gd and in the strength of their Na+ window current. We predict the existence of two types of firing patterns in FS neurons, differing in the sensitivity of the delay duration to noise, in the minimal firing rate of the tonic discharge, and in the existence of subthreshold oscillations. We report experimental results from intracellular recordings supporting this prediction. PMID:17696606

  5. Identification of DVA Interneuron Regulatory Sequences in Caenorhabditis elegans

    PubMed Central

    Puckett Robinson, Carmie; Schwarz, Erich M.; Sternberg, Paul W.

    2013-01-01

    Background The identity of each neuron is determined by the expression of a distinct group of genes comprising its terminal gene battery. The regulatory sequences that control the expression of such terminal gene batteries in individual neurons is largely unknown. The existence of a complete genome sequence for C. elegans and draft genomes of other nematodes let us use comparative genomics to identify regulatory sequences directing expression in the DVA interneuron. Methodology/Principal Findings Using phylogenetic comparisons of multiple Caenorhabditis species, we identified conserved non-coding sequences in 3 of 10 genes (fax-1, nmr-1, and twk-16) that direct expression of reporter transgenes in DVA and other neurons. The conserved region and flanking sequences in an 85-bp intronic region of the twk-16 gene directs highly restricted expression in DVA. Mutagenesis of this 85 bp region shows that it has at least four regions. The central 53 bp region contains a 29 bp region that represses expression and a 24 bp region that drives broad neuronal expression. Two short flanking regions restrict expression of the twk-16 gene to DVA. A shared GA-rich motif was identified in three of these genes but had opposite effects on expression when mutated in the nmr-1 and twk-16 DVA regulatory elements. Conclusions/Significance We identified by multi-species conservation regulatory regions within three genes that direct expression in the DVA neuron. We identified four contiguous regions of sequence of the twk-16 gene enhancer with positive and negative effects on expression, which combined to restrict expression to the DVA neuron. For this neuron a single binding site may thus not achieve sufficient specificity for cell specific expression. One of the positive elements, an 8-bp sequence required for expression was identified in silico by sequence comparisons of seven nematode species, demonstrating the potential resolution of expanded multi-species phylogenetic comparisons. PMID

  6. Two populations of kainate receptors with separate signaling mechanisms in hippocampal interneurons

    PubMed Central

    Rodríguez-Moreno, Antonio; López-García, Juan C.; Lerma, Juan

    2000-01-01

    Consistent with the epileptogenic and deleterious effects of the potent neurotoxin kainate, the activation of kainate receptors reduces the synaptic inhibition induced by the amino acid γ-aminobutyric acid (GABA). Extrapolating from these data led to the conclusion that kainate receptors are located presynaptically. However, kainate directly depolarizes the inhibitory interneurons, causing them to fire repeatedly. This effect might indirectly decrease the size of inhibitory postsynaptic currents recorded from pyramidal cells and places in doubt the presynaptic location for kainate receptors. Here we show that both effects, membrane depolarization and the reduction of inhibitory potentials, can be dissociated by several means, particularly by the natural agonist of kainate receptors, glutamate. Indeed, when applied at low concentrations, glutamate inhibited GABA release without affecting the firing rate of GABA interneurons. These results indicate that CA1 interneurons contain two populations of kainate receptors, each with different agonist sensitivity and coupled to distinct signaling pathways. PMID:10655524

  7. New insights into the classification and nomenclature of cortical GABAergic interneurons

    PubMed Central

    DeFelipe, Javier; López-Cruz, Pedro L.; Benavides-Piccione, Ruth; Bielza, Concha; Larrañaga, Pedro; Anderson, Stewart; Burkhalter, Andreas; Cauli, Bruno; Fairén, Alfonso; Feldmeyer, Dirk; Fishell, Gord; Fitzpatrick, David; Freund, Tamás F.; González-Burgos, Guillermo; Hestrin, Shaul; Hill, Sean; Hof, Patrick R.; Huang, Josh; Jones, Edward G.; Kawaguchi, Yasuo; Kisvárday, Zoltán; Kubota, Yoshiyuki; Lewis, David A.; Marín, Oscar; Markram, Henry; McBain, Chris J.; Meyer, Hanno S.; Monyer, Hannah; Nelson, Sacha B.; Rockland, Kathleen; Rossier, Jean; Rubenstein, John L. R.; Rudy, Bernardo; Scanziani, Massimo; Shepherd, Gordon M.; Sherwood, Chet C.; Staiger, Jochen F.; Tamás, Gábor; Thomson, Alex; Wang, Yun; Yuste, Rafael; Ascoli, Giorgio A.

    2013-01-01

    A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts’ assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus. PMID:23385869

  8. Adult neural stem cells in distinct microdomains generate previously unknown interneuron types

    PubMed Central

    Merkle, Florian T.; Fuentealba, Luis C.; Sanders, Timothy A.; Magno, Lorenza; Kessaris, Nicoletta; Alvarez-Buylla, Arturo

    2014-01-01

    Throughout life, neural stem cells (NSCs) in different domains of the ventricular-subventricular zone (V-SVZ) of the adult rodent brain generate several subtypes of interneurons that regulate the function of the olfactory bulb (OB). The full extent of diversity among adult NSCs and their progeny is not known. Here, we report the generation of at least four previously unknown OB interneuron subtypes that are produced in finely patterned progenitor domains in the anterior ventral V-SVZ of both the neonatal and adult brain. Progenitors of these novel interneurons are responsive to sonic hedgehog (SHH) and are organized into microdomains that correlate with the expression domains of the Nkx6.2 and Zic family of transcription factors. This work reveals an unexpected degree of complexity in the specification and patterning of NSCs in the postnatal mouse brain. PMID:24362763

  9. OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons

    PubMed Central

    Leão, Richardson N; Mikulovic, Sanja; Leão, Katarina E; Munguba, Hermany; Gezelius, Henrik; Enjin, Anders; Patra, Kalicharan; Eriksson, Anders; Loew, Leslie M.; Tort, Adriano BL; Kullander, Klas

    2012-01-01

    The vast diversity of GABAergic interneurons is believed to endow hippocampal microcircuits with the required flexibility for memory encoding and retrieval. However, dissection of the functional roles of defined interneuron types have been hampered by the lack of cell specific tools. Here we report a precise molecular marker for a population of hippocampal GABAergic interneurons known as oriens lacunosum-moleculare (OLM) cells. By combining novel transgenic mice and optogenetic tools, we demonstrate that OLM cells have a key role in gating the information flow in CA1, facilitating the transmission of intrahippocampal information (from CA3) while reducing the influence of extrahippocampal inputs (from the entorhinal cortex). We further demonstrate that OLM cells are interconnected by gap junctions, receive direct cholinergic inputs from subcortical afferents, and account for the effect of nicotine on synaptic plasticity of the Schaffer collateral pathway. Our results suggest that acetylcholine acting through OLM cells can control the mnemonic processes executed by the hippocampus. PMID:23042082

  10. A Transient Translaminar GABAergic Interneuron Circuit Connects Thalamocortical Recipient Layers in Neonatal Somatosensory Cortex.

    PubMed

    Marques-Smith, Andre; Lyngholm, Daniel; Kaufmann, Anna-Kristin; Stacey, Jacqueline A; Hoerder-Suabedissen, Anna; Becker, Esther B E; Wilson, Michael C; Molnár, Zoltán; Butt, Simon J B

    2016-02-01

    GABAergic activity is thought to influence developing neocortical sensory circuits. Yet the late postnatal maturation of local layer (L)4 circuits suggests alternate sources of GABAergic control in nascent thalamocortical networks. We show that a population of L5b, somatostatin (SST)-positive interneuron receives early thalamic synaptic input and, using laser-scanning photostimulation, identify an early transient circuit between these cells and L4 spiny stellates (SSNs) that disappears by the end of the L4 critical period. Sensory perturbation disrupts the transition to a local GABAergic circuit, suggesting a link between translaminar and local control of SSNs. Conditional silencing of SST+ interneurons or conversely biasing the circuit toward local inhibition by overexpression of neuregulin-1 type 1 results in an absence of early L5b GABAergic input in mutants and delayed thalamic innervation of SSNs. These data identify a role for L5b SST+ interneurons in the control of SSNs in the early postnatal neocortex. PMID:26844833

  11. Diversity of Cortical Interneurons in Primates: The Role of the Dorsal Proliferative Niche

    PubMed Central

    Radonjić, Nevena V.; Ayoub, Albert E.; Memi, Fani; Yu, Xiaojing; Maroof, Asif; Jakovcevski, Igor; Anderson, Stewart A.; Rakic, Pasko; Zecevic, Nada

    2015-01-01

    Summary Evolutionary elaboration of tissues starts with changes in the genome and location of the stem cells. For example, GABAergic interneurons of the mammalian neocortex are generated in the ventral telencephalon and migrate tangentially to the neocortex, in contrast to the projection neurons originating in the ventricular/subventricular zone (VZ/SVZ) of the dorsal telencephalon. In human and nonhuman primates, evidence suggests that an additional subset of neocortical GABAergic interneurons is generated in the cortical VZ and a proliferative niche, the outer SVZ. The origin, magnitude, and significance of this species-specific difference are not known. We use a battery of assays applicable to the human, monkey, and mouse organotypic cultures and supravital tissue to identify neuronal progenitors in the cortical VZ/SVZ niche that produce a subset of GABAergic interneurons. Our findings suggest that these progenitors constitute an evolutionary novelty contributing to the elaboration of higher cognitive functions in primates. PMID:25497090

  12. Diversity of cortical interneurons in primates: the role of the dorsal proliferative niche.

    PubMed

    Radonjić, Nevena V; Ayoub, Albert E; Memi, Fani; Yu, Xiaojing; Maroof, Asif; Jakovcevski, Igor; Anderson, Stewart A; Rakic, Pasko; Zecevic, Nada

    2014-12-24

    Evolutionary elaboration of tissues starts with changes in the genome and location of the stem cells. For example, GABAergic interneurons of the mammalian neocortex are generated in the ventral telencephalon and migrate tangentially to the neocortex, in contrast to the projection neurons originating in the ventricular/subventricular zone (VZ/SVZ) of the dorsal telencephalon. In human and nonhuman primates, evidence suggests that an additional subset of neocortical GABAergic interneurons is generated in the cortical VZ and a proliferative niche, the outer SVZ. The origin, magnitude, and significance of this species-specific difference are not known. We use a battery of assays applicable to the human, monkey, and mouse organotypic cultures and supravital tissue to identify neuronal progenitors in the cortical VZ/SVZ niche that produce a subset of GABAergic interneurons. Our findings suggest that these progenitors constitute an evolutionary novelty contributing to the elaboration of higher cognitive functions in primates. PMID:25497090

  13. Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons.

    PubMed

    Canetta, S; Bolkan, S; Padilla-Coreano, N; Song, L J; Sahn, R; Harrison, N L; Gordon, J A; Brown, A; Kellendonk, C

    2016-07-01

    Abnormalities in prefrontal gamma aminobutyric acid (GABA)ergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders, including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, resulted from a decrease in release probability and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to MIA, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders. PMID:26830140

  14. Distinct calcium signals in developing cortical interneurons persist despite disorganization of cortex by Tbr1 KO.

    PubMed

    Easton, C R; Dickey, C W; Moen, S P; Neuzil, K E; Barger, Z; Anderson, T M; Moody, W J; Hevner, R F

    2016-07-01

    Cortical development involves the structuring of network features by genetically programmed molecular signaling pathways. Additionally, spontaneous ion channel activity refines neuronal connections. We examine Ca(2+) fluctuations in the first postnatal week of normal mouse neocortex and that expressing knockout of the transcription factor T-brain-1 (Tbr1): a signaling molecule in cortical patterning and differentiation of excitatory neurons. In cortex, glutamatergic neurons express Tbr1 just before the onset of population electrical activity that is accompanied by intracellular Ca(2+) increases. It is known that glutamatergic cells are disordered with Tbr1 KO such that normal laying of the cortex, with newer born cells residing in superficial layers, does not occur. However, the fate of cortical interneurons is not well studied, nor is the ability of Tbr1 deficient cortex to express normal physiological activity. Using fluorescent proteins targeted to interneurons, we find that cortical interneurons are also disordered in the Tbr1 knockout. Using Ca(2+) imaging we find that population activity in mutant cortex occurs at normal frequencies with similar sensitivity to GABAA receptor blockade as in nonmutant cortex. Finally, using multichannel fluorescence imaging of Ca(2+) indicator dye and interneurons labeled with red fluorescent protein, we identify an additional Ca(2+) signal in interneurons distinct from population activity and with different pharmacological sensitivities. Our results show the population activity described here is a robust property of the developing network that continues in the absence of an important signaling molecule, Tbr1, and that cortical interneurons generate distinct forms of activity that may serve different developmental functions. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 705-720, 2016. PMID:26473411

  15. Ephrin-A5 acts as a repulsive cue for migrating cortical interneurons.

    PubMed

    Zimmer, Geraldine; Garcez, Patricia; Rudolph, Judith; Niehage, Ronny; Weth, Franco; Lent, Roberto; Bolz, Jürgen

    2008-07-01

    Cortical interneurons are born in the germinative zones of the ganglionic eminences in the subpallium, and migrate tangentially in spatially and temporally well-defined corridors into the neocortex. Because ephrin-A5 is expressed in the ventricular zone (VZ) of the ganglionic eminences at these developmental stages, we examined the possible effects of this molecule on interneuron migration. Double-immunocytochemistry of dissociated neurons from the medial ganglionic eminences (MGE) revealed that calbindin-positive cells express the EphA4-receptor. In situ, EphA4 is strongly expressed in the subventricular zone of the ganglionic eminences. Using different in vitro assays, we found that ephrin-A5 acts as a repellent cue for MGE neurons. We then examined interneuron migration in slice overlay experiments, where MGE-derived explants from enhanced green fluorescent protein-expressing transgenic mice were homotopically grafted into host slices from wild-type littermate embryos. In these in vitro preparations, interneurons recapitulated in vivo cell migration in several respects. However, interneurons in brain slices also migrated in the VZ of the ganglionic eminences, a region that is strictly avoided in vivo. In situ hybridizations revealed that ephrin-A5 became downregulated in the VZ in vitro. When recombinant ephrin-A5-Fc was added to the slices, it preferentially bound to the VZ, and migrating MGE neurons avoided the VZ as in vivo. The restoration of the normal migration pathway in slices required ephrin-A5 clustering and signalling of Src family kinases. Together, these experiments suggest that ephrin-A5 acts as an inhibitory flank that contributes to define the pathway of migrating interneurons. PMID:18662335

  16. Age-Related Uptake of Heavy Metals in Human Spinal Interneurons.

    PubMed

    Pamphlett, Roger; Kum Jew, Stephen

    2016-01-01

    Toxic heavy metals have been implicated in the loss of spinal motoneurons in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Motoneuron loss in the spinal anterior horn is severe in ALS/MND at the time of death, making this tissue unsuitable for examination. We therefore examined spinal cords of people without muscle weakness to look for any presence of heavy metals that could make these neurons susceptible to damage. Spinal cord samples from 50 individuals aged 1-95 y who had no clinical or histopathological evidence of spinal motoneuron loss were studied. Seven μm formalin-fixed paraffin-embedded sections were stained for heavy metals with silver nitrate autometallography (AMGHM) which detects intracellular mercury, silver or bismuth. Neurons in the spinal cord were classified as interneurons or α-motoneurons based on their site and cell body diameter. Spinal interneurons containing heavy metals were present in 8 of 24 people (33%) aged 61-95 y, but not at younger ages. These AMGHM interneurons were most numerous in the lumbar spinal cord, with moderate numbers in the caudal cervical cord, few in the rostral cervical cord, and almost none in the thoracic cord. All people with AMGHM interneurons had occasional AMGHM staining in α-motoneurons as well. In one man AMGHM staining was present in addition in dorsomedial nucleus and sensory neurons. In conclusion, heavy metals are present in many spinal interneurons, and in a few α-motoneurons, in a large proportion of older people. Damage to inhibitory interneurons from toxic metals in later life could result in excitotoxic injury to motoneurons and may underlie motoneuron injury or loss in conditions such as ALS/MND, multiple sclerosis, sarcopenia and calf fasciculations. PMID:27611334

  17. Molecular Mechanisms Regulating the Dendritic Development of Newborn Olfactory Bulb Interneurons in a Sensory Experience-Dependent Manner

    PubMed Central

    Yoshihara, Sei-ichi; Takahashi, Hiroo; Tsuboi, Akio

    2016-01-01

    Inhibitory interneurons in the olfactory bulb are generated continuously throughout life in the subventricular zone and differentiate into periglomerular and granule cells. Neural circuits that undergo reorganization by newborn olfactory bulb interneurons are necessary for odor detection, odor discrimination, olfactory memory, and innate olfactory responses. Although sensory experience has been shown to regulate development in a variety of species and in various structures, including the retina, cortex, and hippocampus, little is known about how sensory experience regulates the dendritic development of newborn olfactory bulb interneurons. Recent studies revealed that the 5T4 oncofetal trophoblast glycoprotein and the neuronal Per/Arnt/Sim domain protein 4 (Npas4) transcription factor regulate dendritic branching and dendritic spine formation, respectively, in olfactory bulb interneurons. Here, we summarize the molecular mechanisms that underlie the sensory input-dependent development of newborn interneurons and the formation of functional neural circuitry in the olfactory bulb. PMID:26793053

  18. Characterization of a subpopulation of developing cortical interneurons from human iPSCs within serum-free embryoid bodies

    PubMed Central

    Jacob, Samson; Sun, Bruce; Prè, Deborah; Sproul, Andrew A.; Hong, Seong Im; Woodard, Chris; Zimmer, Matthew; Chinchalongporn, Vorapin; Arancio, Ottavio; Noggle, Scott A.

    2014-01-01

    Production and isolation of forebrain interneuron progenitors are essential for understanding cortical development and developing cell-based therapies for developmental and neurodegenerative disorders. We demonstrate production of a population of putative calretinin-positive bipolar interneurons that express markers consistent with caudal ganglionic eminence identities. Using serum-free embryoid bodies (SFEBs) generated from human inducible pluripotent stem cells (iPSCs), we demonstrate that these interneuron progenitors exhibit morphological, immunocytochemical, and electrophysiological hallmarks of developing cortical interneurons. Finally, we develop a fluorescence-activated cell-sorting strategy to isolate interneuron progenitors from SFEBs to allow development of a purified population of these cells. Identification of this critical neuronal cell type within iPSC-derived SFEBs is an important and novel step in describing cortical development in this iPSC preparation. PMID:25394470

  19. Molecules and mechanisms involved in the generation and migration of cortical interneurons

    PubMed Central

    Hernández-Miranda, Luis R; Parnavelas, John G; Chiara, Francesca

    2010-01-01

    The GABA (γ-aminobutyric acid)-containing interneurons of the neocortex are largely derived from the ganglionic eminences in the subpallium. Numerous studies have previously defined the migratory paths travelled by these neurons from their origins to their destinations in the cortex. We review here results of studies that have identified many of the genes expressed in the subpallium that are involved in the specification of the subtypes of cortical interneurons, and the numerous transcription factors, motogenic factors and guidance molecules that are involved in their migration. PMID:20360946

  20. Molecular and Electrophysiological Characterization of GABAergic Interneurons Expressing the Transcription Factor COUP-TFII in the Adult Human Temporal Cortex

    PubMed Central

    Varga, Csaba; Tamas, Gabor; Barzo, Pal; Olah, Szabolcs; Somogyi, Peter

    2015-01-01

    Transcription factors contribute to the differentiation of cortical neurons, orchestrate specific interneuronal circuits, and define synaptic relationships. We have investigated neurons expressing chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), which plays a role in the migration of GABAergic neurons. Whole-cell, patch-clamp recording in vitro combined with colocalization of molecular cell markers in the adult cortex differentiates distinct interneurons. The majority of strongly COUP-TFII-expressing neurons were in layers I–III. Most calretinin (CR) and/or cholecystokinin- (CCK) and/or reelin-positive interneurons were also COUP-TFII-positive. CR-, CCK-, or reelin-positive neurons formed 80%, 20%, or 17% of COUP-TFII-positive interneurons, respectively. About half of COUP-TFII-/CCK-positive interneurons were CR-positive, a quarter of them reelin-positive, but none expressed both. Interneurons positive for COUP-TFII fired irregular, accommodating and adapting trains of action potentials (APs) and innervated mostly small dendritic shafts and rarely spines or somata. Paired recording showed that a calretinin-/COUP-TFII-positive interneuron elicited inhibitory postsynaptic potentials (IPSPs) in a reciprocally connected pyramidal cell. Calbindin, somatostatin, or parvalbumin-immunoreactive interneurons and most pyramidal cells express no immunohistochemically detectable COUP-TFII. In layers V and VI, some pyramidal cells expressed a low level of COUP-TFII in the nucleus. In conclusion, COUP-TFII is expressed in a diverse subset of GABAergic interneurons predominantly innervating small dendritic shafts originating from both interneurons and pyramidal cells. PMID:25787832

  1. Duration of culture and sonic hedgehog signaling differentially specify PV versus SST cortical interneuron fates from embryonic stem cells

    PubMed Central

    Tyson, Jennifer A.; Goldberg, Ethan M.; Maroof, Asif M.; Xu, Qing; Petros, Timothy J.; Anderson, Stewart A.

    2015-01-01

    Medial ganglionic eminence (MGE)-derived GABAergic cortical interneurons (cINs) consist of multiple subtypes that are involved in many cortical functions. They also have a remarkable capacity to migrate, survive and integrate into cortical circuitry after transplantation into postnatal cortex. These features have engendered considerable interest in generating distinct subgroups of interneurons from pluripotent stem cells (PSCs) for the study of interneuron fate and function, and for the development of cell-based therapies. Although advances have been made, the capacity to generate highly enriched pools of subgroup fate-committed interneuron progenitors from PSCs has remained elusive. Previous studies have suggested that the two main MGE-derived interneuron subgroups – those expressing somatostatin (SST) and those expressing parvalbumin (PV) – are specified in the MGE from Nkx2.1-expressing progenitors at higher or lower levels of sonic hedgehog (Shh) signaling, respectively. To further explore the role of Shh and other factors in cIN fate determination, we generated a reporter line such that Nkx2.1-expressing progenitors express mCherry and postmitotic Lhx6-expressing MGE-derived interneurons express GFP. Manipulations of Shh exposure and time in culture influenced the subgroup fates of ESC-derived interneurons. Exposure to higher Shh levels, and collecting GFP-expressing precursors at 12 days in culture, resulted in the strongest enrichment for SST interneurons over those expressing PV, whereas the strongest enrichment for PV interneurons was produced by lower Shh and by collecting mCherry-expressing cells after 17 days in culture. These findings confirm that fate determination of cIN subgroups is crucially influenced by Shh signaling, and provide a system for the further study of interneuron fate and function. PMID:25804737

  2. Adult Olfactory Bulb Interneuron Phenotypes Identified by Targeting Embryonic and Postnatal Neural Progenitors.

    PubMed

    Figueres-Oñate, Maria; López-Mascaraque, Laura

    2016-01-01

    Neurons are generated during embryonic development and in adulthood, although adult neurogenesis is restricted to two main brain regions, the hippocampus and olfactory bulb. The subventricular zone (SVZ) of the lateral ventricles generates neural stem/progenitor cells that continually provide the olfactory bulb (OB) with new granule or periglomerular neurons, cells that arrive from the SVZ via the rostral migratory stream. The continued neurogenesis and the adequate integration of these newly generated interneurons is essential to maintain homeostasis in the olfactory bulb, where the differentiation of these cells into specific neural cell types is strongly influenced by temporal cues. Therefore, identifying the critical features that control the generation of adult OB interneurons at either pre- or post-natal stages is important to understand the dynamic contribution of neural stem cells. Here, we used in utero and neonatal SVZ electroporation along with a transposase-mediated stable integration plasmid, in order to track interneurons and glial lineages in the OB. These plasmids are valuable tools to study the development of OB interneurons from embryonic and post-natal SVZ progenitors. Accordingly, we examined the location and identity of the adult progeny of embryonic and post-natally transfected progenitors by examining neurochemical markers in the adult OB. These data reveal the different cell types in the olfactory bulb that are generated in function of age and different electroporation conditions. PMID:27242400

  3. A Computational Model of How Cholinergic Interneurons Protect Striatal-Dependent Learning

    ERIC Educational Resources Information Center

    Ashby, F. Gregory; Crossley, Matthew J.

    2011-01-01

    An essential component of skill acquisition is learning the environmental conditions in which that skill is relevant. This article proposes and tests a neurobiologically detailed theory of how such learning is mediated. The theory assumes that a key component of this learning is provided by the cholinergic interneurons in the striatum known as…

  4. NPAS1 Represses the Generation of Specific Subtypes of Cortical Interneurons

    PubMed Central

    Stanco, Amelia; Pla, Ramón; Vogt, Daniel; Chen, Yiran; Mandal, Shyamali; Walker, Jamie; Hunt, Robert F.; Lindtner, Susan; Erdman, Carolyn A.; Pieper, Andrew A.; Hamilton, Steven P.; Xu, Duan; Baraban, Scott C.; Rubenstein, John L. R.

    2014-01-01

    Summary Little is known about genetic mechanisms that regulate the ratio of cortical excitatory and inhibitory neurons. We show that NPAS1 and NPAS3 transcription factors (TF) are expressed in progenitor domains of the mouse basal ganglia (subpallium, MGE and CGE). NPAS1−/− mutants had increased proliferation, ERK signaling and expression of Arx in the MGE and CGE. NPAS1−/− mutants also had increased neocortical inhibition (sIPSC and mIPSC), and generated an excess of somatostatin+ (SST) (MGE-derived) and vasoactive intestinal polypeptide+ (VIP) (CGE-derived) neocortical interneurons, but had a normal density of parvalbumin+ (PV) (MGE-derived) interneurons. In contrast, NPAS3−/− mutants showed decreased proliferation and ERK signaling in progenitors of the ganglionic eminences and had fewer SST+ and VIP+ interneurons. NPAS1 repressed activity of an Arx enhancer, and Arx over-expression resulted in increased proliferation of CGE progenitors. These results provide novel insights into genetic regulation of cortical interneuron numbers and cortical inhibitory tone. PMID:25467980

  5. Exposure to Sevoflurane Affects the Development of Parvalbumin Interneurons in the Main Olfactory Bulb in Mice

    PubMed Central

    Yang, Jing; Chen, Jing; Cai, Guohong; Lu, Rui; Sun, Tingting; Luo, Tingting; Wu, Shengxi; Ling, Shucai

    2016-01-01

    Sevoflurane is widely used in adult and pediatric patients during clinical surgeries. Although studies have shown that exposure to sevoflurane impairs solfactory memory after an operation, the neuropathological changes underlying this effect are not clear. This study detected the effect of sevoflurane exposure on the development of calcium-binding proteins-expressing interneurons in the main olfactory bulb (MOB). We exposed neonatal mice to 2% sevoflurane at two different developmental time points and found that exposing mice to sevoflurane at postnatal day (PD) 7 significantly decreased the expression of GAD67 and parvalbumin (PV) in the olfactory bulb (OB) but did not alter the expression of calretinin (CR) or calbindin D28k (CB). The number and dendritic morphology of PV-expressing interneurons in the MOB were impaired by exposure to sevoflurane at PD7. However, exposure to sevoflurane at PD10 had no effect on calcium-binding protein expression or the number and dendritic morphology of PV-expressing interneurons in the MOB. These results suggest that exposing neonatal mice to sevoflurane during a critical period of olfactory development affects the development of PV-expressing interneurons in the MOB. PMID:27445710

  6. Heterogeneity and Bipotency of Astroglial-Like Cerebellar Progenitors along the Interneuron and Glial Lineages.

    PubMed

    Parmigiani, Elena; Leto, Ketty; Rolando, Chiara; Figueres-Oñate, María; López-Mascaraque, Laura; Buffo, Annalisa; Rossi, Ferdinando

    2015-05-13

    Cerebellar GABAergic interneurons in mouse comprise multiple subsets of morphologically and neurochemically distinct phenotypes located at strategic nodes of cerebellar local circuits. These cells are produced by common progenitors deriving from the ventricular epithelium during embryogenesis and from the prospective white matter (PWM) during postnatal development. However, it is not clear whether these progenitors are also shared by other cerebellar lineages and whether germinative sites different from the PWM originate inhibitory interneurons. Indeed, the postnatal cerebellum hosts another germinal site along the Purkinje cell layer (PCL), in which Bergmann glia are generated up to first the postnatal weeks, which was proposed to be neurogenic. Both PCL and PWM comprise precursors displaying traits of juvenile astroglia and neural stem cell markers. First, we examine the proliferative and fate potential of these niches, showing that different proliferative dynamics regulate progenitor amplification at these sites. In addition, PCL and PWM differ in the generated progeny. GABAergic interneurons are produced exclusively by PWM astroglial-like progenitors, whereas PCL precursors produce only astrocytes. Finally, through in vitro, ex vivo, and in vivo clonal analyses we provide evidence that the postnatal PWM hosts a bipotent progenitor that gives rise to both interneurons and white matter astrocytes. PMID:25972168

  7. The endogenous peptide antisecretory factor promotes tonic GABAergic signaling in CA1 stratum radiatum interneurons

    PubMed Central

    Strandberg, Joakim; Lindquist, Catarina; Lange, Stefan; Asztely, Fredrik; Hanse, Eric

    2014-01-01

    Tonic GABAergic inhibition regulates neuronal excitability and has been implicated to be involved in both neurological and psychiatric diseases. We have previously shown that the endogenous peptide antisecretory factor (AF) decreases phasic GABAergic inhibition onto pyramidal CA1 neurons. In the present study, using whole-cell patch-clamp recordings, we investigated the mechanisms behind this disinhibition of CA1 pyramidal neurons by AF. We found that application of AF to acute rat hippocampal slices resulted in a reduction of the frequency, but not of the amplitude, of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons. Miniature inhibitory postsynaptic currents (mIPSCs), recorded in the presence of tetrodotoxin (TTX), were however not affected by AF, neither in CA1 pyramidal cells, nor in stratum radiatum interneurons. Instead, AF caused an increase of the tonic GABAA current in stratum radiatum interneurons, leaving the tonic GABAergic transmission in CA1 pyramidal cells unaffected. These results show that the endogenous peptide AF enhances tonic, but not phasic, GABAergic signaling in CA1 stratum radiatum interneurons, without affecting tonic GABAergic signaling in CA1 pyramidal neurons. We suggest that this increased tonic GABAergic signaling in GABAergic interneurons could be a mechanism for the AF-mediated disinhibition of pyramidal neurons. PMID:24478633

  8. VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons.

    PubMed

    Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Barker, David J; Miranda-Barrientos, Jorge; Morales, Marisela

    2016-05-01

    The ventral tegmental area (VTA) is best known for its dopamine neurons, some of which project to nucleus accumbens (nAcc). However, the VTA also has glutamatergic neurons that project to nAcc. The function of the mesoaccumbens glutamatergic pathway remains unknown. Here we report that nAcc photoactivation of mesoaccumbens glutamatergic fibers promotes aversion. Although we found that these mesoaccumbens glutamatergic fibers lack GABA, the aversion evoked by their photoactivation depended on glutamate- and GABA-receptor signaling, and not on dopamine-receptor signaling. We found that mesoaccumbens glutamatergic fibers established multiple asymmetric synapses on single parvalbumin GABAergic interneurons and that nAcc photoactivation of these fibers drove AMPA-mediated cellular firing of parvalbumin GABAergic interneurons. These parvalbumin GABAergic interneurons in turn inhibited nAcc medium spiny output neurons, thereby controlling inhibitory neurotransmission in nAcc. To our knowledge, the mesoaccumbens glutamatergic pathway is the first glutamatergic input to nAcc shown to mediate aversion instead of reward, and the first pathway shown to establish excitatory synapses on nAcc parvalbumin GABAergic interneurons. PMID:27019014

  9. Adult Olfactory Bulb Interneuron Phenotypes Identified by Targeting Embryonic and Postnatal Neural Progenitors

    PubMed Central

    Figueres-Oñate, Maria; López-Mascaraque, Laura

    2016-01-01

    Neurons are generated during embryonic development and in adulthood, although adult neurogenesis is restricted to two main brain regions, the hippocampus and olfactory bulb. The subventricular zone (SVZ) of the lateral ventricles generates neural stem/progenitor cells that continually provide the olfactory bulb (OB) with new granule or periglomerular neurons, cells that arrive from the SVZ via the rostral migratory stream. The continued neurogenesis and the adequate integration of these newly generated interneurons is essential to maintain homeostasis in the olfactory bulb, where the differentiation of these cells into specific neural cell types is strongly influenced by temporal cues. Therefore, identifying the critical features that control the generation of adult OB interneurons at either pre- or post-natal stages is important to understand the dynamic contribution of neural stem cells. Here, we used in utero and neonatal SVZ electroporation along with a transposase-mediated stable integration plasmid, in order to track interneurons and glial lineages in the OB. These plasmids are valuable tools to study the development of OB interneurons from embryonic and post-natal SVZ progenitors. Accordingly, we examined the location and identity of the adult progeny of embryonic and post-natally transfected progenitors by examining neurochemical markers in the adult OB. These data reveal the different cell types in the olfactory bulb that are generated in function of age and different electroporation conditions. PMID:27242400

  10. Functional adaptation of cortical interneurons to attenuated activity is subtype-specific.

    PubMed

    Karayannis, Theofanis; De Marco García, Natalia V; Fishell, Gordon J

    2012-01-01

    Functional neuronal homeostasis has been studied in a variety of model systems and contexts. Many studies have shown that there are a number of changes that can be activated within individual cells or networks in order to compensate for perturbations or changes in levels of activity. Dissociating the cell autonomous from the network-mediated events has been complicated due to the difficulty of sparsely targeting specific populations of neurons in vivo. Here, we make use of a recent in vivo approach we developed that allows for the sparse labeling and manipulation of activity within superficial caudal ganglionic eminence (CGE)-derived GABAergic interneurons. Expression of the inward rectifying potassium channel Kir2.1 cell-autonomously reduced neuronal activity and lead to specific developmental changes in their intrinsic electrophysiological properties and the synaptic input they received. In contrast to previous studies on homeostatic scaling of pyramidal cells, we did not detect any of the typically observed compensatory mechanisms in these interneurons. Rather, we instead saw a specific alteration of the kinetics of excitatory synaptic events within the reelin-expressing subpopulation of interneurons. These results provide the first in vivo observations for the capacity of interneurons to cell-autonomously regulate their excitability. PMID:23015781

  11. Probing diversity within subpopulations of locomotor-related V0 interneurons.

    PubMed

    Griener, Anna; Zhang, Wei; Kao, Henry; Wagner, Christine; Gosgnach, Simon

    2015-11-01

    The V0 interneuronal population is derived from Dbx1 expressing progenitors. Initial studies on these interneurons in the mouse spinal cord demonstrated that they project commissural axons and are involved in coordinating left-right alternation during locomotion. Subsequent work has indicated that the V0 population can be divided into genetically distinct ventral (V0V) and dorsal (V0D) subpopulations, and experimental evidence suggests that each is responsible for left-right alternation at different locomotor speeds. In this study, we perform a series of experiments to probe the location and connectivity of these subpopulations in neonatal mice and demonstrate that they are more diverse than previously predicted. While the distribution of either subpopulation remains consistent along the extent of the lumbar spinal cord, a cluster of V0D cells lateral to the central canal receive substantial input from primary afferents. Retrograde tracing and activity dependent labeling experiments demonstrate that a group of V0 interneurons located in this same region preferentially project axons towards contralateral motoneurons via an oligosynaptic pathway, and are active during fictive locomotion. Our results suggest that this subset of V0 interneurons may be primarily responsible for coordination of left-right alternation during locomotion. Furthermore these experiments indicate that while genetic identity is one determinant of the function of a neuron during locomotion, the specific position in which the cell is located may also play a key role. PMID:25649879

  12. Focal Cortical Lesions Induce Bidirectional Changes in the Excitability of Fast Spiking and Non Fast Spiking Cortical Interneurons

    PubMed Central

    Mittmann, Thomas

    2014-01-01

    A physiological brain function requires neuronal networks to operate within a well-defined range of activity. Indeed, alterations in neuronal excitability have been associated with several pathological conditions, ranging from epilepsy to neuropsychiatric disorders. Changes in inhibitory transmission are known to play a key role in the development of hyperexcitability. However it is largely unknown whether specific interneuronal subpopulations contribute differentially to such pathological condition. In the present study we investigated functional alterations of inhibitory interneurons embedded in a hyperexcitable cortical circuit at the border of chronically induced focal lesions in mouse visual cortex. Interestingly, we found opposite alterations in the excitability of non fast-spiking (Non Fs) and fast-spiking (Fs) interneurons in acute cortical slices from injured animals. Non Fs interneurons displayed a depolarized membrane potential and a higher frequency of spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, Fs interneurons showed a reduced sEPSCs amplitude. The observed downscaling of excitatory synapses targeting Fs interneurons may prevent the recruitment of this specific population of interneurons to the hyperexcitable network. This mechanism is likely to seriously affect neuronal network function and to exacerbate hyperexcitability but it may be important to protect this particular vulnerable population of GABAegic neurons from excitotoxicity. PMID:25347396

  13. Roles of Rac1 and Rac3 GTPases during the development of cortical and hippocampal GABAergic interneurons

    PubMed Central

    de Curtis, Ivan

    2014-01-01

    Rac GTPases are regulators of the cytoskeleton that play an important role in several aspects of neuronal and brain development. Two distinct Rac GTPases are expressed in the developing nervous system, the widely expressed Rac1 and the neural-specific Rac3 proteins. Recent experimental evidence supports a central role of these two Rac proteins in the development of inhibitory GABAergic interneurons, important modulatory elements of the brain circuitry. The combined inactivation of the genes for the two Rac proteins has profound effects on distinct aspects of interneuron development, and has highlighted a synergistic contribution of the two proteins to the postmitotic maturation of specific populations of cortical and hippocampal interneurons. Rac function is modulated by different types of regulators, and can influence the activity of specific effectors. Some of these proteins have been associated to the development and maturation of interneurons. Cortical interneuron dysfunction is implicated in several neurological and psychiatric diseases characterized by cognitive impairment. Therefore the description of the cellular processes regulated by the Rac GTPases, and the identification of the molecular networks underlying these processes during interneuron development is relevant to the understanding of the role of GABAergic interneurons in cognitive functions. PMID:25309333

  14. Oscillation-Driven Spike-Timing Dependent Plasticity Allows Multiple Overlapping Pattern Recognition in Inhibitory Interneuron Networks.

    PubMed

    Garrido, Jesús A; Luque, Niceto R; Tolu, Silvia; D'Angelo, Egidio

    2016-08-01

    The majority of operations carried out by the brain require learning complex signal patterns for future recognition, retrieval and reuse. Although learning is thought to depend on multiple forms of long-term synaptic plasticity, the way this latter contributes to pattern recognition is still poorly understood. Here, we have used a simple model of afferent excitatory neurons and interneurons with lateral inhibition, reproducing a network topology found in many brain areas from the cerebellum to cortical columns. When endowed with spike-timing dependent plasticity (STDP) at the excitatory input synapses and at the inhibitory interneuron-interneuron synapses, the interneurons rapidly learned complex input patterns. Interestingly, induction of plasticity required that the network be entrained into theta-frequency band oscillations, setting the internal phase-reference required to drive STDP. Inhibitory plasticity effectively distributed multiple patterns among available interneurons, thus allowing the simultaneous detection of multiple overlapping patterns. The addition of plasticity in intrinsic excitability made the system more robust allowing self-adjustment and rescaling in response to a broad range of input patterns. The combination of plasticity in lateral inhibitory connections and homeostatic mechanisms in the inhibitory interneurons optimized mutual information (MI) transfer. The storage of multiple complex patterns in plastic interneuron networks could be critical for the generation of sparse representations of information in excitatory neuron populations falling under their control. PMID:27079422

  15. Differential expression of Na+/K+-ATPase α-subunits in mouse hippocampal interneurones and pyramidal cells

    PubMed Central

    Richards, Kathryn S; Bommert, Kurt; Szabo, Gabor; Miles, Richard

    2007-01-01

    The sodium pump (Na+/K+-ATPase), maintains intracellular and extracellular concentrations of sodium and potassium by catalysing ATP. Three sodium pump α subunits, ATP1A1, ATP1A2 and ATP1A3, are expressed in brain. We compared their role in pyramidal cells and a subset of interneurones in the subiculum. Interneurones were identified by their expression of GFP under the GAD-65 promoter. We used the sensitivity to the cardiac glycoside, ouabain, to discriminate between different α subunit isoforms. GFP-positive interneurones were depolarized by nanomolar doses of ouabain, but higher concentrations were needed to depolarize pyramidal cells. Comparison of pump currents in these cells revealed a current sensitive to low doses of ouabain in interneurones, while micromolar doses of ouabain were needed to suppress the pump current in subicular pyramidal cells. As predicted, nanomolar doses of ouabain increased the frequency but not the amplitudes of IPSPs in pyramidal cells. Immunostaining confirmed a differential distribution of α-subunits of the Na+/K+-ATPase in subicular interneurones and pyramidal cells. In conclusion, these data suggest that while ATP1A3-isoforms regulate sodium and potassium homeostasis in subicular interneurones, ATP1A1-isoforms assume this function in pyramidal cells. This differential expression of sodium pump isoforms may contribute to differences in resting membrane potential of subicular interneurones and pyramidal cells. PMID:17947306

  16. Functional differences between neurochemically defined populations of inhibitory interneurons in the rat spinal dorsal horn☆

    PubMed Central

    Polgár, Erika; Sardella, Thomas C.P.; Tiong, Sheena Y.X.; Locke, Samantha; Watanabe, Masahiko; Todd, Andrew J.

    2013-01-01

    In order to understand how nociceptive information is processed in the spinal dorsal horn we need to unravel the complex synaptic circuits involving interneurons, which constitute the vast majority of the neurons in laminae I–III. The main limitation has been the difficulty in defining functional populations among these cells. We have recently identified 4 non-overlapping classes of inhibitory interneuron, defined by expression of galanin, neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS) and parvalbumin, in the rat spinal cord. In this study we demonstrate that these form distinct functional populations that differ in terms of sst2A receptor expression and in their responses to painful stimulation. The sst2A receptor was expressed by nearly all of the nNOS- and galanin-containing inhibitory interneurons but by few of those with NPY and none of the parvalbumin cells. Many galanin- and NPY-containing cells exhibited phosphorylated extracellular signal-regulated kinases (pERK) after mechanical, thermal or chemical noxious stimuli, but very few nNOS-containing cells expressed pERK after any of these stimuli. However, many nNOS-positive inhibitory interneurons up-regulated Fos after noxious thermal stimulation or injection of formalin, but not after capsaicin injection. Parvalbumin cells did not express either activity-dependent marker following any of these stimuli. These results suggest that interneurons belonging to the NPY, nNOS and galanin populations are involved in attenuating pain, and for NPY and nNOS cells this is likely to result from direct inhibition of nociceptive projection neurons. They also suggest that the nociceptive inputs to the nNOS cells differ from those to the galanin and NPY populations. PMID:23707280

  17. Inhibitory coupling between inhibitory interneurons in the spinal cord dorsal horn.

    PubMed

    Labrakakis, Charalampos; Lorenzo, Louis-Etienne; Bories, Cyril; Ribeiro-da-Silva, Alfredo; De Koninck, Yves

    2009-01-01

    Local inhibitory interneurons in the dorsal horn play an important role in the control of excitability at the segmental level and thus determine how nociceptive information is relayed to higher structures. Regulation of inhibitory interneuron activity may therefore have critical consequences on pain perception. Indeed, disinhibition of dorsal horn neuronal networks disrupts the balance between excitation and inhibition and is believed to be a key mechanism underlying different forms of pain hypersensitivity and chronic pain states. In this context, studying the source and the synaptic properties of the inhibitory inputs that the inhibitory interneurons receive is important in order to predict the impact of drug action at the network level. To address this, we studied inhibitory synaptic transmission in lamina II inhibitory interneurons identified under visual guidance in spinal slices taken from transgenic mice expressing enhanced green fluorescent protein (EGFP) under the control of the GAD promoter. The majority of these cells fired tonically to a long depolarizing current pulse. Monosynaptically evoked inhibitory postsynaptic currents (eIPSCs) in these cells were mediated by both GABAA and glycine receptors. Consistent with this, both GABAA and glycine receptor-mediated miniature IPSCs were recorded in all of the cells. These inhibitory inputs originated at least in part from local lamina II interneurons as verified by simultaneous recordings from pairs of EGFP+ cells. These synapses appeared to have low release probability and displayed potentiation and asynchronous release upon repeated activation. In summary, we report on a previously unexamined component of the dorsal horn circuitry that likely constitutes an essential element of the fine tuning of nociception. PMID:19432997

  18. Dendritic orientation and branching distinguish a class of multifunctional turtle spinal interneurons

    PubMed Central

    Holmes, Jonathan R.; Berkowitz, Ari

    2014-01-01

    Spinal interneurons can integrate diverse propriospinal and supraspinal inputs that trigger or modulate locomotion and other limb movements. These synaptic inputs can occur on distal dendrites and yet must remain effective at the soma. Active dendritic conductances may amplify distal dendritic inputs, but appear to play a minimal role during scratching, at least. Another possibility is that spinal interneurons that integrate inputs on distal dendrites have unusually simple dendritic trees that effectively funnel current to the soma. We previously described a class of spinal interneurons, called transverse interneurons (or T neurons), in adult turtles. T neurons were defined as having dendrites that extend further in the transverse plane than rostrocaudally and a soma that extends further mediolaterally than rostrocaudally. T neurons are multifunctional, as they were activated during both swimming and scratching motor patterns. T neurons had higher peak firing rates and larger membrane potential oscillations during scratching than scratch-activated interneurons with different dendritic morphologies (“non-T” neurons). These characteristics make T neurons good candidates to play an important role in integrating diverse inputs and generating or relaying rhythmic motor patterns. Here, we quantitatively investigated additional dendritic morphological characteristics of T neurons as compared to non-T neurons. We found that T neurons have less total dendritic length, a greater proportion of dendritic length in primary dendrites, and dendrites that are oriented more mediolaterally. Thus, T neuron dendritic trees extend far mediolaterally, yet are unusually simple, which may help channel synaptic current from distal dendrites in the lateral and ventral funiculi to the soma. In combination with T neuron physiological properties, these dendritic properties may help integrate supraspinal and propriospinal inputs and generate and/or modulate rhythmic limb movements. PMID

  19. Differential involvement of oriens/pyramidale interneurones in hippocampal network oscillations in vitro.

    PubMed

    Gloveli, Tengis; Dugladze, Tamar; Saha, Sikha; Monyer, Hannah; Heinemann, Uwe; Traub, Roger D; Whittington, Miles A; Buhl, Eberhard H

    2005-01-01

    Using whole-cell patch-clamp recordings in conjunction with post hoc anatomy we investigated the physiological properties of hippocampal stratum oriens and stratum pyramidale inhibitory interneurones, before and following the induction of pharmacologically evoked gamma frequency network oscillations. Prior to kainate-induced transient epochs of gamma activity, two distinct classes of oriens interneurones, oriens lacunosum-moleculare (O-LM) and trilaminar cells, showed prominent differences in their membrane and firing properties, as well as in the amplitude and kinetics of their excitatory postsynaptic events. In the active network both types of neurone received a phasic barrage of gamma frequency excitatory inputs but, due to their differential functional integration, showed clear differences in their output patterns. While O-LM cells fired intermittently at theta frequency, trilaminar interneurones discharged on every gamma cycle and showed a propensity to fire spike doublets. Two other classes of fast spiking interneurones, perisomatic targeting basket and bistratified cells, in the active network discharged predominantly single action potentials on every gamma cycle. Thus, within a locally excited network, O-LM cells are likely to provide a theta-frequency patterned output to distal dendritic segments, whereas basket and bistratified cells are involved in the generation of locally synchronous gamma band oscillations. The anatomy and output profile of trilaminar cells suggest they are involved in the projection of locally generated gamma rhythms to distal sites. Therefore a division of labour appears to exist whereby different frequencies and spatiotemporal properties of hippocampal rhythms are mediated by different interneurone subtypes. PMID:15486016

  20. Distribution of interneurons in the CA2 region of the rat hippocampus

    PubMed Central

    Botcher, Nicola A.; Falck, Joanne E.; Thomson, Alex M.; Mercer, Audrey

    2014-01-01

    The CA2 region of the mammalian hippocampus is a unique region with its own distinctive properties, inputs and pathologies. Disruption of inhibitory circuits in this region appears to be linked with the pathology of specific psychiatric disorders, promoting interest in its local circuitry, its role in hippocampal function and its dysfunction in disease. In previous studies, CA2 interneurons, including a novel subclass of CA2 dendrite-preferring interneurons that has not been identified in other CA regions, have been shown to display physiological, synaptic and morphological properties unique to this sub-field and may therefore play a crucial role in the hippocampal circuitry. The distributions of immuno-labeled interneurons in dorsal CA2 were studied and compared with those of interneurons in CA1 and CA3. Like those in CA1 and CA3, the somata of CA2 parvalbumin-immunoperoxidase-labeled interneurons were located primarily in Stratum Pyramidale (SP) and Stratum Oriens (SO), with very few cells in Stratum Radiatum (SR) and none in Stratum Lacunosum Moleculare (SLM). There was, however, a greater proportion of GAD-positive cells were immunopositive for PV in SP in CA2 than in CA1 or CA3. CA2 SP also contained a larger density of somatostatin-, calbindin-, and VIP-immunopositive somata than CA1 and/or CA3. Like those in CA1 and CA3, CCK-immunopositive somata in CA2 were mostly located in SR. Reelin- and NPY- immunolabeled cell bodies were located in all layers of the three CA regions. However, a higher density of Reelin-positive somata was found in SP and SR of CA2 than in CA1 or CA3. PMID:25309345

  1. Evolution of a new sense for wind in flying phasmids? Afferents and interneurons

    NASA Astrophysics Data System (ADS)

    Hustert, Reinhold; Klug, Rebecca

    2009-12-01

    The evolution of winged stick insects (phasmids) from secondarily wingless ancestors was proposed in recent studies. We explored the cuticle of flying phasmids for wind sensors that could be involved in their flight control, comparable to those known for locusts. Surprisingly, wind-sensitive hairs (wsH) occur on the palps of mouthparts and on the antennae of the winged phasmid Sipyloidea sipylus which can fly in tethered position only when air currents blow over the mouthparts. The present study describes the morphology and major functional properties of these “new” wsH with soft and bulging hair bases which are different from the beaker-like hair bases of the wsH on the cerci of phasmids and the wsH described in other insects. The most sensitive wsH of antennae and palps respond with phasic-tonic afferents to air currents exceeding 0.2 ms-1. The fields of wsH on one side of the animal respond mainly to ventral, lateral, and frontal wind on the ipsilateral side of the head. Afferent inputs from the wsH converge but also diverge to a group of specific interneurons at their branches in the suboesophageal ganglion and can send their integrated input from wsH fields of the palps and antennae to the thoracic central nervous system. Response types of individual wsH-interneurons are either phasic or phasic-tonic to air puffs or constant air currents and also, the receptive fields of individual interneurons differ. We conclude that the “new” wsH system and its interneurons mainly serve to maintain flight activity in airborne phasmids and also, the “new” wsH must have emerged together with the integrating interneurons during the evolution from wingless to the recent winged forms of phasmids.

  2. Excitatory effects of parvalbumin-expressing interneurons maintain hippocampal epileptiform activity via synchronous afterdischarges.

    PubMed

    Ellender, Tommas J; Raimondo, Joseph V; Irkle, Agnese; Lamsa, Karri P; Akerman, Colin J

    2014-11-12

    Epileptic seizures are characterized by periods of hypersynchronous, hyperexcitability within brain networks. Most seizures involve two stages: an initial tonic phase, followed by a longer clonic phase that is characterized by rhythmic bouts of synchronized network activity called afterdischarges (ADs). Here we investigate the cellular and network mechanisms underlying hippocampal ADs in an effort to understand how they maintain seizure activity. Using in vitro hippocampal slice models from rats and mice, we performed electrophysiological recordings from CA3 pyramidal neurons to monitor network activity and changes in GABAergic signaling during epileptiform activity. First, we show that the highest synchrony occurs during clonic ADs, consistent with the idea that specific circuit dynamics underlie this phase of the epileptiform activity. We then show that ADs require intact GABAergic synaptic transmission, which becomes excitatory as a result of a transient collapse in the chloride (Cl(-)) reversal potential. The depolarizing effects of GABA are strongest at the soma of pyramidal neurons, which implicates somatic-targeting interneurons in AD activity. To test this, we used optogenetic techniques to selectively control the activity of somatic-targeting parvalbumin-expressing (PV(+)) interneurons. Channelrhodopsin-2-mediated activation of PV(+) interneurons during the clonic phase generated excitatory GABAergic responses in pyramidal neurons, which were sufficient to elicit and entrain synchronous AD activity across the network. Finally, archaerhodopsin-mediated selective silencing of PV(+) interneurons reduced the occurrence of ADs during the clonic phase. Therefore, we propose that activity-dependent Cl(-) accumulation subverts the actions of PV(+) interneurons to perpetuate rather than terminate pathological network hyperexcitability during the clonic phase of seizures. PMID:25392490

  3. GABA Regulates the Multidirectional Tangential Migration of GABAergic Interneurons in Living Neonatal Mice

    PubMed Central

    Inada, Hiroyuki; Watanabe, Miho; Uchida, Taku; Ishibashi, Hitoshi; Wake, Hiroaki; Nemoto, Tomomi; Yanagawa, Yuchio; Fukuda, Atsuo; Nabekura, Junichi

    2011-01-01

    Cortical GABAergic interneurons originate from ganglionic eminences and tangentially migrate into the cortical plate at early developmental stages. To elucidate the characteristics of this migration of GABAergic interneurons in living animals, we established an experimental design specialized for in vivo time-lapse imaging of the neocortex of neonate mice with two-photon laser-scanning microscopy. In vesicular GABA/glycine transporter (VGAT)-Venus transgenic mice from birth (P0) through P3, we observed multidirectional tangential migration of genetically-defined GABAergic interneurons in the neocortical marginal zone. The properties of this migration, such as the motility rate (distance/hr), the direction moved, and the proportion of migrating neurons to stationary neurons, did not change through P0 to P3, although the density of GABAergic neurons at the marginal zone decreased with age. Thus, the characteristics of the tangential motility of individual GABAergic neurons remained constant in development. Pharmacological block of GABAA receptors and of the Na+-K+-Cl− cotransporters, and chelating intracellular Ca2+, all significantly reduced the motility rate in vivo. The motility rate and GABA content within the cortex of neonatal VGAT-Venus transgenic mice were significantly greater than those of GAD67-GFP knock-in mice, suggesting that extracellular GABA concentration could facilitate the multidirectional tangential migration. Indeed, diazepam applied to GAD67-GFP mice increased the motility rate substantially. In an in vitro neocortical slice preparation, we confirmed that GABA induced a NKCC sensitive depolarization of GABAergic interneurons in VGAT-Venus mice at P0-P3. Thus, activation of GABAAR by ambient GABA depolarizes GABAergic interneurons, leading to an acceleration of their multidirectional motility in vivo. PMID:22180776

  4. Zebrafish Mnx proteins specify one motoneuron subtype and suppress acquisition of interneuron characteristics

    PubMed Central

    2012-01-01

    Background Precise matching between motoneuron subtypes and the muscles they innervate is a prerequisite for normal behavior. Motoneuron subtype identity is specified by the combination of transcription factors expressed by the cell during its differentiation. Here we investigate the roles of Mnx family transcription factors in specifying the subtypes of individually identified zebrafish primary motoneurons. Results Zebrafish has three Mnx family members. We show that each of them has a distinct and temporally dynamic expression pattern in each primary motoneuron subtype. We also show that two Mnx family members are expressed in identified VeLD interneurons derived from the same progenitor domain that generates primary motoneurons. Surprisingly, we found that Mnx proteins appear unnecessary for differentiation of VeLD interneurons or the CaP motoneuron subtype. Mnx proteins are, however, required for differentiation of the MiP motoneuron subtype. We previously showed that MiPs require two temporally-distinct phases of Islet1 expression for normal development. Here we show that in the absence of Mnx proteins, the later phase of Islet1 expression is initiated but not sustained, and MiPs become hybrids that co-express morphological and molecular features of motoneurons and V2a interneurons. Unexpectedly, these hybrid MiPs often extend CaP-like axons, and some MiPs appear to be entirely transformed to a CaP morphology. Conclusions Our results suggest that Mnx proteins promote MiP subtype identity by suppressing both interneuron development and CaP axon pathfinding. This is, to our knowledge, the first report of transcription factors that act to distinguish CaP and MiP subtype identities. Our results also suggest that MiP motoneurons are more similar to V2 interneurons than are CaP motoneurons. PMID:23122226

  5. Firing and Cellular Properties of V2a Interneurons in the Rodent Spinal Cord

    PubMed Central

    Dougherty, Kimberly J.

    2010-01-01

    Previous studies have shown that a group of ventrally located neurons, designated V2a interneurons, play a key role in maintaining locomotor rhythmicity and in ensuring appropriate left–right alternation during locomotion (Crone et al., 2008, 2009). These V2a interneurons express the transcription factor Chx10. The aim of the present study was to characterize the locomotor-related activity of individual V2a interneurons, their cellular properties, and their detailed anatomical attributes in Chx10-GFP mice. A dorsal horn-removed preparation was developed to allow for visual whole-cell patch recordings from V2a interneurons along the entire lumbar spinal cord while at the same time leaving enough of the spinal cord intact to generate fictive locomotion. During drug-evoked locomotor-like activity, a large proportion of Chx10 cells showed rhythmic firing or membrane potential fluctuations related to either flexor or extensor activity in every lumbar segment. Chx10 cells received predominantly rhythmic excitatory input. Chx10 neurons displayed a wide variety of firing and potential rhythmogenic properties. However, none of these properties was obviously related to the observed rhythmicity during locomotor-like activity. In dual recordings, we found no evidence of Chx10 neuron interconnectivity. Intracellular fills revealed diverse projection patterns with most Chx10 interneurons being local with projections to the central pattern generator and motor neuron regions of the spinal cord and others with long ascending and/or descending branches. These data are compatible with V2a neurons having a role in regulating segmental left–right alternation and ipsilateral motor neuron firing with little effect on rhythm generation. PMID:20053884

  6. PGC-1α Provides a Transcriptional Framework for Synchronous Neurotransmitter Release from Parvalbumin-Positive Interneurons

    PubMed Central

    Lucas, Elizabeth K.; Dougherty, Sarah E.; McMeekin, Laura J.; Reid, Courtney S.; Dobrunz, Lynn E.; West, Andrew B.; Hablitz, John J.

    2014-01-01

    Accumulating evidence strongly implicates the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in the pathophysiology of multiple neurological disorders, but the downstream gene targets of PGC-1α in the brain have remained enigmatic. Previous data demonstrate that PGC-1α is primarily concentrated in inhibitory neurons and that PGC-1α is required for the expression of the interneuron-specific Ca2+-binding protein parvalbumin (PV) throughout the cortex. To identify other possible transcriptional targets of PGC-1α in neural tissue, we conducted a microarray on neuroblastoma cells overexpressing PGC-1α, mined results for genes with physiological relevance to interneurons, and measured cortical gene and protein expression of these genes in mice with underexpression and overexpression of PGC-1α. We observed bidirectional regulation of novel PGC-1α-dependent transcripts spanning synaptic [synaptotagmin 2 (Syt2) and complexin 1 (Cplx1)], structural [neurofilament heavy chain (Nefh)], and metabolic [neutral cholesterol ester hydrolase 1 (Nceh1), adenylate kinase 1 (Ak1), inositol polyphosphate 5-phosphatase J (Inpp5j), ATP synthase mitochondrial F1 complex O subunit (Atp5o), phytanol-CoA-2hydroxylase (Phyh), and ATP synthase mitrochondrial F1 complex α subunit 1 (Atp5a1)] functions. The neuron-specific genes Syt2, Cplx1, and Nefh were developmentally upregulated in an expression pattern consistent with that of PGC-1α and were expressed in cortical interneurons. Conditional deletion of PGC-1α in PV-positive neurons significantly decreased cortical transcript expression of these genes, promoted asynchronous GABA release, and impaired long-term memory. Collectively, these data demonstrate that PGC-1α is required for normal PV-positive interneuron function and that loss of PGC-1α in this interneuron subpopulation could contribute to cortical dysfunction in disease states. PMID:25339750

  7. Paradoxical proepileptic response to NMDA receptor blockade linked to cortical interneuron defect in stargazer mice.

    PubMed

    Maheshwari, Atul; Nahm, Walter K; Noebels, Jeffrey L

    2013-01-01

    Paradoxical seizure exacerbation by anti-epileptic medication is a well-known clinical phenomenon in epilepsy, but the cellular mechanisms remain unclear. One possibility is enhanced network disinhibition by unintended suppression of inhibitory interneurons. We investigated this hypothesis in the stargazer mouse model of absence epilepsy, which bears a mutation in stargazin, an AMPA receptor trafficking protein. If AMPA signaling onto inhibitory GABAergic neurons is impaired, their activation by glutamate depends critically upon NMDA receptors. Indeed, we find that stargazer seizures are exacerbated by NMDA receptor blockade with CPP (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid) and MK-801, whereas other genetic absence epilepsy models are sensitive to these antagonists. To determine how an AMPA receptor trafficking defect could lead to paradoxical network activation, we analyzed stargazin and AMPA receptor localization and found that stargazin is detected exclusively in parvalbumin-positive (PV (+)) fast-spiking interneurons in somatosensory cortex, where it is co-expressed with the AMPA receptor subunit GluA4. PV (+) cortical interneurons in stargazer show a near twofold decrease in the dendrite:soma GluA4 expression ratio compared to wild-type (WT) littermates. We explored the functional consequence of this trafficking defect on network excitability in neocortical slices. Both NMDA receptor antagonists suppressed 0 Mg (2) (+)-induced network discharges in WT but augmented bursting in stargazer cortex. Interneurons mediate this paradoxical response, since the difference between genotypes was masked by GABA receptor blockade. Our findings provide a cellular locus for AMPA receptor-dependent signaling defects in stargazer cortex and define an interneuron-dependent mechanism for paradoxical seizure exacerbation in absence epilepsy. PMID:24065886

  8. Acetylcholine release in mouse hippocampal CA1 preferentially activates inhibitory-selective interneurons via α4β2* nicotinic receptor activation

    PubMed Central

    Bell, L. Andrew; Bell, Karen A.; McQuiston, A. Rory

    2015-01-01

    Acetylcholine (ACh) release onto nicotinic receptors directly activates subsets of inhibitory interneurons in hippocampal CA1. However, the specific interneurons activated and their effect on the hippocampal network is not completely understood. Therefore, we investigated subsets of hippocampal CA1 interneurons that respond to ACh release through the activation of nicotinic receptors and the potential downstream effects this may have on hippocampal CA1 network function. ACh was optogenetically released in mouse hippocampal slices by expressing the excitatory optogenetic protein oChIEF-tdTomato in medial septum/diagonal band of Broca cholinergic neurons using Cre recombinase-dependent adeno-associated viral mediated transfection. The actions of optogenetically released ACh were assessed on both pyramidal neurons and different interneuron subtypes via whole cell patch clamp methods. Vasoactive intestinal peptide (VIP)-expressing interneurons that selectively innervate other interneurons (VIP/IS) were excited by ACh through the activation of nicotinic receptors containing α4 and β2 subunits (α4β2*). ACh release onto VIP/IS was presynaptically inhibited by M2 muscarinic autoreceptors. ACh release produced spontaneous inhibitory postsynaptic current (sIPSC) barrages blocked by dihydro-β-erythroidine in interneurons but not pyramidal neurons. Optogenetic suppression of VIP interneurons did not inhibit these sIPSC barrages suggesting other interneuron-selective interneurons were also excited by α4β2* nicotinic receptor activation. In contrast, interneurons that innervate pyramidal neuron perisomatic regions were not activated by ACh release onto nicotinic receptors. Therefore, we propose ACh release in CA1 facilitates disinhibition through activation of α4β2* nicotinic receptors on interneuron-selective interneurons whereas interneurons that innervate pyramidal neurons are less affected by nicotinic receptor activation. PMID:25918499

  9. Caudal Ganglionic Eminence Precursor Transplants Disperse and Integrate as Lineage-Specific Interneurons but Do Not Induce Cortical Plasticity.

    PubMed

    Larimer, Phillip; Spatazza, Julien; Espinosa, Juan Sebastian; Tang, Yunshuo; Kaneko, Megumi; Hasenstaub, Andrea R; Stryker, Michael P; Alvarez-Buylla, Arturo

    2016-08-01

    The maturation of inhibitory GABAergic cortical circuits regulates experience-dependent plasticity. We recently showed that the heterochronic transplantation of parvalbumin (PV) or somatostatin (SST) interneurons from the medial ganglionic eminence (MGE) reactivates ocular dominance plasticity (ODP) in the postnatal mouse visual cortex. Might other types of interneurons similarly induce cortical plasticity? Here, we establish that caudal ganglionic eminence (CGE)-derived interneurons, when transplanted into the visual cortex of neonatal mice, migrate extensively in the host brain and acquire laminar distribution, marker expression, electrophysiological properties, and visual response properties like those of host CGE interneurons. Although transplants from the anatomical CGE do induce ODP, we found that this plasticity reactivation is mediated by a small fraction of MGE-derived cells contained in the transplant. These findings demonstrate that transplanted CGE cells can successfully engraft into the postnatal mouse brain and confirm the unique role of MGE lineage neurons in the induction of ODP. PMID:27425623

  10. Parvalbumin and neuropeptide Y expressing hippocampal GABA-ergic inhibitory interneuron numbers decline in a model of Gulf War illness

    PubMed Central

    Megahed, Tarick; Hattiangady, Bharathi; Shuai, Bing; Shetty, Ashok K.

    2015-01-01

    Cognitive dysfunction is amongst the most conspicuous symptoms in Gulf War illness (GWI). Combined exposure to the nerve gas antidote pyridostigmine bromide (PB), pesticides and stress during the Persian Gulf War-1 (PGW-1) are presumed to be among the major causes of GWI. Indeed, our recent studies in rat models have shown that exposure to GWI-related (GWIR) chemicals and mild stress for 4 weeks engenders cognitive impairments accompanied with several detrimental changes in the hippocampus. In this study, we tested whether reduced numbers of hippocampal gamma-amino butyric acid (GABA)-ergic interneurons are among the pathological changes induced by GWIR-chemicals and stress. Animals were exposed to low doses of GWIR-chemicals and mild stress for 4 weeks. Three months after this exposure, subpopulations of GABA-ergic interneurons expressing the calcium binding protein parvalbumin (PV), the neuropeptide Y (NPY) and somatostatin (SS) in the hippocampus were stereologically quantified. Animals exposed to GWIR-chemicals and stress for 4 weeks displayed reduced numbers of PV-expressing GABA-ergic interneurons in the dentate gyrus and NPY-expressing interneurons in the CA1 and CA3 subfields. However, no changes in SS+ interneuron population were observed in the hippocampus. Furthermore, GABA-ergic interneuron deficiency in these animals was associated with greatly diminished hippocampus neurogenesis. Because PV+ and NPY+ interneurons play roles in maintaining normal cognitive function and neurogenesis, and controlling the activity of excitatory neurons in the hippocampus, reduced numbers of these interneurons may be one of the major causes of cognitive dysfunction and reduced neurogenesis observed in GWI. Hence, strategies that improve inhibitory neurotransmission in the hippocampus may prove beneficial for reversing cognitive dysfunction in GWI. PMID:25620912

  11. Prox1 Regulates the Subtype-Specific Development of Caudal Ganglionic Eminence-Derived GABAergic Cortical Interneurons

    PubMed Central

    Young, Allison; Petros, Timothy; Karayannis, Theofanis; McKenzie Chang, Melissa; Lavado, Alfonso; Iwano, Tomohiko; Nakajima, Miho; Taniguchi, Hiroki; Huang, Z. Josh; Heintz, Nathaniel; Oliver, Guillermo; Matsuzaki, Fumio; Machold, Robert P.

    2015-01-01

    Neurogliaform (RELN+) and bipolar (VIP+) GABAergic interneurons of the mammalian cerebral cortex provide critical inhibition locally within the superficial layers. While these subtypes are known to originate from the embryonic caudal ganglionic eminence (CGE), the specific genetic programs that direct their positioning, maturation, and integration into the cortical network have not been elucidated. Here, we report that in mice expression of the transcription factor Prox1 is selectively maintained in postmitotic CGE-derived cortical interneuron precursors and that loss of Prox1 impairs the integration of these cells into superficial layers. Moreover, Prox1 differentially regulates the postnatal maturation of each specific subtype originating from the CGE (RELN, Calb2/VIP, and VIP). Interestingly, Prox1 promotes the maturation of CGE-derived interneuron subtypes through intrinsic differentiation programs that operate in tandem with extrinsically driven neuronal activity-dependent pathways. Thus Prox1 represents the first identified transcription factor specifically required for the embryonic and postnatal acquisition of CGE-derived cortical interneuron properties. SIGNIFICANCE STATEMENT Despite the recognition that 30% of GABAergic cortical interneurons originate from the caudal ganglionic eminence (CGE), to date, a specific transcriptional program that selectively regulates the development of these populations has not yet been identified. Moreover, while CGE-derived interneurons display unique patterns of tangential and radial migration and preferentially populate the superficial layers of the cortex, identification of a molecular program that controls these events is lacking. Here, we demonstrate that the homeodomain transcription factor Prox1 is expressed in postmitotic CGE-derived cortical interneuron precursors and is maintained into adulthood. We found that Prox1 function is differentially required during both embryonic and postnatal stages of development to

  12. A barrel-related interneuron in layer 4 of rat somatosensory cortex with a high intrabarrel connectivity.

    PubMed

    Koelbl, Christian; Helmstaedter, Moritz; Lübke, Joachim; Feldmeyer, Dirk

    2015-03-01

    Synaptic connections between identified fast-spiking (FS), parvalbumin (PV)-positive interneurons, and excitatory spiny neurons in layer 4 (L4) of the barrel cortex were investigated using patch-clamp recordings and simultaneous biocytin fillings. Three distinct clusters of FS L4 interneurons were identified based on their axonal morphology relative to the barrel column suggesting that these neurons do not constitute a homogeneous interneuron population. One L4 FS interneuron type had an axonal domain strictly confined to a L4 barrel and was therefore named "barrel-confined inhibitory interneuron" (BIn). BIns established reliable inhibitory synaptic connections with L4 spiny neurons at a high connectivity rate of 67%, of which 69% were reciprocal. Unitary IPSPs at these connections had a mean amplitude of 0.9 ± 0.8 mV with little amplitude variation and weak short-term synaptic depression. We found on average 3.7 ± 1.3 putative inhibitory synaptic contacts that were not restricted to perisomatic areas. In conclusion, we characterized a novel type of barrel cortex interneuron in the major thalamo-recipient layer 4 forming dense synaptic networks with L4 spiny neurons. These networks constitute an efficient and powerful inhibitory feedback system, which may serve to rapidly reset the barrel microcircuitry following sensory activation. PMID:24076498

  13. Altered Disrupted-in-Schizophrenia-1 Function Affects the Development of Cortical Parvalbumin Interneurons by an Indirect Mechanism.

    PubMed

    Borkowska, Malgorzata; Millar, J Kirsty; Price, David J

    2016-01-01

    Disrupted-in-Schizophrenia-1 (DISC1) gene has been linked to schizophrenia and related major mental illness. Mouse Disc1 has been implicated in brain development, mainly in the proliferation, differentiation, lamination, neurite outgrowth and synapse formation and maintenance of cortical excitatory neurons. Here, the effects of two loss-of-function point mutations in the mouse Disc1 sequence (Q31L and L100P) on cortical inhibitory interneurons were investigated. None of the mutations affected the overall number of interneurons. However, the 100P, but not the 31L, mutation resulted in a significant decrease in the numbers of interneurons expressing parvalbumin mRNA and protein across the sensory cortex. To investigate role of Disc1 in regulation of parvalbumin expression, mouse wild-type Disc-1 or the 100P mutant form were electroporated in utero into cortical excitatory neurons. Overexpression of wild-type Disc1 in these cells caused increased densities of parvalbumin-expressing interneurons in the electroporated area and in areas connected with it, whereas expression of Disc1-100P did not. We conclude that the 100P mutation prevents expression of parvalbumin by a normally sized cohort of interneurons and that altering Disc1 function in cortical excitatory neurons indirectly affects parvalbumin expression by cortical interneurons, perhaps as a result of altered functional input from the excitatory neurons. PMID:27244370

  14. Choline acetyltransferase-like immunoreactivity in a physiologically distinct subtype of olfactory nonspiking local interneurons in the cockroach (periplaneta americana).

    PubMed

    Fusca, Debora; Husch, Andreas; Baumann, Arnd; Kloppenburg, Peter

    2013-10-15

    Behavioral and physiological studies have shown that local interneurons are pivotal for processing odor information in the insect antennal lobe. They mediate inhibitory and excitatory interactions between the glomerular pathways and ultimately shape the tuning profile of projection neurons. To identify putative cholinergic local interneurons in the antennal lobe of Periplaneta americana, an antibody raised against the biosynthetic enzyme choline acetyltransferase (ChAT) was applied to individual morphologically and electrophysiologically characterized local interneurons. In nonspiking type IIa1 local interneurons, which were classified in this study, we found ChAT-like immunoreactivity suggesting that they are most likely excitatory. This is a well-defined population of neurons that generates Ca(2+) -driven spikelets upon depolarization and stimulation with odorants, but not Na(+) -driven action potentials, because they lack voltage-activated transient Na(+) currents. The nonspiking type IIa2 and type IIb local interneurons, in which Ca(2+) -driven spikelets were absent, had no ChAT-like immunoreactivity. The GABA-like immunoreactive, spiking type I local interneurons had no ChAT-like immunoreactivity. In addition, we showed that uniglomerular projection neurons with cell bodies located in the ventral portion of the ventrolateral somata group and projections along the inner antennocerebral tract exhibited ChAT-like immunoreactivity. Assigning potential transmitters and neuromodulators to distinct morphological and electrophysiological types of antennal lobe neurons is an important prerequisite for a detailed understanding of odor information processing in insects. PMID:23749599

  15. Altered Disrupted-in-Schizophrenia-1 Function Affects the Development of Cortical Parvalbumin Interneurons by an Indirect Mechanism

    PubMed Central

    Millar, J. Kirsty; Price, David J.

    2016-01-01

    Disrupted-in-Schizophrenia-1 (DISC1) gene has been linked to schizophrenia and related major mental illness. Mouse Disc1 has been implicated in brain development, mainly in the proliferation, differentiation, lamination, neurite outgrowth and synapse formation and maintenance of cortical excitatory neurons. Here, the effects of two loss-of-function point mutations in the mouse Disc1 sequence (Q31L and L100P) on cortical inhibitory interneurons were investigated. None of the mutations affected the overall number of interneurons. However, the 100P, but not the 31L, mutation resulted in a significant decrease in the numbers of interneurons expressing parvalbumin mRNA and protein across the sensory cortex. To investigate role of Disc1 in regulation of parvalbumin expression, mouse wild-type Disc-1 or the 100P mutant form were electroporated in utero into cortical excitatory neurons. Overexpression of wild-type Disc1 in these cells caused increased densities of parvalbumin-expressing interneurons in the electroporated area and in areas connected with it, whereas expression of Disc1-100P did not. We conclude that the 100P mutation prevents expression of parvalbumin by a normally sized cohort of interneurons and that altering Disc1 function in cortical excitatory neurons indirectly affects parvalbumin expression by cortical interneurons, perhaps as a result of altered functional input from the excitatory neurons. PMID:27244370

  16. Modular organization of the multipartite central pattern generator for turtle rostral scratch: knee-related interneurons during deletions.

    PubMed

    Stein, Paul S G; Daniels-McQueen, Susan; Lai, Jessica; Liu, Z; Corman, Tanya S

    2016-06-01

    Central pattern generators (CPGs) are neuronal networks in the spinal cord that generate rhythmic patterns of motor activity in the absence of movement-related sensory feedback. For many vertebrate rhythmic behaviors, CPGs generate normal patterns of motor neuron activities as well as variations of the normal patterns, termed deletions, in which bursts in one or more motor nerves are absent from one or more cycles of the rhythm. Prior work with hip-extensor deletions during turtle rostral scratch supports hypotheses of hip-extensor interneurons in a hip-extensor module and of hip-flexor interneurons in a hip-flexor module. We present here single-unit interneuronal recording data that support hypotheses of knee-extensor interneurons in a knee-extensor module and of knee-flexor interneurons in a knee-flexor module. Members of knee-related modules are not members of hip-related modules and vice versa. These results in turtle provide experimental support at the single-unit interneuronal level for the organizational concept that the rostral-scratch CPG for the turtle hindlimb is multipartite, that is, composed of more than two modules. This work, when combined with experimental and computational work in other vertebrates, does not support the classical view that the vertebrate limb CPG is bipartite with only two modules, one controlling all the flexors of the limb and the other controlling all the extensors of the limb. Instead, these results support the general principle that spinal CPGs are multipartite. PMID:27030737

  17. Lamina VIII interneurones interposed in crossed reflex pathways in the cat.

    PubMed Central

    Harrison, P J; Jankowska, E; Zytnicki, D

    1986-01-01

    The location of a group of interneurones projecting to contralateral motor nuclei has been established using retrograde transneuronal transport of horseradish peroxidase conjugated with wheat germ agglutinin (WGA-HRP). After labelling the motoneurones of semitendinosus, medial gastrocnemius or quadriceps muscles, interneurones which were secondarily labelled were found in lamina VIII and in the neighbouring narrow strip of lamina VII. They were found to be distributed from the 4th lumbar to the 1st sacral segments, with the highest concentration in the 6th and 7th lumbar segments and at the border between the 4th and 5th lumbar segments. The electrophysiological properties of lamina VIII interneurones of the 6th lumbar segment have been investigated using both extracellular and intracellular recording. Many of these interneurones could be antidromically activated following weak stimuli applied in contralateral motor nuclei. Post-synaptic potentials were evoked from a variety of primary afferents including group I muscle afferents. However, when present, the post-synaptic potentials (p.s.p.s) of group I origin were of considerably smaller amplitudes than p.s.p.s. evoked from higher threshold muscle or cutaneous afferents and smaller than p.s.p.s. which followed stimulation of the spinal cord at the thoracic level. P.s.p.s. from the latter two sources appear to constitute the main input to lamina VIII interneurones. Group I input has been found in forty lamina VIII interneurones. These were usually affected by either ipsilateral or contralateral group I afferents and only exceptionally by both. Excitatory post-synaptic potentials (e.p.s.p.s) from ipsilateral afferents were evoked in about twice as many neurones as e.p.s.p.s from the contralateral afferents. E.p.s.p.s were often accompanied by inhibitory post-synaptic potentials (i.p.s.p.s). Group Ia afferents appeared to contribute to both e.p.s.p.s and i.p.s.p.s, whether these were evoked from ipsilateral or from

  18. Somatostatin Interneurons Control a Key Component of Mismatch Negativity in Mouse Visual Cortex.

    PubMed

    Hamm, Jordan P; Yuste, Rafael

    2016-07-19

    Patients with schizophrenia have deficient sensory processing, undermining how they perceive and relate to a changing environment. This impairment can be captured by the reduced mismatch negativity (MMN) index, an electroencephalographic biomarker of psychosis. The biological factors contributing to MMN are unclear, though mouse research, in which genetic and optical methods could be applied, has given some insight. Using fast two-photon calcium imaging and multielectrode recordings in awake mice, we find that visual cortical circuits display adapted (decreased) responses to repeated stimuli and amplified responses to a deviant stimulus, the key component of human MMN. Moreover, pharmacogenetic silencing of somatostatin-containing interneurons specifically eliminated this amplification, along with its associated theta/alpha-band response, leaving stimulus-specific adaption and related gamma-band modulations intact. Our results validate a mouse model of MMN and suggest that abnormalities in somatostatin-containing interneurons cause sensory deficits underlying MMN and schizophrenia. PMID:27396334

  19. Striatal Cholinergic Interneurons Control Motor Behavior and Basal Ganglia Function in Experimental Parkinsonism.

    PubMed

    Maurice, Nicolas; Liberge, Martine; Jaouen, Florence; Ztaou, Samira; Hanini, Marwa; Camon, Jeremy; Deisseroth, Karl; Amalric, Marianne; Kerkerian-Le Goff, Lydia; Beurrier, Corinne

    2015-10-27

    Despite evidence showing that anticholinergic drugs are of clinical relevance in Parkinson's disease (PD), the causal role of striatal cholinergic interneurons (CINs) in PD pathophysiology remains elusive. Here, we show that optogenetic inhibition of CINs alleviates motor deficits in PD mouse models, providing direct demonstration for their implication in parkinsonian motor dysfunctions. As neural correlates, CIN inhibition in parkinsonian mice differentially impacts the excitability of striatal D1 and D2 medium spiny neurons, normalizes pathological bursting activity in the main basal ganglia output structure, and increases the functional weight of the direct striatonigral pathway in cortical information processing. By contrast, CIN inhibition in non-lesioned mice does not affect locomotor activity, equally modulates medium spiny neuron excitability, and does not modify spontaneous or cortically driven activity in the basal ganglia output, suggesting that the role of these interneurons in motor function is highly dependent on dopamine tone. PMID:26489458

  20. Central relay of bitter taste to the protocerebrum by peptidergic interneurons in the Drosophila brain.

    PubMed

    Hückesfeld, Sebastian; Peters, Marc; Pankratz, Michael J

    2016-01-01

    Bitter is a taste modality associated with toxic substances evoking aversive behaviour in most animals, and the valence of different taste modalities is conserved between mammals and Drosophila. Despite knowledge gathered in the past on the peripheral perception of taste, little is known about the identity of taste interneurons in the brain. Here we show that hugin neuropeptide-containing neurons in the Drosophila larval brain are necessary for avoidance behaviour to caffeine, and when activated, result in cessation of feeding and mediates a bitter taste signal within the brain. Hugin neuropeptide-containing neurons project to the neurosecretory region of the protocerebrum and functional imaging demonstrates that these neurons are activated by bitter stimuli and by activation of bitter sensory receptor neurons. We propose that hugin neurons projecting to the protocerebrum act as gustatory interneurons relaying bitter taste information to higher brain centres in Drosophila larvae. PMID:27619503

  1. Irregular Firing of Isolated Cortical Interneurons in Vitro Driven by Intrinsic Stochastic Mechanisms

    PubMed Central

    Englitz, Bernhard; Stiefel, Klaus M.; Sejnowski, Terrence J.

    2009-01-01

    Pharmacologically isolated GABAergic irregular spiking and stuttering interneurons in the mouse visual cortex display highly irregular spike times, with high coefficients of variation ≈0.9–3, in response to a depolarizing, constant current input. This is in marked contrast to cortical pyramidal cells, which spike quite regularly in response to the same current injection. We applied time-series analysis methods to show that the irregular behavior of the interneurons was not a consequence of low-dimensional, deterministic processes. These methods were also applied to the Hindmarsh and Rose neuronal model to confirm that the methods are adequate for the types of data under investigation. This result has important consequences for the origin of fluctuations observed in the cortex in vivo. PMID:18045000

  2. Interneuron Activity Leads to Initiation of Low-Voltage Fast-Onset Seizures

    PubMed Central

    Shiri, Zahra; Manseau, Frédéric; Lévesque, Maxime; Williams, Sylvain; Avoli, Massimo

    2016-01-01

    Seizures in temporal lobe epilepsy can be classified as hypersynchronous and low-voltage fast according to their onset patterns. Experimental evidence suggests that low-voltage fast-onset seizures mainly result from the synchronous activity of γ-aminobutyric acid–releasing cells. In this study, we tested this hypothesis using the optogenetic control of parvalbumin-positive interneurons in the entorhinal cortex, in the in vitro 4-aminopyridine model. We found that both spontaneous and optogenetically induced seizures had similar low-voltage fast-onset patterns. In addition, both types of seizures presented with higher ripple than fast ripple rates. Our data demonstrate the involvement of interneuronal networks in the initiation of low-voltage fast-onset seizures. PMID:25546300

  3. Tuning of fast-spiking interneuron properties by an activity-dependent transcriptional switch*

    PubMed Central

    Dehorter, Nathalie; Ciceri, Gabriele; Bartolini, Giorgia; Lim, Lynette; del Pino, Isabel; Marín, Oscar

    2015-01-01

    The function of neural circuits depends on the generation of specific classes of neurons. Neural identity is typically established near the time when neurons exit the cell cycle to become postmitotic cells, and it is generally accepted that, once the identity of a neuron has been established, its fate is maintained throughout life. Here, we show that network activity dynamically modulates the properties of fast-spiking (FS) interneurons through the postmitotic expression of the transcriptional regulator Er81. In the adult cortex, Er81 protein levels define a spectrum of FS basket cells with different properties, whose relative proportions are, however, continuously adjusted in response to neuronal activity. Our findings therefore suggest that interneuron properties are malleable in the adult cortex, at least to a certain extent. PMID:26359400

  4. Tonic excitation or inhibition is set by GABAA conductance in hippocampal interneurons

    PubMed Central

    Song, Inseon; Savtchenko, Leonid; Semyanov, Alexey

    2011-01-01

    Inhibition is a physiological process that decreases the probability of a neuron generating an action potential. The two main mechanisms that have been proposed for inhibition are hyperpolarization and shunting. Shunting results from increased membrane conductance, and it reduces the neuron-firing probability. Here we show that ambient GABA, the main inhibitory neurotransmitter in the brain, can excite adult hippocampal interneurons. In these cells, the GABAA current reversal potential is depolarizing, making baseline tonic GABAA conductance excitatory. Increasing the tonic conductance enhances shunting-mediated inhibition, which eventually overpowers the excitation. Such a biphasic change in interneuron firing leads to corresponding changes in the GABAA-mediated synaptic signalling. The described phenomenon suggests that the excitatory or inhibitory actions of the current are set not only by the reversal potential, but also by the conductance. PMID:21730957

  5. Control of response reliability by parvalbumin-expressing interneurons in visual cortex.

    PubMed

    Zhu, Yingjie; Qiao, Wenhui; Liu, Kefei; Zhong, Huiyuan; Yao, Haishan

    2015-01-01

    The responses of visual cortical neurons to natural stimuli are both reliable and sparse. These properties require inhibition, yet the contribution of specific types of inhibitory neurons is not well understood. Here we demonstrate that optogenetic suppression of parvalbumin (PV)- but not somatostatin (SOM)-expressing interneurons reduces response reliability in the primary visual cortex of anaesthetized and awake mice. PV suppression leads to increases in the low firing rates and decreases in the high firing rates of cortical neurons, resulting in an overall reduction of the signal-to-noise ratio (SNR). In contrast, SOM suppression generally increases the overall firing rate for most neurons, without affecting the SNR. Further analysis reveals that PV, but not SOM, suppression impairs neural discrimination of natural stimuli. Together, these results reveal a critical role for PV interneurons in the formation of reliable visual cortical representations of natural stimuli. PMID:25869033

  6. Interneuron- and GABAA receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells

    NASA Astrophysics Data System (ADS)

    He, Qionger; Duguid, Ian; Clark, Beverley; Panzanelli, Patrizia; Patel, Bijal; Thomas, Philip; Fritschy, Jean-Marc; Smart, Trevor G.

    2015-07-01

    Inhibitory synaptic plasticity is important for shaping both neuronal excitability and network activity. Here we investigate the input and GABAA receptor subunit specificity of inhibitory synaptic plasticity by studying cerebellar interneuron-Purkinje cell (PC) synapses. Depolarizing PCs initiated a long-lasting increase in GABA-mediated synaptic currents. By stimulating individual interneurons, this plasticity was observed at somatodendritic basket cell synapses, but not at distal dendritic stellate cell synapses. Basket cell synapses predominantly express β2-subunit-containing GABAA receptors; deletion of the β2-subunit ablates this plasticity, demonstrating its reliance on GABAA receptor subunit composition. The increase in synaptic currents is dependent upon an increase in newly synthesized cell surface synaptic GABAA receptors and is abolished by preventing CaMKII phosphorylation of GABAA receptors. Our results reveal a novel GABAA receptor subunit- and input-specific form of inhibitory synaptic plasticity that regulates the temporal firing pattern of the principal output cells of the cerebellum.

  7. Interneurons contribute to the hemodynamic/metabolic response to epileptiform discharges.

    PubMed

    Saillet, Sandrine; Quilichini, Pascale P; Ghestem, Antoine; Giusiano, Bernard; Ivanov, Anton I; Hitziger, Sebastian; Vanzetta, Ivo; Bernard, Christophe; Bénar, Christian-G

    2016-03-01

    Interpretation of hemodynamic responses in epilepsy is hampered by an incomplete understanding of the underlying neurovascular coupling, especially the contributions of excitation and inhibition. We made simultaneous multimodal recordings of local field potentials (LFPs), firing of individual neurons, blood flow, and oxygen level in the somatosensory cortex of anesthetized rats. Epileptiform discharges induced by bicuculline injections were used to trigger large local events. LFP and blood flow were robustly coupled, as were LFP and tissue oxygen. In a parametric linear model, LFP and the baseline activities of cerebral blood flow and tissue partial oxygen tension contributed significantly to blood flow and oxygen responses. In an analysis of recordings from 402 neurons, blood flow/tissue oxygen correlated with the discharge of putative interneurons but not of principal cells. Our results show that interneuron activity is important in the vascular and metabolic responses during epileptiform discharges. PMID:26745250

  8. Dendritic sprouting and compensatory synaptogenesis in an identified interneuron follow auditory deprivation in a cricket.

    PubMed Central

    Hoy, R R; Nolen, T G; Casaday, G C

    1985-01-01

    We examined the effect of chronic afferent deprivation on an identified interneuron (Int-1) in the auditory system of the Australian field cricket Teleogryllus oceanicus. In normal intact crickets, the auditory afferents from each ear terminate ipsilaterally onto a single Int-1. Each bilaterally paired Int-1 is excited by ultrasound stimulation of its ipsilateral ear but not by the contralateral ear. Unilateral removal of an ear early in postembryonic development deprives the developing Int-1 of ipsilateral auditory innervation. Consequently, the ipsilateral dendrites of the deprived interneuron sprout, grow aberrantly across the ganglionic midline, and terminate specifically in the intact auditory neuropile of the contralateral (unlesioned) side, where they form functional synapses with the contralateral afferents. This unusual compensatory dendritic sprouting restores auditory function to the neuron. Thus, it is demonstrated that the dendritic shape of an identified Int, as well as its synaptic connectivity, is altered as a consequence of chronic sensory deprivation. Images PMID:3865195

  9. Single axon IPSPs elicited in pyramidal cells by three classes of interneurones in slices of rat neocortex.

    PubMed

    Thomson, A M; West, D C; Hahn, J; Deuchars, J

    1996-10-01

    1. Using dual intracellular recordings in slices of adult rat neocortex, twenty-four IPSPs activated by single presynaptic interneurones were studied in simultaneously recorded pyramidal cells. Fast spiking interneurones inhibited one in four or five of their close pyramidal neighbours. No reciprocal connections were observed. After recordings neurones were filled with biocytin. 2. Interneurones that elicited IPSPs were classified as classical fast spiking (n = 10), as non-classical fast spiking (n = 3, including one burst-firing interneurone), as unclassified, or slow interneurones (n = 8), or as regular spiking interneurones (n = 3), i.e. interneurones whose electrophysiological characteristics were indistinguishable from those of pyramidal cells. 3. All of the seven classical fast spiking cells anatomically fully recovered had aspiny, beaded dendrites. Their partially myelinated axons ramified extensively, varying widely in shape and extent, but randomly selected labelled axon terminals typically innervated somata and large calibre dendrites on electron microscopic examination. One 'autapse' was demonstrated. One presumptive regular spiking interneurone axon made four somatic and five dendritic connections with unlabelled targets. 4. Full anatomical reconstructions of labelled classical fast spiking interneurones and their postsynaptic pyramids (n = 5) demonstrated one to five boutons per connection. The two recorded IPSPs that were fully reconstructed morphologically (3 and 5 terminals) were, however, amongst the smallest recorded (< 0.4 mV). Some connections may therefore involve larger numbers of contacts. 5. Single axon IPSPs were between 0.2 and 3.5 mV in average amplitude at -55 to -60 mV. Extrapolated reversal potentials were between -70 and -82 mV. IPSP time course correlated with the type of presynaptic interneurone, but not with IPSP latency, amplitude, reversal potential, or sensitivity to current injected at the soma. 6. Classical fast spiking

  10. Short-Term Synaptic Plasticity at Interneuronal Synapses Could Sculpt Rhythmic Motor Patterns

    PubMed Central

    Jia, Yan; Parker, David

    2016-01-01

    The output of a neuronal network depends on the organization and functional properties of its component cells and synapses. While the characterization of synaptic properties has lagged cellular analyses, a potentially important aspect in rhythmically active networks is how network synapses affect, and are in turn affected by, network activity. This could lead to a potential circular interaction where short-term activity-dependent synaptic plasticity is both influenced by and influences the network output. The analysis of synaptic plasticity in the lamprey locomotor network was extended here to characterize the short-term plasticity of connections between network interneurons and to try and address its potential network role. Paired recordings from identified interneurons in quiescent networks showed synapse-specific synaptic properties and plasticity that supported the presence of two hemisegmental groups that could influence bursting: depression in an excitatory interneuron group, and facilitation in an inhibitory feedback circuit. The influence of activity-dependent synaptic plasticity on network activity was investigated experimentally by changing Ringer Ca2+ levels, and in a simple computer model. A potential caveat of the experimental analyses was that changes in Ringer Ca2+ (and compensatory adjustments in Mg2+ in some cases) could alter several other cellular and synaptic properties. Several of these properties were tested, and while there was some variability, these were not usually significantly affected by the Ringer changes. The experimental analyses suggested that depression of excitatory inputs had the strongest influence on the patterning of network activity. The simulation supported a role for this effect, and also suggested that the inhibitory facilitating group could modulate the influence of the excitatory synaptic depression. Short-term activity-dependent synaptic plasticity has not generally been considered in spinal cord models. These results

  11. Fast-spiking interneurons have an initial orientation bias that is lost with vision

    PubMed Central

    Kuhlman, Sandra J.; Tring, Elaine; Trachtenberg, Joshua T.

    2011-01-01

    We find that following eye opening fast-spiking parvalbumin-positive GABAergic interneurons in mice have well-defined orientation tuning preferences and that subsequent visual experience broadens this tuning. Broad inhibitory tuning is not required for the developmental sharpening of excitatory tuning, but does precede binocular matching of orientation tuning. We propose that the experience-dependent broadening of inhibition is a novel candidate for opening the critical period. PMID:21750548

  12. Short-Term Synaptic Plasticity at Interneuronal Synapses Could Sculpt Rhythmic Motor Patterns.

    PubMed

    Jia, Yan; Parker, David

    2016-01-01

    The output of a neuronal network depends on the organization and functional properties of its component cells and synapses. While the characterization of synaptic properties has lagged cellular analyses, a potentially important aspect in rhythmically active networks is how network synapses affect, and are in turn affected by, network activity. This could lead to a potential circular interaction where short-term activity-dependent synaptic plasticity is both influenced by and influences the network output. The analysis of synaptic plasticity in the lamprey locomotor network was extended here to characterize the short-term plasticity of connections between network interneurons and to try and address its potential network role. Paired recordings from identified interneurons in quiescent networks showed synapse-specific synaptic properties and plasticity that supported the presence of two hemisegmental groups that could influence bursting: depression in an excitatory interneuron group, and facilitation in an inhibitory feedback circuit. The influence of activity-dependent synaptic plasticity on network activity was investigated experimentally by changing Ringer Ca(2+) levels, and in a simple computer model. A potential caveat of the experimental analyses was that changes in Ringer Ca(2+) (and compensatory adjustments in Mg(2+) in some cases) could alter several other cellular and synaptic properties. Several of these properties were tested, and while there was some variability, these were not usually significantly affected by the Ringer changes. The experimental analyses suggested that depression of excitatory inputs had the strongest influence on the patterning of network activity. The simulation supported a role for this effect, and also suggested that the inhibitory facilitating group could modulate the influence of the excitatory synaptic depression. Short-term activity-dependent synaptic plasticity has not generally been considered in spinal cord models. These

  13. COUP-TFI controls activity-dependent tyrosine hydroxylase expression in adult dopaminergic olfactory bulb interneurons.

    PubMed

    Bovetti, Serena; Bonzano, Sara; Garzotto, Donatella; Giannelli, Serena Gea; Iannielli, Angelo; Armentano, Maria; Studer, Michèle; De Marchis, Silvia

    2013-12-01

    COUP-TFI is an orphan nuclear receptor acting as a strong transcriptional regulator in different aspects of forebrain embryonic development. In this study, we investigated COUP-TFI expression and function in the mouse olfactory bulb (OB), a highly plastic telencephalic region in which continuous integration of newly generated inhibitory interneurons occurs throughout life. OB interneurons belong to different populations that originate from distinct progenitor lineages. Here, we show that COUP-TFI is highly expressed in tyrosine hydroxylase (TH)-positive dopaminergic interneurons in the adult OB glomerular layer (GL). We found that odour deprivation, which is known to downregulate TH expression in the OB, also downregulates COUP-TFI in dopaminergic cells, indicating a possible correlation between TH- and COUP-TFI-activity-dependent action. Moreover, we demonstrate that conditional inactivation of COUP-TFI in the EMX1 lineage results in a significant reduction of both TH and ZIF268 expression in the GL. Finally, lentiviral vector-mediated COUP-TFI deletion in adult-generated interneurons confirmed that COUP-TFI acts cell-autonomously in the control of TH and ZIF268 expression. These data indicate that COUP-TFI regulates TH expression in OB cells through an activity-dependent mechanism involving ZIF268 induction and strongly argue for a maintenance rather than establishment function of COUP-TFI in dopaminergic commitment. Our study reveals a previously unknown role for COUP-TFI in the adult brain as a key regulator in the control of sensory-dependent plasticity in olfactory dopaminergic neurons. PMID:24227652

  14. Collagen XIX Is Expressed by Interneurons and Contributes to the Formation of Hippocampal Synapses

    PubMed Central

    Su, Jianmin; Gorse, Karen; Ramirez, Francesco; Fox, Michael A.

    2010-01-01

    Extracellular matrix (ECM) molecules contribute to the formation and maintenance of synapses in the mammalian nervous system. We previously discovered a family of nonfibrillar collagens that organize synaptic differentiation at the neuromuscular junction (NMJ). Although many NMJ-organizing cues contribute to central nervous system (CNS) synaptogenesis, whether similar roles for collagens exist at central synapses remained unclear. In the present study we discovered that col19a1, the gene encoding nonfibrillar collagen XIX, is expressed by subsets of hippocampal neurons. Colocalization with the interneuron-specific enzyme glutamate decarboxylase 67 (Gad67), but not other cell-type-specific markers, suggests that hippocampal expression of col19a1 is restricted to interneurons. However, not all hippocampal interneurons express col19a1 mRNA; subsets of neuropeptide Y (NPY)-, somatostatin (Som)-, and calbindin (Calb)-immunoreactive interneurons express col19a1, but those containing parvalbumin (Parv) or calretinin (Calr) do not. To assess whether collagen XIX is required for the normal formation of hippocampal synapses, we examined synaptic morphology and composition in targeted mouse mutants lacking collagen XIX. We show here that subsets of synaptotagmin 2 (Syt2)-containing hippocampal nerve terminals appear malformed in the absence of collagen XIX. The presence of Syt2 in inhibitory hippocampal synapses, the altered distribution of Gad67 in collagen XIX-deficient subiculum, and abnormal levels of gephyrin in collagen XIX-deficient hippocampal extracts all suggest inhibitory synapses are affected by the loss of collagen XIX. Together, these data not only reveal that collagen XIX is expressed by central neurons, but show for the first time that a nonfibrillar collagen is necessary for the formation of hippocampal synapses. PMID:19937713

  15. Kalirin-7 Is an Essential Component of both Shaft and Spine Excitatory Synapses in Hippocampal Interneurons

    PubMed Central

    Ma, Xin-Ming; Wang, Yanping; Ferraro, Francesco; Mains, Richard E.; Eipper, Betty A.

    2008-01-01

    Kalirin, a multifunctional Rho GDP/GTP exchange factor, plays a vital role in cytoskeletal organization, affecting process initiation and outgrowth in neurons. Through alternative splicing, the Kalirin gene generates multiple functionally distinct proteins. Kalirin-7 (Kal7) is the most prevalent isoform in the adult rat hippocampus; it terminates with a PDZ binding motif, is localized to the post-synaptic density, interacts with PSD95 and causes the formation of dendritic spines when over-expressed in pyramidal neurons. Levels of Kal7 are low in the dendrites of hippocampal aspiny interneurons. In these interneurons, Kal7 is localized to the postsynaptic side of excitatory synapses onto dendritic shafts, overlapping clusters of PSD95 and NMDA receptor subunit NR1. Selectively decreasing levels of Kal7 decreases the density of PSD95 positive, bassoon positive clusters along the dendritic shaft of hippocampal interneurons. Over-expression of Kal7 increases dendritic branching, inducing formation of spine-like structures along the dendrites and on the soma of normally aspiny hippocampal interneurons. Essentially all of the spine-like structures formed in response to Kal7 are apposed to VGLUT1 positive, bassoon positive presynaptic endings; GAD positive, VGAT positive inhibitory endings are unaffected. Almost every Kal7 positive dendritic cluster contains PSD95 along with NMDA (NR1) and AMPA (GluR1 and GluR2) receptor subunits. Kal7-induced formation of spine-like structures requires its PDZ binding motif, and interruption of interactions between the PDZ binding motif and its interactors decreases Kal7-induced formation of spine-like structures. Kal7 thus joins Shank3 and GluR2 as molecules whose level of expression at excitatory synapses titrates the number of dendritic spines. PMID:18199770

  16. Delta opioid receptors colocalize with corticotropin releasing factor in hippocampal interneurons

    PubMed Central

    Williams, Tanya J.; Milner, Teresa A.

    2011-01-01

    The hippocampal formation (HF) is an important site at which stress circuits and endogenous opioid systems intersect, likely playing a critical role in the interaction between stress and drug addiction. Prior study findings suggest that the stress-related neuropeptide corticotropin releasing factor (CRF) and the delta opioid receptor (DOR) may localize to similar neuronal populations within HF lamina. Here, hippocampal sections of male and cycling female adult Sprague-Dawley rats were processed for immunolabeling using antisera directed against the DOR and CRF peptide, as well as interneuron subtype markers somatostatin or parvalbumin, and analyzed by fluorescence and electron microscopy. Both DOR- and CRF-labeling was observed in interneurons in the CA1, CA3, and dentate hilus. Males and normal cycling females displayed a similar number of CRF immunoreactive neurons co-labeled with DOR and a similar average number of CRF-labeled neurons in the dentate hilus and stratum oriens of CA1 and CA3. In addition, 70% of DOR/CRF dual-labeled neurons in the hilar region co-labeled with somatostatin, suggesting a role for these interneurons in regulating perforant path input to dentate granule cells. Ultrastructural analysis of CRF-labeled axon terminals within the hilar region revealed that proestrus females have a similar number of CRF-labeled axon terminals that contain DORs compared to males but an increased number of CRF-labeled axon terminals without DORs. Taken together, these findings suggest that while DORs are anatomically positioned to modulate CRF immunoreactive interneuron activity and CRF peptide release, their ability to exert such regulatory activity may be compromised in females when estrogen levels are high. PMID:21277946

  17. Sox5 controls dorsal progenitor and interneuron specification in the spinal cord.

    PubMed

    Quiroga, Alejandra C; Stolt, C Claus; Diez del Corral, Ruth; Dimitrov, Spas; Pérez-Alcalá, Siro; Sock, Elisabeth; Barbas, Julio A; Wegner, Michael; Morales, Aixa V

    2015-05-01

    The basic organization of somatosensory circuits in the spinal cord is already setup during the initial patterning of the dorsal neural tube. Extrinsic signals, such as Wnt and TGF-β pathways, activate combinatorial codes of transcription factors that are responsible for generating a pattern of discrete domains of dorsal progenitors (dp). These progenitors will give rise to distinct dorsal interneurons (dI). The Wnt/ βcatenin signaling pathway controls specification of dp/dI1-3 progenitors and interneurons. According to the current model in the field, Wnt/βcatenin activity seems to act in a graded fashion in the spinal cord, as different relative levels determine the identity of adjacent progenitors. However, it is not clear how this activity gradient is controlled and how the identities of dI1-3 are differentially regulated by Wnt signalling. We have determined that two SoxD transcription factors, Sox5 and Sox6, are expressed in restricted domains of dorsal progenitors in the neural tube. Using gain- and loss-of function approaches in chicken embryos, we have established that Sox5 controls cell fate specification of dp2 and dp3 progenitors and, as a result, controls the correct number of the corresponding dorsal interneurons (dI2 and dI3). Furthermore, Sox5 exerts its function by restricting dorsally Wnt signaling activity via direct transcriptional induction of the negative Wnt pathway regulator Axin2. By that way, Sox5 acts as a Wnt pathway modulator that contributes to sharpen the dorsal gradient of Wnt/βcatenin activity to control the distinction of two functionally distinct types of interneurons, dI2 and dI3 involved in the somatosensory relay. PMID:25363628

  18. Cryptic organisation within an apparently irregular rostrocaudal distribution of interneurons in the embryonic zebrafish spinal cord

    SciTech Connect

    Wells, Simon; Conran, John G.; Tamme, Richard; Gaudin, Arnaud; Webb, Jonathan; Lardelli, Michael

    2010-11-15

    The molecules and mechanisms involved in patterning the dorsoventral axis of the developing vertebrate spinal cord have been investigated extensively and many are well known. Conversely, knowledge of mechanisms patterning cellular distributions along the rostrocaudal axis is relatively more restricted. Much is known about the rostrocaudal distribution of motoneurons and spinal cord cells derived from neural crest but there is little known about the rostrocaudal patterning of most of the other spinal cord neurons. Here we report data from our analyses of the distribution of dorsal longitudinal ascending (DoLA) interneurons in the developing zebrafish spinal cord. We show that, although apparently distributed irregularly, these cells have cryptic organisation. We present a novel cell-labelling technique that reveals that DoLA interneurons migrate rostrally along the dorsal longitudinal fasciculus of the spinal cord during development. This cell-labelling strategy may be useful for in vivo analysis of factors controlling neuron migration in the central nervous system. Additionally, we show that DoLA interneurons persist in the developing spinal cord for longer than previously reported. These findings illustrate the need to investigate factors and mechanisms that determine 'irregular' patterns of cell distribution, particularly in the central nervous system but also in other tissues of developing embryos.

  19. Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes.

    PubMed

    Brown, J A; Ramikie, T S; Schmidt, M J; Báldi, R; Garbett, K; Everheart, M G; Warren, L E; Gellért, L; Horváth, S; Patel, S; Mirnics, Károly

    2015-12-01

    Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of schizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a microRNA engineered to target specifically Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in γ-aminobutyric acid (GABA) release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in the prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic (Tg) mice uncovered that the Pvalb/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty-seeking and reduced fear extinction. Furthermore, NMDA (N-methyl-d-aspartate) receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABAergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia. PMID:25623945

  20. Identification of Parvalbumin Interneurons as Cellular Substrate of Fear Memory Persistence.

    PubMed

    Çalışkan, Gürsel; Müller, Iris; Semtner, Marcus; Winkelmann, Aline; Raza, Ahsan S; Hollnagel, Jan O; Rösler, Anton; Heinemann, Uwe; Stork, Oliver; Meier, Jochen C

    2016-05-01

    Parvalbumin-positive (PV) basket cells provide perisomatic inhibition in the cortex and hippocampus and control generation of memory-related network activity patterns, such as sharp wave ripples (SPW-R). Deterioration of this class of fast-spiking interneurons has been observed in neuropsychiatric disorders and evidence from animal models suggests their involvement in the acquisition and extinction of fear memories. Here, we used mice with neuron type-targeted expression of the presynaptic gain-of-function glycine receptor RNA variant GlyR α3L(185L)to genetically enhance the network activity of PV interneurons. These mice showed reduced extinction of contextual fear memory but normal auditory cued fear memory. They furthermore displayed increase of SPW-R activity in area CA3 and CA1 and facilitated propagation of this particular network activity pattern, as determined in ventral hippocampal slice preparations. Individual freezing levels during extinction and SPW-R propagation were correlated across genotypes. The same was true for parvalbumin immunoreactivity in the ventral hippocampus, which was generally augmented in the GlyR mutant mice and correlated with individual freezing levels. Together, these results identify PV interneurons as critical cellular substrate of fear memory persistence and associated SPW-R activity in the hippocampus. Our findings may be relevant for the identification and characterization of physiological correlates for posttraumatic stress and anxiety disorders. PMID:26908632

  1. Glutamatergic Monopolar Interneurons Provide a Novel Pathway of Excitation in the Mouse Retina.

    PubMed

    Della Santina, Luca; Kuo, Sidney P; Yoshimatsu, Takeshi; Okawa, Haruhisa; Suzuki, Sachihiro C; Hoon, Mrinalini; Tsuboyama, Kotaro; Rieke, Fred; Wong, Rachel O L

    2016-08-01

    Excitatory and inhibitory neurons in the CNS are distinguished by several features, including morphology, transmitter content, and synapse architecture [1]. Such distinctions are exemplified in the vertebrate retina. Retinal bipolar cells are polarized glutamatergic neurons receiving direct photoreceptor input, whereas amacrine cells are usually monopolar inhibitory interneurons with synapses almost exclusively in the inner retina [2]. Bipolar but not amacrine cell synapses have presynaptic ribbon-like structures at their transmitter release sites. We identified a monopolar interneuron in the mouse retina that resembles amacrine cells morphologically but is glutamatergic and, unexpectedly, makes ribbon synapses. These glutamatergic monopolar interneurons (GluMIs) do not receive direct photoreceptor input, and their light responses are strongly shaped by both ON and OFF pathway-derived inhibitory input. GluMIs contact and make almost as many synapses as type 2 OFF bipolar cells onto OFF-sustained A-type (AOFF-S) retinal ganglion cells (RGCs). However, GluMIs and type 2 OFF bipolar cells possess functionally distinct light-driven responses and may therefore mediate separate components of the excitatory synaptic input to AOFF-S RGCs. The identification of GluMIs thus unveils a novel cellular component of excitatory circuits in the vertebrate retina, underscoring the complexity in defining cell types even in this well-characterized region of the CNS. PMID:27426514

  2. Complementary control of sensory adaptation by two types of cortical interneurons

    PubMed Central

    Natan, Ryan G; Briguglio, John J; Mwilambwe-Tshilobo, Laetitia; Jones, Sara I; Aizenberg, Mark; Goldberg, Ethan M; Geffen, Maria Neimark

    2015-01-01

    Reliably detecting unexpected sounds is important for environmental awareness and survival. By selectively reducing responses to frequently, but not rarely, occurring sounds, auditory cortical neurons are thought to enhance the brain's ability to detect unexpected events through stimulus-specific adaptation (SSA). The majority of neurons in the primary auditory cortex exhibit SSA, yet little is known about the underlying cortical circuits. We found that two types of cortical interneurons differentially amplify SSA in putative excitatory neurons. Parvalbumin-positive interneurons (PVs) amplify SSA by providing non-specific inhibition: optogenetic suppression of PVs led to an equal increase in responses to frequent and rare tones. In contrast, somatostatin-positive interneurons (SOMs) selectively reduce excitatory responses to frequent tones: suppression of SOMs led to an increase in responses to frequent, but not to rare tones. A mutually coupled excitatory-inhibitory network model accounts for distinct mechanisms by which cortical inhibitory neurons enhance the brain's sensitivity to unexpected sounds. DOI: http://dx.doi.org/10.7554/eLife.09868.001 PMID:26460542

  3. Depression of excitatory synapses onto parvalbumin interneurons in the medial prefrontal cortex in susceptibility to stress.

    PubMed

    Perova, Zinaida; Delevich, Kristen; Li, Bo

    2015-02-18

    In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events. PMID:25698754

  4. Laterodorsal tegmentum interneuron subtypes oppositely regulate olfactory cue-induced innate fear.

    PubMed

    Yang, Hongbin; Yang, Junhua; Xi, Wang; Hao, Sijia; Luo, Benyan; He, Xiaobin; Zhu, Liya; Lou, Huifang; Yu, Yan-qin; Xu, Fuqiang; Duan, Shumin; Wang, Hao

    2016-02-01

    Innate fear has a critical role in survival of animals. Unlike conditioned fear, the neuronal circuitry underlying innate fear is largely unknown. We found that the laterodorsal tegmentum (LDT) and lateral habenula (LHb) are specifically activated by the mouse predator odorant trimethylthiazoline (TMT). Using optogenetics to selectively stimulate GABAergic neurons in the LDT immediately produced fear-like responses (freezing, accelerated heart rate and increased serum corticosterone), whereas prolonged stimulation caused anxiety-like behaviors. Notably, although selective stimulation of parvalbumin (PV)-positive interneurons similarly induced fear-like responses, stimulation of somatostatin-positive interneurons or inhibition of PV neurons in the LDT suppressed TMT-induced fear-like responses without affecting conditioned fear. Finally, activation of LHb glutamatergic inputs to LDT interneurons was sufficient to generate fear-like responses. Thus, the LHb-LDT pathway is important for regulating olfactory cue-induced innate fear. Our results provide a potential target for therapeutic intervention for anxiety disorder. PMID:26727549

  5. Characterization and Distribution of Reelin-Positive Interneuron Subtypes in the Rat Barrel Cortex

    PubMed Central

    Pohlkamp, Theresa; Dávid, Csaba; Cauli, Bruno; Gallopin, Thierry; Bouché, Elisabeth; Karagiannis, Anastassios; May, Petra; Herz, Joachim; Frotscher, Michael; Staiger, Jochen F.; Bock, Hans H.

    2014-01-01

    GABAergic inhibitory interneurons (IN) represent a heterogeneous population with different electrophysiological, morphological, and molecular properties. The correct balance between interneuronal subtypes is important for brain function and is impaired in several neurological and psychiatric disorders. Here we show the data of 123 molecularly and electrophysiologically characterized neurons of juvenile rat barrel cortex acute slices, 48 of which expressed Reelin (Reln). Reln mRNA was exclusively detected in Gad65/67-positive cells but was found in interneuronal subtypes in different proportions: all cells of the adapting-Somatostatin (SST) cluster expressed Reln, whereas 63% of the adapting-neuropeptide Y (NPY, 50% of the fast-spiking Parvalbumin (PVALB), and 27% of the adapting/bursting-Vasoactive Intestinal Peptide (VIP) cluster were Reln-positive. Silhouette analysis revealed a high impact of the parameter Reln on cluster quality. By analyzing the co-localization of RELN immunoreactivity with those of different IN-markers, we found that RELN is produced layer-independently in SST-, NPY-, and NOS1-expressing INs, whereas co-localization of RELN and VIP was mostly absent. Of note, RELN co-localized with PVALB, predominantly in INs of layers IV/V (>30%). Our findings emphasize RELN's role as an important IN-marker protein and provide a basis for the functional characterization of Reln-expressing INs and its role in the regulation of inhibitory IN networks. PMID:23803971

  6. A Transient Translaminar GABAergic Interneuron Circuit Connects Thalamocortical Recipient Layers in Neonatal Somatosensory Cortex

    PubMed Central

    Marques-Smith, Andre; Lyngholm, Daniel; Kaufmann, Anna-Kristin; Stacey, Jacqueline A.; Hoerder-Suabedissen, Anna; Becker, Esther B.E.; Wilson, Michael C.; Molnár, Zoltán; Butt, Simon J.B.

    2016-01-01

    Summary GABAergic activity is thought to influence developing neocortical sensory circuits. Yet the late postnatal maturation of local layer (L)4 circuits suggests alternate sources of GABAergic control in nascent thalamocortical networks. We show that a population of L5b, somatostatin (SST)-positive interneuron receives early thalamic synaptic input and, using laser-scanning photostimulation, identify an early transient circuit between these cells and L4 spiny stellates (SSNs) that disappears by the end of the L4 critical period. Sensory perturbation disrupts the transition to a local GABAergic circuit, suggesting a link between translaminar and local control of SSNs. Conditional silencing of SST+ interneurons or conversely biasing the circuit toward local inhibition by overexpression of neuregulin-1 type 1 results in an absence of early L5b GABAergic input in mutants and delayed thalamic innervation of SSNs. These data identify a role for L5b SST+ interneurons in the control of SSNs in the early postnatal neocortex. PMID:26844833

  7. GABAergic Interneurons are Required for Generation of Slow CA1 Oscillation in Rat Hippocampus.

    PubMed

    Xu, Yuan; Wang, Lidan; Liu, Yu-Zhang; Yang, Yan; Xue, Xiaolin; Wang, Zhiru

    2016-08-01

    Neuronal oscillations are fundamental to hippocampal function. It has been shown that GABAergic interneurons make an important contribution to hippocampal oscillations, but the underlying mechanism is not well understood. Here, using whole-cell recording in the complete hippocampal formation isolated from rats at postnatal days 14-18, we showed that GABAA receptor-mediated activity enhanced the generation of slow CA1 oscillations. In vitro, slow oscillations (0.5-1.5 Hz) were generated in CA1 neurons, and they consisted primarily of excitatory rather than inhibitory membrane-potential changes. These oscillations were greatly reduced by blocking GABAA receptor-mediated activity with bicuculline and were enhanced by increasing such activity with midazolam, suggesting that interneurons are required for oscillation generation. Consistently, CA1 fast-spiking interneurons were found to generate action potentials usually preceding those in CA1 pyramidal cells. These findings indicate a GABAA receptor-based mechanism for the generation of the slow CA1 oscillation in the hippocampus. PMID:27439706

  8. c-fos expression in brainstem premotor interneurons during cholinergically induced active sleep in the cat.

    PubMed

    Morales, F R; Sampogna, S; Yamuy, J; Chase, M H

    1999-11-01

    The present study was undertaken to identify trigeminal premotor interneurons that become activated during carbachol-induced active sleep (c-AS). Their identification is a critical step in determining the neural circuits responsible for the atonia of active sleep. Accordingly, the retrograde tracer cholera toxin subunit B (CTb) was injected into the trigeminal motor nuclei complex to label trigeminal interneurons. To identify retrograde-labeled activated neurons, immunocytochemical techniques, designed to label the Fos protein, were used. Double-labeled (i.e., CTb(+), Fos(+)) neurons were found exclusively in the ventral portion of the medullary reticular formation, medial to the facial motor nucleus and lateral to the inferior olive. This region, which encompasses the ventral portion of the nucleus reticularis gigantocellularis and the nucleus magnocellularis, corresponds to the rostral portion of the classic inhibitory region of. This region contained a mean of 606 +/- 41.5 ipsilateral and 90 +/- 32.0 contralateral, CTb-labeled neurons. These cells were of medium-size with an average soma diameter of 20-35 micrometer. Approximately 55% of the retrogradely labeled cells expressed c-fos during a prolonged episode of c-AS. We propose that these neurons are the interneurons responsible for the nonreciprocal postsynaptic inhibition of trigeminal motoneurons that occurs during active sleep. PMID:10531453

  9. Different roles for homologous interneurons in species exhibiting similar rhythmic behaviors.

    PubMed

    Sakurai, Akira; Newcomb, James M; Lillvis, Joshua L; Katz, Paul S

    2011-06-21

    It is often assumed that similar behaviors in related species are produced by similar neural mechanisms. To test this, we examined the neuronal basis of a simple swimming behavior in two nudibranchs (Mollusca, Opisthobranchia), Melibe leonina and Dendronotus iris. The side-to-side swimming movements of Dendronotus [1] strongly resemble those of Melibe [2, 3]. In Melibe, it was previously shown that the central pattern generator (CPG) for swimming is composed of two bilaterally symmetric pairs of identified interneurons, swim interneuron 1 (Si1) and swim interneuron 2 (Si2), which are electrically coupled ipsilaterally and mutually inhibit both contralateral counterparts [2, 4]. We identified homologs of Si1 and Si2 in Dendronotus. (Henceforth, homologous neurons in each species will be distinguished by the subscripts (Den) and (Mel).) We found that Si2(Den) and Si2(Mel) play similar roles in generating the swim motor pattern. However, unlike Si1(Mel), Si1(Den) was not part of the swim CPG, was not strongly coupled to the ipsilateral Si2(Den), and did not inhibit the contralateral neurons. Thus, species differences exist in the neuronal organization of the swim CPGs despite the similarity of the behaviors. Therefore, similarity in species-typical behavior is not necessarily predictive of common neural mechanisms, even for homologous neurons in closely related species. PMID:21620707

  10. Hearing loss differentially affects thalamic drive to two cortical interneuron subtypes

    PubMed Central

    Kotak, Vibhakar C.; Sharma, Neeti; Sanes, Dan H.

    2013-01-01

    Sensory deprivation, such as developmental hearing loss, leads to an adjustment of synaptic and membrane properties throughout the central nervous system. These changes are thought to compensate for diminished sound-evoked activity. This model predicts that compensatory changes should be synergistic with one another along each functional pathway. To test this idea, we examined the excitatory thalamic drive to two types of cortical inhibitory interneurons that display differential effects in response to developmental hearing loss. The inhibitory synapses made by fast-spiking (FS) cells are weakened by hearing loss, whereas those made by low threshold-spiking (LTS) cells remain strong but display greater short-term depression (Takesian et al. 2010). Whole-cell recordings were made from FS or LTS interneurons in a thalamocortical brain slice, and medial geniculate (MG)-evoked postsynaptic potentials were analyzed. Following hearing loss, MG-evoked net excitatory potentials were smaller than normal at FS cells but larger than normal at LTS cells. Furthermore, MG-evoked excitatory potentials displayed less short-term depression at FS cells and greater short-term depression at LTS cells. Thus deprivation-induced adjustments of excitatory synapses onto inhibitory interneurons are cell-type specific and parallel the changes made by the inhibitory afferents. PMID:23719211

  11. Distinct and synergistic feedforward inhibition of pyramidal cells by basket and bistratified interneurons

    PubMed Central

    Ferrante, Michele; Ascoli, Giorgio A.

    2015-01-01

    Feedforward inhibition (FFI) enables pyramidal cells in area CA1 of the hippocampus (CA1PCs) to remain easily excitable while faithfully representing a broad range of excitatory inputs without quickly saturating. Despite the cortical ubiquity of FFI, its specific function is not completely understood. FFI in CA1PCs is mediated by two physiologically and morphologically distinct GABAergic interneurons: fast-spiking, perisomatic-targeting basket cells and regular-spiking, dendritic-targeting bistratified cells. These two FFI pathways might create layer-specific computational sub-domains within the same CA1PC, but teasing apart their specific contributions remains experimentally challenging. We implemented a biophysically realistic model of CA1PCs using 40 digitally reconstructed morphologies and constraining synaptic numbers, locations, amplitude, and kinetics with available experimental data. First, we validated the model by reproducing the known combined basket and bistratified FFI of CA1PCs at the population level. We then analyzed how the two interneuron types independently affected the CA1PC spike probability and timing as a function of inhibitory strength. Separate FFI by basket and bistratified respectively modulated CA1PC threshold and gain. Concomitant FFI by both interneuron types synergistically extended the dynamic range of CA1PCs by buffering their spiking response to excitatory stimulation. These results suggest testable hypotheses on the precise effects of GABAergic diversity on cortical computation. PMID:26594151

  12. Identification of Parvalbumin Interneurons as Cellular Substrate of Fear Memory Persistence

    PubMed Central

    Çalışkan, Gürsel; Müller, Iris; Semtner, Marcus; Winkelmann, Aline; Raza, Ahsan S.; Hollnagel, Jan O.; Rösler, Anton; Heinemann, Uwe; Stork, Oliver; Meier, Jochen C.

    2016-01-01

    Parvalbumin-positive (PV) basket cells provide perisomatic inhibition in the cortex and hippocampus and control generation of memory-related network activity patterns, such as sharp wave ripples (SPW-R). Deterioration of this class of fast-spiking interneurons has been observed in neuropsychiatric disorders and evidence from animal models suggests their involvement in the acquisition and extinction of fear memories. Here, we used mice with neuron type-targeted expression of the presynaptic gain-of-function glycine receptor RNA variant GlyR α3L185L to genetically enhance the network activity of PV interneurons. These mice showed reduced extinction of contextual fear memory but normal auditory cued fear memory. They furthermore displayed increase of SPW-R activity in area CA3 and CA1 and facilitated propagation of this particular network activity pattern, as determined in ventral hippocampal slice preparations. Individual freezing levels during extinction and SPW-R propagation were correlated across genotypes. The same was true for parvalbumin immunoreactivity in the ventral hippocampus, which was generally augmented in the GlyR mutant mice and correlated with individual freezing levels. Together, these results identify PV interneurons as critical cellular substrate of fear memory persistence and associated SPW-R activity in the hippocampus. Our findings may be relevant for the identification and characterization of physiological correlates for posttraumatic stress and anxiety disorders. PMID:26908632

  13. Serotonin 5-HT3 receptors in rat CA1 hippocampal interneurons: functional and molecular characterization

    PubMed Central

    Sudweeks, Sterling N; van Hooft, Johannes A; Yakel, Jerrel L

    2002-01-01

    The molecular makeup of the serotonin 5-HT3 receptor (5-HT3R) channel was investigated in rat hippocampal CA1 interneurons in slices using single-cell RT-PCR and patch-clamp recording techniques. We tested for the expression of the 5-HT3A (both short and long splice variants) and 5-HT3B subunits, as well as the expression of the α4 subunit of the neuronal nicotinic ACh receptors (nAChRs), the latter of which has been shown to co-assemble with the 5-HT3A subunit in heterologous expression systems. Both the 5-HT3A-short and α4-nAChR subunits were expressed in these interneurons, but we could not detect any expression of either the 5-HT3B or the 5-HT3A-long subunits. Furthermore, there was a strong tendency for the 5-HT3A-short and α4-nAChR subunits to be co-expressed in individual interneurons. To assess whether there was any functional evidence for co-assembly between the 5-HT3A-short and α4-nAChR subunits, we used the sulphydryl agent 2-aminoethyl methanethiosulphonate (MTSEA), which has previously been shown to modulate expressed 5-HT3Rs that contain the α4-nAChR subunit. In half of the interneurons examined, MTSEA significantly enhanced the amplitude of the 5-HT3R-mediated responses, which is consistent with the notion that the α4-nAChR subunit co-assembles with the 5-HT3A subunit to form a native heteromeric 5-HT3R channel in rat CA1 hippocampal interneurons in vivo. In addition, the single-channel properties of the 5-HT3R were investigated in outside-out patches. No resolvable single-channel currents were observed. Using non-stationary fluctuation analysis, we obtained an estimate of the single-channel conductance of 4 pS, which is well below that expected for channels containing both the 5-HT3A and 5-HT3B subunits. PMID:12411518

  14. Pathological alterations in GABAergic interneurons and reduced tonic inhibition in the basolateral amygdala during epileptogenesis.

    PubMed

    Fritsch, B; Qashu, F; Figueiredo, T H; Aroniadou-Anderjaska, V; Rogawski, M A; Braga, M F M

    2009-09-29

    An acute brain insult such as traumatic head/brain injury, stroke, or an episode of status epilepticus can trigger epileptogenesis, which, after a latent, seizure-free period, leads to epilepsy. The discovery of effective pharmacological interventions that can prevent the development of epilepsy requires knowledge of the alterations that occur during epileptogenesis in brain regions that play a central role in the induction and expression of epilepsy. In the present study, we investigated pathological alterations in GABAergic interneurons in the rat basolateral amygdala (BLA), and the functional impact of these alterations on inhibitory synaptic transmission, on days 7 to 10 after status epilepticus induced by kainic acid. Using design-based stereology combined with glutamic acid decarboxylase (GAD) 67 immunohistochemistry, we found a more extensive loss of GABAergic interneurons compared to the loss of principal cells. Fluoro-Jade C staining showed that neuronal degeneration was still ongoing. These alterations were accompanied by an increase in the levels of GAD and the alpha1 subunit of the GABA(A) receptor, and a reduction in the GluK1 (previously known as GluR5) subunit, as determined by Western blots. Whole-cell recordings from BLA pyramidal neurons showed a significant reduction in the frequency and amplitude of action potential-dependent spontaneous inhibitory postsynaptic currents (IPSCs), a reduced frequency but not amplitude of miniature IPSCs, and impairment in the modulation of IPSCs via GluK1-containing kainate receptors (GluK1Rs). Thus, in the BLA, GABAergic interneurons are more vulnerable to seizure-induced damage than principal cells. Surviving interneurons increase their expression of GAD and the alpha1 GABA(A) receptor subunit, but this does not compensate for the interneuronal loss; the result is a dramatic reduction of tonic inhibition in the BLA circuitry. As activation of GluK1Rs by ambient levels of glutamate facilitates GABA release, the

  15. Properties of a calcium-activated K(+) current on interneurons in the developing rat hippocampus.

    PubMed

    Aoki, T; Baraban, S C

    2000-06-01

    Calcium-activated potassium currents have an essential role in regulating excitability in a variety of neurons. Although it is well established that mature CA1 pyramidal neurons possess a Ca(2+)-activated K(+) conductance (I(K(Ca))) with early and late components, modulation by various endogenous neurotransmitters, and sensitivity to K(+) channel toxins, the properties of I(K(Ca)) on hippocampal interneurons (or immature CA1 pyramidal neurons) are relatively unknown. To address this problem, whole-cell voltage-clamp recordings were made from visually identified interneurons in stratum lacunosum-moleculare (L-M) and CA1 pyramidal cells in hippocampal slices from immature rats (P3-P25). A biphasic calcium-activated K(+) tail current was elicited following a brief depolarization from the holding potential (-50 mV). Analysis of the kinetic properties of I(K(Ca)) suggests that an early current component differs between these two cell types. An early I(K(Ca)) with a large peak current amplitude (200.8 +/- 13.2 pA, mean +/- SE), slow time constant of decay (70.9 +/- 3.3 ms), and relatively rapid time to peak (within 15 ms) was observed on L-M interneurons (n = 88), whereas an early I(K(Ca)) with a small peak current amplitude (112.5 +/- 7.3 pA), a fast time constant of decay (39.4 +/- 1.6 ms), and a slower time-to-peak (within 26 ms) was observed on CA1 pyramidal neurons (n = 85). Removal of extracellular calcium or addition of inorganic Ca(2+) channel blockers (cadmium, nickel, or cobalt) was used to demonstrate the calcium dependence of these currents. Addition of norepinephrine, carbachol, and a variety of channel toxins (apamin, iberiotoxin, verruculogen, paxilline, penitrem A, and charybdotoxin) were used to further distinguish between I(K(Ca)) on these two hippocampal cell types. Verruculogen (100 nM), carbachol (100 microM), apamin (100 nM), TEA (1 mM), and iberiotoxin (50 nM) significantly reduced early I(K(Ca)) on CA1 pyramidal neurons; early I(K(Ca)) on L

  16. Vibratory interneurons in the non-hearing cave cricket indicate evolutionary origin of sound processing elements in Ensifera.

    PubMed

    Stritih, Natasa; Stumpner, Andreas

    2009-01-01

    Tympanal hearing organs in the front tibiae of ensiferan insects supposedly evolved from vibration-sensitive tibial organs (TO), like those in the cave cricket Troglophilus neglectus (Rhaphidophoridae). If this is true, one expects to find interneurons in the cave cricket that are homologous to auditory neurons from hearing Ensifera. Therefore, we examined the central projections of the foreleg TO of the cave cricket, as well as morphology and response properties of interneurons responding to foreleg vibration. Sensory axons of the TO adjoined to the "tympanal nerve" terminate in the equivalent portion of the ring tract neuropile in the prothoracic ganglion as corresponding receptors of crickets and weta. We found nine putatively homologous elements to sound- and/or vibration-sensitive interneurons of Ensifera--one local neuron (unpaired median, DUM), three T-fibres (TN), three descending (DN) and two ascending neurons (AN). Presumable first-order interneurons arborising in the ring tract correspond to a local auditory DUM cell of bush crickets and to TN1, DN1 and AN2 of various Ensifera, respectively. Homologues of some prominent auditory cells, the "omega" neuron(s) and the ascending neuron 1 (AN1), however, were not found. We conclude that (a) T. neglectus interneurons are morphologically primitive with respect to those of hearing taxa, (b) significant changes in the dendritic structure/synaptic connectivity have taken place during the evolution of the most specialised first-order auditory interneurons of Ensifera, (c) the data do not contradict independent evolution of hearing in Grylloidea and Tettigonoidea. Other interneurons appear morpho-physiologically conserved across hearing and non-hearing species, possibly as a part of a multimodal "alert" system. PMID:18835145

  17. Neurochemical characterisation of lamina II inhibitory interneurons that express GFP in the PrP-GFP mouse

    PubMed Central

    2013-01-01

    Background Inhibitory interneurons in the superficial dorsal horn play important roles in modulating sensory transmission, and these roles are thought to be performed by distinct functional populations. We have identified 4 non-overlapping classes among the inhibitory interneurons in the rat, defined by the presence of galanin, neuropeptide Y, neuronal nitric oxide synthase (nNOS) and parvalbumin. The somatostatin receptor sst2A is expressed by ~50% of the inhibitory interneurons in this region, and is particularly associated with nNOS- and galanin-expressing cells. The main aim of the present study was to test whether a genetically-defined population of inhibitory interneurons, those expressing green fluorescent protein (GFP) in the PrP-GFP mouse, belonged to one or more of the neurochemical classes identified in the rat. Results The expression of sst2A and its relation to other neurochemical markers in the mouse was similar to that in the rat, except that a significant number of cells co-expressed nNOS and galanin. The PrP-GFP cells were entirely contained within the set of inhibitory interneurons that possessed sst2A receptors, and virtually all expressed nNOS and/or galanin. GFP was present in ~3-4% of neurons in the superficial dorsal horn, corresponding to ~16% of the inhibitory interneurons in this region. Consistent with their sst2A-immunoreactivity, all of the GFP cells were hyperpolarised by somatostatin, and this was prevented by administration of a selective sst2 receptor antagonist or a blocker of G-protein-coupled inwardly rectifying K+ channels. Conclusions These findings support the view that neurochemistry provides a valuable way of classifying inhibitory interneurons in the superficial laminae. Together with previous evidence that the PrP-GFP cells form a relatively homogeneous population in terms of their physiological properties, they suggest that these neurons have specific roles in processing sensory information in the dorsal horn. PMID

  18. Identification of Inhibitory Premotor Interneurons Activated at a Late Phase in a Motor Cycle during Drosophila Larval Locomotion

    PubMed Central

    Itakura, Yuki; Kohsaka, Hiroshi; Ohyama, Tomoko; Zlatic, Marta

    2015-01-01

    Rhythmic motor patterns underlying many types of locomotion are thought to be produced by central pattern generators (CPGs). Our knowledge of how CPG networks generate motor patterns in complex nervous systems remains incomplete, despite decades of work in a variety of model organisms. Substrate borne locomotion in Drosophila larvae is driven by waves of muscular contraction that propagate through multiple body segments. We use the motor circuitry underlying crawling in larval Drosophila as a model to try to understand how segmentally coordinated rhythmic motor patterns are generated. Whereas muscles, motoneurons and sensory neurons have been well investigated in this system, far less is known about the identities and function of interneurons. Our recent study identified a class of glutamatergic premotor interneurons, PMSIs (period-positive median segmental interneurons), that regulate the speed of locomotion. Here, we report on the identification of a distinct class of glutamatergic premotor interneurons called Glutamatergic Ventro-Lateral Interneurons (GVLIs). We used calcium imaging to search for interneurons that show rhythmic activity and identified GVLIs as interneurons showing wave-like activity during peristalsis. Paired GVLIs were present in each abdominal segment A1-A7 and locally extended an axon towards a dorsal neuropile region, where they formed GRASP-positive putative synaptic contacts with motoneurons. The interneurons expressed vesicular glutamate transporter (vGluT) and thus likely secrete glutamate, a neurotransmitter known to inhibit motoneurons. These anatomical results suggest that GVLIs are premotor interneurons that locally inhibit motoneurons in the same segment. Consistent with this, optogenetic activation of GVLIs with the red-shifted channelrhodopsin, CsChrimson ceased ongoing peristalsis in crawling larvae. Simultaneous calcium imaging of the activity of GVLIs and motoneurons showed that GVLIs’ wave-like activity lagged behind that of

  19. Cortex contacts both output neurons and nitrergic interneurons in the superior colliculus: Direct and Indirect routes for multisensory integration

    PubMed Central

    Fuentes-Santamaria, Veronica; Alvarado, Juan Carlos; Stein, Barry E.; McHaffie, John G.

    2010-01-01

    The ability of cat superior colliculus (SC) neurons to integrate information from different senses is thought to depend on direct projections from regions along the anterior ectosylvian sulcus (AES). However, electrical stimulation of AES also activates SC output neurons polysynaptically. In the present study we found that nitric oxide containing (nitrergic) interneurons are a target of AES projections, forming a component of this cortico-SC circuitry. The dendritic and axonal processes of these cortico-recipient nitrergic interneurons apposed the soma and dendrites of presumptive SC output neurons. Often, an individual cortical fiber targeted both an output neuron and a neighboring nitrergic interneuron that, in turn, contacted the output neuron. Many (46%) nitrergic neurons also colocalized with γ-aminobutyric acid (GABA), suggesting that a substantial subset have the potential for inhibiting output neurons. These observations suggest that nitrergic interneurons are positioned to convey cortical influences onto SC output neurons disynaptically via nitrergic mechanisms as well as conventional neurotransmitter systems utilizing GABA and other, possibly excitatory, neurotransmitters. In addition, because NO also acts as a retrograde messenger, cortically-mediated NO release from the post-synaptic elements of nitrergic interneurons could influence presynaptic cortico-SC terminals that directly contact output neurons. PMID:18003596

  20. Decrease of a Current Mediated by Kv1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism.

    PubMed

    Tubert, Cecilia; Taravini, Irene R E; Flores-Barrera, Eden; Sánchez, Gonzalo M; Prost, María Alejandra; Avale, María Elena; Tseng, Kuei Y; Rela, Lorena; Murer, Mario Gustavo

    2016-09-01

    The mechanism underlying a hypercholinergic state in Parkinson's disease (PD) remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.3 subunits contribute significantly to the orphan potassium current known as IsAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons. However, such inhibitory control of cholinergic interneuron excitability by Kv1.3-mediated current is markedly diminished in the parkinsonian striatum, suggesting that targeting Kv1.3 subunits and their regulatory pathways may have therapeutic potential in PD therapy. These studies reveal unexpected roles of Kv1.3 subunit-containing channels in the regulation of firing patterns of striatal cholinergic interneurons, which were thought to be largely dependent on KCa channels. PMID:27568555

  1. Specificity of prenatal cocaine exposure effects on cortical interneurons is independent from dopamine D1 receptor co-localization.

    PubMed

    Thompson, Barbara L; Stanwood, Gregg D; Levitt, Pat

    2010-07-01

    Gestational cocaine exposure in a rabbit model leads to a persistent increase in parvalbumin immunoreactive cells and processes, reduces dopamine D1 receptor coupling to Gsalpha by means of improper trafficking of the receptor, changes pyramidal neuron morphology, and disrupts cognitive function. Here, experiments investigated whether changes in parvalbumin neurons were specific, or extended to other subpopulations of interneurons. Additionally, we examined dopamine D1 receptor expression patterns and its overlap with specific interneuron populations in the rabbit prefrontal cortex as a possible correlate for alterations in interneuron development following prenatal cocaine exposure. Analysis of calbindin and calretinin interneuron subtypes revealed that they did not exhibit any differences in cell number or process development. Thus, specific consequences of prenatal cocaine in the rabbit appear to be limited to parvalbumin-positive interneurons. Dopamine D1 receptor expression did not correlate with the selective effects of cocaine exposure, however, as both parvalbumin and calbindin cell types expressed the receptor. The findings suggest that additional, unique properties of parvalbumin neurons contribute to their developmental sensitivity to in utero cocaine exposure. PMID:20080176

  2. Postmitotic Nkx2-1 controls the migration of telencephalic interneurons by direct repression of guidance receptors

    PubMed Central

    Nóbrega-Pereira, Sandrina; Kessaris, Nicoletta; Du, Tonggong; Kimura, Shioko; Anderson, Stewart A.; Marín, Oscar

    2008-01-01

    Summary The homeodomain transcription factor Nkx2-1 plays key roles in the developing telencephalon, where it regulates the identity of progenitor cells in the medial ganglionic eminence (MGE) and mediates the specification of several classes of GABAergic and cholinergic neurons. Here we have investigated the postmitotic function of Nkx2-1 in the migration of interneurons originating in the MGE. Experimental manipulations and mouse genetics show that downregulation of Nkx2-1 expression in postmitotic cells is necessary for the migration of interneurons to the cortex, whereas maintenance of Nkx2-1 expression is required for interneuron migration to the striatum. Nkx2-1 exerts this role in the migration of MGE-derived interneurons by directly regulating the expression of a guidance receptor, Neuropilin-2, which enables interneurons to invade the developing striatum. Our results demonstrate a novel role for the cell-fate determinant Nkx2-1 in regulating neuronal migration by direct transcriptional regulation of guidance receptors in postmitotic cells. PMID:18786357

  3. Trajectory of the main GABAergic interneuron populations from early development to old age in the rat primary auditory cortex

    PubMed Central

    Ouellet, Lydia; de Villers-Sidani, Etienne

    2014-01-01

    In both humans and rodents, decline in cognitive function is a hallmark of the aging process; the basis for this decrease has yet to be fully characterized. However, using aged rodent models, deficits in auditory processing have been associated with significant decreases in inhibitory signaling attributed to a loss of GABAergic interneurons. Not only are these interneurons crucial for pattern detection and other large-scale population dynamics, but they have also been linked to mechanisms mediating plasticity and learning, making them a prime candidate for study and modeling of modifications to cortical communication pathways in neurodegenerative diseases. Using the rat primary auditory cortex (A1) as a model, we probed the known markers of GABAergic interneurons with immunohistological methods, using antibodies against gamma aminobutyric acid (GABA), parvalbumin (PV), somatostatin (SOM), calretinin (CR), vasoactive intestinal peptide (VIP), choline acetyltransferase (ChAT), neuropeptide Y (NPY), and cholecystokinin (CCK) to document the changes observed in interneuron populations across the rat's lifespan. This analysis provided strong evidence that several but not all GABAergic neurons were affected by the aging process, showing most dramatic changes in expression of parvalbumin (PV) and somatostatin (SOM) expression. With this evidence, we show how understanding these trajectories of cell counts may be factored into a simple model to quantify changes in inhibitory signaling across the course of life, which may be applied as a framework for creating more advanced simulations of interneuronal implication in normal cerebral processing, normal aging, or pathological processes. PMID:24917792

  4. Sensory gating of an embryonic zebrafish interneuron during spontaneous motor behaviors

    PubMed Central

    Knogler, Laura D.; Drapeau, Pierre

    2014-01-01

    In all but the simplest monosynaptic reflex arcs, sensory stimuli are encoded by sensory neurons that transmit a signal via sensory interneurons to downstream partners in order to elicit a response. In the embryonic zebrafish (Danio rerio), cutaneous Rohon-Beard (RB) sensory neurons fire in response to mechanical stimuli and excite downstream glutamatergic commissural primary ascending (CoPA) interneurons to produce a flexion response contralateral to the site of stimulus. In the absence of sensory stimuli, zebrafish spinal locomotor circuits are spontaneously active during development due to pacemaker activity resulting in repetitive coiling of the trunk. Self-generated movement must therefore be distinguishable from external stimuli in order to ensure the appropriate activation of touch reflexes. Here, we recorded from CoPAs during spontaneous and evoked fictive motor behaviors in order to examine how responses to self-movement are gated in sensory interneurons. During spontaneous coiling, CoPAs received glycinergic inputs coincident with contralateral flexions that shunted firing for the duration of the coiling event. Shunting inactivation of CoPAs was caused by a slowly deactivating chloride conductance that resulted in lowered membrane resistance and increased action potential threshold. During spontaneous burst swimming, which develops later, CoPAs received glycinergic inputs that arrived in phase with excitation to ipsilateral motoneurons and provided persistent shunting. During a touch stimulus, short latency glutamatergic inputs produced cationic currents through AMPA receptors that drove a single, large amplitude action potential in the CoPA before shunting inhibition began, providing a brief window for the activation of downstream neurons. We compared the properties of CoPAs to those of other spinal neurons and propose that glycinergic signaling onto CoPAs acts as a corollary discharge signal for reflex inhibition during movement. PMID:25324729

  5. Generation of rhythmic patterns of activity by ventral interneurones in rat organotypic spinal slice culture

    PubMed Central

    Ballerini, Laura; Galante, Micaela; Grandolfo, Micaela; Nistri, Andrea

    1999-01-01

    In the presence of certain excitatory substances the rat isolated spinal cord generates rhythmic oscillations believed to be an in-built locomotor programme (fictive locomotion). However, it is unknown whether a long-term culture of the same tissue can express rhythmic activity. Such a simplified model system would provide useful data on the minimal circuitry involved and the cellular mechanisms mediating this phenomenon. For this purpose we performed patch clamp recording (under whole-cell voltage or current clamp conditions) from visually identified ventral horn interneurones of an organotypic slice culture of the rat spinal cord. Ventral horn interneurones expressed rhythmic bursting when the extracellular [K+] was raised from 4 to 6-7 mM. Under voltage clamp this activity consisted of composite synaptic currents grouped into bursts lasting 0.9 ± 0.5 s (2.8 ± 1.5 s period) and was generated at network level as it was blocked by tetrodotoxin or low-Ca2+-high-Mg2+ solution and its periodicity was unchanged at different potential levels. In current clamp mode bursting was usually observed as episodes comprising early depolarizing potentials followed by hyperpolarizing events with tight temporal patterning. Bursting was fully suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and reduced in amplitude and duration by N-methyl-D-aspartate (NMDA) receptor antagonism without change in periodicity. Extracellular field recording showed bursting activity over a wide area of the ventral horn. Regular, rhythmic activity similar to that induced by K+ also appeared spontaneously in Mg2+-free solution. The much slower rhythmic pattern induced by strychnine and bicuculline was also accelerated by high-K+ solution. The fast and regular rhythmic activity of interneurones in the spinal organotypic culture is a novel observation which suggests that the oversimplified circuit present in this culture is a useful model for investigating spinal rhythmic activity. PMID:10332095

  6. Spinal Interneurons and Forelimb Plasticity after Incomplete Cervical Spinal Cord Injury in Adult Rats

    PubMed Central

    Rombola, Angela M.; Rousseau, Celeste A.; Mercier, Lynne M.; Fitzpatrick, Garrett M.; Reier, Paul J.; Fuller, David D.; Lane, Michael A.

    2015-01-01

    Abstract Cervical spinal cord injury (cSCI) disrupts bulbospinal projections to motoneurons controlling the upper limbs, resulting in significant functional impairments. Ongoing clinical and experimental research has revealed several lines of evidence for functional neuroplasticity and recovery of upper extremity function after SCI. The underlying neural substrates, however, have not been thoroughly characterized. The goals of the present study were to map the intraspinal motor circuitry associated with a defined upper extremity muscle, and evaluate chronic changes in the distribution of this circuit following incomplete cSCI. Injured animals received a high cervical (C2) lateral hemisection (Hx), which compromises supraspinal input to ipsilateral spinal motoneurons controlling the upper extremities (forelimb) in the adult rat. A battery of behavioral tests was used to characterize the time course and extent of forelimb motor recovery over a 16 week period post-injury. A retrograde transneuronal tracer – pseudorabies virus – was used to define the motor and pre-motor circuitry controlling the extensor carpi radialis longus (ECRL) muscle in spinal intact and injured animals. In the spinal intact rat, labeling was observed unilaterally within the ECRL motoneuron pool and within spinal interneurons bilaterally distributed within the dorsal horn and intermediate gray matter. No changes in labeling were observed 16 weeks post-injury, despite a moderate degree of recovery of forelimb motor function. These results suggest that recovery of the forelimb function assessed following C2Hx injury does not involve recruitment of new interneurons into the ipsilateral ECRL motor pathway. However, the functional significance of these existing interneurons to motor recovery requires further exploration. PMID:25625912

  7. Bulbar Microcircuit Model Predicts Connectivity and Roles of Interneurons in Odor Coding

    PubMed Central

    Gilra, Aditya; Bhalla, Upinder S.

    2015-01-01

    Stimulus encoding by primary sensory brain areas provides a data-rich context for understanding their circuit mechanisms. The vertebrate olfactory bulb is an input area having unusual two-layer dendro-dendritic connections whose roles in odor coding are unclear. To clarify these roles, we built a detailed compartmental model of the rat olfactory bulb that synthesizes a much wider range of experimental observations on bulbar physiology and response dynamics than has hitherto been modeled. We predict that superficial-layer inhibitory interneurons (periglomerular cells) linearize the input-output transformation of the principal neurons (mitral cells), unlike previous models of contrast enhancement. The linearization is required to replicate observed linear summation of mitral odor responses. Further, in our model, action-potentials back-propagate along lateral dendrites of mitral cells and activate deep-layer inhibitory interneurons (granule cells). Using this, we propose sparse, long-range inhibition between mitral cells, mediated by granule cells, to explain how the respiratory phases of odor responses of sister mitral cells can be sometimes decorrelated as observed, despite receiving similar receptor input. We also rule out some alternative mechanisms. In our mechanism, we predict that a few distant mitral cells receiving input from different receptors, inhibit sister mitral cells differentially, by activating disjoint subsets of granule cells. This differential inhibition is strong enough to decorrelate their firing rate phases, and not merely modulate their spike timing. Thus our well-constrained model suggests novel computational roles for the two most numerous classes of interneurons in the bulb. PMID:25942312

  8. Analysis of non-radial interneuron migration dynamics and its disruption in Lis1+/- mice.

    PubMed

    Nasrallah, Ilya M; McManus, Matthew F; Pancoast, Maclean M; Wynshaw-Boris, Anthony; Golden, Jeffrey A

    2006-06-20

    Cell migration is an integral process in neural development. Analyses of radial cell migration (RCM) have revealed three modes of migration and specific defects in migration in various mouse mutants. In contrast, the dynamics of non-radial cell migration (NRCM) are incompletely understood. To investigate the dynamics of NRCM, we utilized a slice culture assay coupled with time-lapse videomicroscopy. This analysis revealed that non-radially migrating cells have a complex pattern of extending and retracting one or multiple processes while the nucleus advances concurrently or independently. These data indicate that the process of interneuron migration is unique to that seen for any mode of RCM. Non-radially migrating neurons moved for an average of 0.85 microm/min and paused for approximately 14% of the time observed. Given the novel morphology of NRCM, we hypothesized that specific aspects of migration would be defective with mutations in known cell migration genes, as described for RCM. This was tested by examining the dynamics of migration in the Lis1 mutant mouse; a well-defined cell migration mutant with known defects in NRCM. In contrast to wild-type cells, the rate of nuclear movement was significantly reduced in Lis1+/- interneurons, whereas the rate of active leading edge movement was similar. Morphologically, the leading process was significantly longer and the number of branches reduced in Lis1+/- mice. Together, these data indicate that the NRCM defect in Lis1+/- mice affects specific cellular processes. These data provide insight into NRCM and practical methods for future studies on the role(s) of specific genes in interneuron migration. PMID:16628622

  9. Functional Genetic Screen to Identify Interneurons Governing Behaviorally Distinct Aspects of Drosophila Larval Motor Programs.

    PubMed

    Clark, Matt Q; McCumsey, Stephanie J; Lopez-Darwin, Sereno; Heckscher, Ellie S; Doe, Chris Q

    2016-01-01

    Drosophila larval crawling is an attractive system to study rhythmic motor output at the level of animal behavior. Larval crawling consists of waves of muscle contractions generating forward or reverse locomotion. In addition, larvae undergo additional behaviors, including head casts, turning, and feeding. It is likely that some neurons (e.g., motor neurons) are used in all these behaviors, but the identity (or even existence) of neurons dedicated to specific aspects of behavior is unclear. To identify neurons that regulate specific aspects of larval locomotion, we performed a genetic screen to identify neurons that, when activated, could elicit distinct motor programs. We used 165 Janelia CRM-Gal4 lines-chosen for sparse neuronal expression-to ectopically express the warmth-inducible neuronal activator TrpA1, and screened for locomotor defects. The primary screen measured forward locomotion velocity, and we identified 63 lines that had locomotion velocities significantly slower than controls following TrpA1 activation (28°). A secondary screen was performed on these lines, revealing multiple discrete behavioral phenotypes, including slow forward locomotion, excessive reverse locomotion, excessive turning, excessive feeding, immobile, rigid paralysis, and delayed paralysis. While many of the Gal4 lines had motor, sensory, or muscle expression that may account for some or all of the phenotype, some lines showed specific expression in a sparse pattern of interneurons. Our results show that distinct motor programs utilize distinct subsets of interneurons, and provide an entry point for characterizing interneurons governing different elements of the larval motor program. PMID:27172197

  10. Functional Genetic Screen to Identify Interneurons Governing Behaviorally Distinct Aspects of Drosophila Larval Motor Programs

    PubMed Central

    Clark, Matt Q.; McCumsey, Stephanie J.; Lopez-Darwin, Sereno; Heckscher, Ellie S.; Doe, Chris Q.

    2016-01-01

    Drosophila larval crawling is an attractive system to study rhythmic motor output at the level of animal behavior. Larval crawling consists of waves of muscle contractions generating forward or reverse locomotion. In addition, larvae undergo additional behaviors, including head casts, turning, and feeding. It is likely that some neurons (e.g., motor neurons) are used in all these behaviors, but the identity (or even existence) of neurons dedicated to specific aspects of behavior is unclear. To identify neurons that regulate specific aspects of larval locomotion, we performed a genetic screen to identify neurons that, when activated, could elicit distinct motor programs. We used 165 Janelia CRM-Gal4 lines—chosen for sparse neuronal expression—to ectopically express the warmth-inducible neuronal activator TrpA1, and screened for locomotor defects. The primary screen measured forward locomotion velocity, and we identified 63 lines that had locomotion velocities significantly slower than controls following TrpA1 activation (28°). A secondary screen was performed on these lines, revealing multiple discrete behavioral phenotypes, including slow forward locomotion, excessive reverse locomotion, excessive turning, excessive feeding, immobile, rigid paralysis, and delayed paralysis. While many of the Gal4 lines had motor, sensory, or muscle expression that may account for some or all of the phenotype, some lines showed specific expression in a sparse pattern of interneurons. Our results show that distinct motor programs utilize distinct subsets of interneurons, and provide an entry point for characterizing interneurons governing different elements of the larval motor program. PMID:27172197