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Dive into the research topics where Gordon Fishell is active.

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Featured researches published by Gordon Fishell.


Developmental Neurobiology | 2011

Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons

Bernardo Rudy; Gordon Fishell; SooHyun Lee; Jens Hjerling-Leffler

An understanding of the diversity of cortical GABAergic interneurons is critical to understand the function of the cerebral cortex. Recent data suggest that neurons expressing three markers, the Ca2+‐binding protein parvalbumin (PV), the neuropeptide somatostatin (SST), and the ionotropic serotonin receptor 5HT3a (5HT3aR) account for nearly 100% of neocortical interneurons. Interneurons expressing each of these markers have a different embryological origin. Each group includes several types of interneurons that differ in morphological and electrophysiological properties and likely have different functions in the cortical circuit. The PV group accounts for ∼40% of GABAergic neurons and includes fast spiking basket cells and chandelier cells. The SST group, which represents ∼30% of GABAergic neurons, includes the Martinotti cells and a set of neurons that specifically target layerIV. The 5HT3aR group, which also accounts for ∼30% of the total interneuronal population, is heterogeneous and includes all of the neurons that express the neuropeptide VIP, as well as an equally numerous subgroup of neurons that do not express VIP and includes neurogliaform cells. The universal modulation of these neurons by serotonin and acetylcholine via ionotropic receptors suggests that they might be involved in shaping cortical circuits during specific brain states andbehavioral contexts.


The Journal of Neuroscience | 2010

The Largest Group of Superficial Neocortical GABAergic Interneurons Expresses Ionotropic Serotonin Receptors

SooHyun Lee; Jens Hjerling-Leffler; Edward Zagha; Gordon Fishell; Bernardo Rudy

A highly diverse population of neocortical GABAergic inhibitory interneurons has been implicated in multiple functions in information processing within cortical circuits. The diversity of cortical interneurons is determined during development and primarily depends on their embryonic origins either from the medial (MGE) or the caudal (CGE) ganglionic eminences. Although MGE-derived parvalbumin (PV)- or somatostatin (SST)-expressing interneurons are well characterized, less is known about the other types of cortical GABAergic interneurons, especially those of CGE lineage, because of the lack of specific neuronal markers for these interneuron subtypes. Using a bacterial artificial chromosome transgenic mouse line, we show that, in the somatosensory cortex of the mouse, the serotonin 5-hydroxytryptamine 3A (5-HT3A) receptor, the only ionotropic serotonergic receptor, is expressed in most, if not all, neocortical GABAergic interneurons that do not express PV or SST. Genetic fate mapping and neurochemical profile demonstrate that 5-HT3AR-expressing neurons include the entire spectrum of CGE-derived interneurons. We report that, in addition to serotonergic responsiveness via 5-HT3ARs, acetylcholine also depolarizes 5-HT3AR-expressing neurons via nicotinic receptors. 5-HT3AR-expressing neurons in thalamocortical (TC) recipient areas receive weak but direct monosynaptic inputs from the thalamus. TC input depolarizes a subset of TC-recipient 5-HT3AR neurons as strongly as fast-spiking cells, in part because of their high input resistance. Hence, fast modulation of serotonergic and cholinergic transmission may influence cortical activity through an enhancement of GABAergic synaptic transmission from 5-HT3AR-expressing neurons during sensory process depending on different behavioral states.


Nature Neuroscience | 2012

Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche.

Daniel A. Lee; Joseph L. Bedont; Thomas Pak; Hong Wang; Juan Song; Ana Miranda-Angulo; Vani Takiar; Vanessa Charubhumi; Francesca Balordi; Hirohide Takebayashi; Susan Aja; Eric W. Ford; Gordon Fishell; Seth Blackshaw

Adult hypothalamic neurogenesis has recently been reported, but the cell of origin and the function of these newborn neurons are unknown. Using genetic fate mapping, we found that median eminence tanycytes generate newborn neurons. Blocking this neurogenesis altered the weight and metabolic activity of adult mice. These findings reveal a previously unreported neurogenic niche in the mammalian hypothalamus with important implications for metabolism.


Neuron | 2008

The Requirement of Nkx2-1 in the Temporal Specification of Cortical Interneuron Subtypes

Simon J. B. Butt; Vitor H. Sousa; Marc V. Fuccillo; Jens Hjerling-Leffler; Goichi Miyoshi; Shioko Kimura; Gordon Fishell

Previous work has demonstrated that the character of mouse cortical interneuron subtypes can be directly related to their embryonic temporal and spatial origins. The relationship between embryonic origin and the character of mature interneurons is likely reflected by the developmental expression of genes that direct cell fate. However, a thorough understanding of the early genetic events that specify subtype identity has been hampered by the perinatal lethality resulting from the loss of genes implicated in the determination of cortical interneurons. Here, we employ a conditional loss-of-function approach to demonstrate that the transcription factor Nkx2-1 is required for the proper specification of specific interneuron subtypes. Removal of this gene at distinct neurogenic time points results in a switch in the subtypes of neurons observed at more mature ages. Our strategy reveals a causal link between the embryonic genetic specification by Nkx2-1 in progenitors and the functional attributes of their neuronal progeny in the mature nervous system.


Nature | 2014

Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission

Theofanis Karayannis; Eunkyu Au; J. C. Patel; Ilya Kruglikov; Sander Markx; Richard Delorme; Delphine Héron; Daniela Salomon; Joseph T. Glessner; Sophie Restituito; Andrew Gordon; Laura Rodriguez-Murillo; N. C. Roy; Joseph A. Gogos; Bernardo Rudy; M. E. Rice; Maria Karayiorgou; Hakon Hakonarson; Boris Keren; Guillaume Huguet; Thomas Bourgeron; Charles A. Hoeffer; Richard W. Tsien; Elior Peles; Gordon Fishell

Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.


Neural Development | 2007

Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip.

Robert P. Machold; Deborah Jones Kittell; Gordon Fishell

BackgroundDuring the embryonic development of the cerebellum, neurons are produced from progenitor cells located along a ventricular zone within dorsal rhombomere 1 that extends caudally to the roof plate of the fourth ventricle. The apposition of the caudal neuroepithelium and roof plate results in a unique inductive region termed the cerebellar rhombic lip, which gives rise to granule cell precursors and other glutamatergic neuronal lineages. Recently, we and others have shown that, at early embryonic stages prior to the emergence of granule cell precursors (E12), waves of neurogenesis in the cerebellar rhombic lip produce specific hindbrain nuclei followed by deep cerebellar neurons. How the induction of rhombic lip-derived neurons from cerebellar progenitors is regulated during this phase of cerebellar development to produce these temporally discrete neuronal populations while maintaining a progenitor pool for subsequent neurogenesis is not known.ResultsEmploying both gain- and loss-of-function methods, we find that Notch1 signaling in the cerebellar primordium regulates the responsiveness of progenitor cells to bone morphogenetic proteins (BMPs) secreted from the roof plate that stimulate the production of rhombic lip-derived neurons. In the absence of Notch1, cerebellar progenitors are depleted during the early production of hindbrain neurons, resulting in a severe decrease in the deep cerebellar nuclei that are normally born subsequently. Mechanistically, we demonstrate that Notch1 activity prevents the induction of Math1 by antagonizing the BMP receptor-signaling pathway at the level of Msx2 expression.ConclusionOur results provide a mechanism by which a balance between neural induction and maintenance of neural progenitors is achieved in the rhombic lip throughout embryonic development.


The Journal of Neuroscience | 2012

Satb1 Is an Activity-Modulated Transcription Factor Required for the Terminal Differentiation and Connectivity of Medial Ganglionic Eminence-Derived Cortical Interneurons

Jennie Close; Han Xu; Natalia De Marco Garcia; Renata Batista-Brito; Elsa Rossignol; Bernardo Rudy; Gordon Fishell

Although previous work identified transcription factors crucial for the specification and migration of parvalbumin (PV)-expressing and somatostatin (SST)-expressing interneurons, the intrinsic factors required for the terminal differentiation, connectivity, and survival of these cell types remain uncharacterized. Here we demonstrate that, within subpopulations of cortical interneurons, Satb1 (special AT-rich binding protein) promotes terminal differentiation, connectivity, and survival in interneurons that express PV and SST. We find that conditional removal of Satb1 in mouse interneurons results in the loss of a majority of SST-expressing cells across all cortical layers, as well as some PV-expressing cells in layers IV and VI, by postnatal day 21. SST-expressing cells initially migrate to the cortex in Satb1 mutant mice, but receive reduced levels of afferent input and begin to die during the first postnatal week. Electrophysiological characterization indicates that loss of Satb1 function in interneurons results in a loss of functional inhibition of excitatory principal cells. These data suggest that Satb1 is required for medial ganglionic eminence-derived interneuron differentiation, connectivity, and survival.


Proceedings of the National Academy of Sciences of the United States of America | 2014

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Wenfei Kang; Francesca Balordi; Nan Su; Lin Chen; Gordon Fishell; Jean M. Hébert

Significance Most if not all types of insults to the brain, including trauma, stroke, tumor growth, and neurodegeneration, for example, are believed to elicit a complex response involving several cell types. Central to this response is the activation of astrocytes. Although many proinflammatory molecules activate astrocytes, few factors are known to suppress their activation. Here we show that disrupting one particular signal specifically in adult astrocytes in the normal or injured neocortex leads to an increase in astrocyte activation. Conversely, increasing this signal after injury suppresses their activation. Therefore, at least one suppressor of astrocyte activation exists. Of potential therapeutic interest, disrupting this suppressor in astrocytes after injury results in smaller scars without affecting neuron survival. In the brain, astrocytes are multifunctional cells that react to insults and contain damage. However, excessive or sustained reactive astrocytes can be deleterious to functional recovery or contribute to chronic inflammation and neuronal dysfunction. Therefore, astrocyte activation in response to damage is likely to be tightly regulated. Although factors that activate astrocytes have been identified, whether factors also exist that maintain astrocytes as nonreactive or reestablish their nonreactive state after containing damage remains unclear. By using loss- and gain-of-function genetic approaches, we show that, in the unperturbed adult neocortex, FGF signaling is required in astrocytes to maintain their nonreactive state. Similarly, after injury, FGF signaling delays the response of astrocytes and accelerates their deactivation. In addition, disrupting astrocytic FGF receptors results in reduced scar size without affecting neuronal survival. Overall, this study reveals that the activation of astrocytes in the normal and injured neocortex is not only regulated by proinflammatory factors, but also by factors such as FGFs that suppress activation, providing alternative therapeutic targets.


Gene Expression Patterns | 2011

Genes expressed in Atoh1 neuronal lineages arising from the r1/isthmus rhombic lip

Robert P. Machold; Corinna Klein; Gordon Fishell

During embryogenesis, the rhombic lip of the fourth ventricle is the germinal origin of a diverse collection of neuronal populations that ultimately reside in the brainstem and cerebellum. Rhombic lip neurogenesis requires the bHLH transcription factor Atoh1 (Math1), and commences shortly after neural tube closure (E9.5). Within the rhombomere 1-isthmus region, the rhombic lip first produces brainstem and deep cerebellar neurons (E9.5-E12), followed by granule cell precursors after E12. While Atoh1 function is essential for all of these populations to be specified, the downstream genetic programs that confer specific properties to early and late born Atoh1 lineages are not well characterized. We have performed a comparative microarray analysis of gene expression within early and later born cohorts of Atoh1 expressing neural precursors purified from E14.5 embryos using a transgenic labeling strategy. We identify novel transcription factors, cell surface molecules, and cell cycle regulators within each pool of Atoh1 lineages that likely contribute to their distinct developmental trajectories and cell fates. In particular, our analysis reveals new insights into the genetic programs that regulate the specification and proliferation of granule cell precursors, the putative cell of origin for the majority of medulloblastomas.


Frontiers in Neural Circuits | 2012

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

Theofanis Karayannis; Natalia De Marco Garcia; Gordon Fishell

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.

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Jean M. Hébert

Albert Einstein College of Medicine

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