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  1. Article ; Online: Differential Coupling of Adult-Born Granule Cells to Parvalbumin and Somatostatin Interneurons.

    Groisman, Ayelén I / Yang, Sung M / Schinder, Alejandro F

    Cell reports

    2020  Volume 30, Issue 1, Page(s) 202–214.e4

    Abstract: A strong GABAergic tone imposes sparse levels of activity in the dentate gyrus of the hippocampus. This balance is challenged by the addition of new granule cells (GCs) with high excitability. How developing GCs integrate within local inhibitory networks ...

    Abstract A strong GABAergic tone imposes sparse levels of activity in the dentate gyrus of the hippocampus. This balance is challenged by the addition of new granule cells (GCs) with high excitability. How developing GCs integrate within local inhibitory networks remains unknown. We used optogenetics to study synaptogenesis between new GCs and GABAergic interneurons expressing parvalbumin (PV-INs) and somatostatin (SST-INs). PV-INs target the soma, and synapses become mature after 6 weeks. This transition is accelerated by exposure to an enriched environment. PV-INs exert efficient control of GC spiking and participate in both feedforward and feedback loops, a mechanism that would favor lateral inhibition and sparse coding. SST-INs target the dendrites, and synapses mature after 8 weeks. Outputs from GCs onto PV-INs develop faster than those onto SST-INs. Our results reveal a long-lasting transition wherein adult-born neurons remain poorly coupled to inhibition, which might enhance activity-dependent plasticity of input and output synapses.
    MeSH term(s) Aging/metabolism ; Animals ; Cytoplasmic Granules/metabolism ; GABAergic Neurons/metabolism ; HEK293 Cells ; Humans ; Interneurons/metabolism ; Mice ; Neural Inhibition ; Neurogenesis ; Neuronal Plasticity ; Parvalbumins/metabolism ; Somatostatin/metabolism ; Subcellular Fractions/metabolism ; Synapses/metabolism
    Chemical Substances Parvalbumins ; Somatostatin (51110-01-1)
    Language English
    Publishing date 2020-01-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2019.12.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: TAAR1 agonist ulotaront modulates striatal and hippocampal glutamate function in a state-dependent manner.

    Yang, Sung M / Ghoshal, Ayan / Hubbard, Jeffrey M / Gackière, Florian / Teyssié, Romain / Neale, Stuart A / Hopkins, Seth C / Koblan, Kenneth S / Bristow, Linda J / Dedic, Nina

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

    2023  

    Abstract: Aberrant dopaminergic and glutamatergic function, particularly within the striatum and hippocampus, has repeatedly been associated with the pathophysiology of schizophrenia. Supported by preclinical and recent clinical data, trace amine-associated ... ...

    Abstract Aberrant dopaminergic and glutamatergic function, particularly within the striatum and hippocampus, has repeatedly been associated with the pathophysiology of schizophrenia. Supported by preclinical and recent clinical data, trace amine-associated receptor 1 (TAAR1) agonism has emerged as a potential new treatment approach for schizophrenia. While current evidence implicates TAAR1-mediated regulation of dopaminergic tone as the primary circuit mechanism, little is known about the effects of TAAR1 agonists on the glutamatergic system and excitation-inhibition balance. Here we assessed the impact of ulotaront (SEP-363856), a TAAR1 agonist in Phase III clinical development for schizophrenia, on glutamate function in the mouse striatum and hippocampus. Ulotaront reduced spontaneous glutamatergic synaptic transmission and neuronal firing in striatal and hippocampal brain slices, respectively. Interestingly, ulotaront potentiated electrically-evoked excitatory synaptic transmission in both brain regions, suggesting the ability to modulate glutamatergic signaling in a state-dependent manner. Similar striatal effects were also observed with the TAAR1 agonist, RO5166017. Furthermore, we show that ulotaront regulates excitation-inhibition balance in the striatum by specifically modulating glutamatergic, but not GABAergic, spontaneous synaptic events. These findings expand the mechanistic circuit hypothesis of ulotaront and TAAR1 agonists, which may be uniquely positioned to normalize both the excessive dopaminergic tone and regulate abnormal glutamatergic function associated with schizophrenia.
    Language English
    Publishing date 2023-12-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 639471-1
    ISSN 1740-634X ; 0893-133X
    ISSN (online) 1740-634X
    ISSN 0893-133X
    DOI 10.1038/s41386-023-01779-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2379: Show issues Location:
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  3. Article ; Online: Reliable Genetic Labeling of Adult-Born Dentate Granule Cells Using Ascl1 CreERT2 and Glast CreERT2 Murine Lines.

    Yang, Sung M / Alvarez, Diego D / Schinder, Alejandro F

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2015  Volume 35, Issue 46, Page(s) 15379–15390

    Abstract: Newly generated dentate granule cells (GCs) are relevant for input discrimination in the adult hippocampus. Yet, their precise contribution to information processing remains unclear. To address this question, it is essential to develop approaches to ... ...

    Abstract Newly generated dentate granule cells (GCs) are relevant for input discrimination in the adult hippocampus. Yet, their precise contribution to information processing remains unclear. To address this question, it is essential to develop approaches to precisely label entire cohorts of adult-born GCs. In this work, we used genetically modified mice to allow conditional expression of tdTomato (Tom) in adult-born GCs and characterized their development and functional integration. Ascl1(CreERT2);CAG(floxStopTom) and Glast(CreERT2);CAG(floxStopTom) mice resulted in indelible expression of Tom in adult neural stem cells and their lineage upon tamoxifen induction. Whole-cell recordings were performed to measure intrinsic excitability, firing behavior, and afferent excitatory connectivity. Developing GCs were also staged by the expression of early and late neuronal markers. The slow development of adult-born GCs characterized here is consistent with previous reports using retroviral approaches that have revealed that a mature phenotype is typically achieved after 6-8 weeks. Our findings demonstrate that Ascl1(CreERT2) and Glast(CreERT2) mouse lines enable simple and reliable labeling of adult-born GC lineages within restricted time windows. Therefore, these mice greatly facilitate tagging new neurons and manipulating their activity, required for understanding adult neurogenesis in the context of network remodeling, learning, and behavior.
    Significance statement: Our study shows that Ascl1(CreERT2) and Glast(CreERT2) mice lines can be used to label large cohorts of adult-born dentate granule cells with excellent time resolution. Neurons labeled in this manner display developmental and functional profiles that are in full agreement with previous findings using thymidine analogs and retroviral labeling, thus providing an alternative approach to tackle fundamental questions on circuit remodeling. Because of the massive neuronal targeting and the simplicity of this method, genetic labeling will contribute to expand research on adult neurogenesis.
    MeSH term(s) Action Potentials/drug effects ; Action Potentials/physiology ; Animals ; Animals, Newborn ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Calbindin 1/metabolism ; Computer Simulation ; Dentate Gyrus/cytology ; Estrogen Antagonists/pharmacology ; Excitatory Amino Acid Transporter 1/deficiency ; Excitatory Amino Acid Transporter 1/metabolism ; Excitatory Postsynaptic Potentials/drug effects ; Excitatory Postsynaptic Potentials/genetics ; Female ; In Vitro Techniques ; Integrases/genetics ; Integrases/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Models, Neurological ; Nerve Tissue Proteins/metabolism ; Neurogenesis/drug effects ; Neurogenesis/physiology ; Neurons/classification ; Neurons/drug effects ; Neurons/physiology ; RNA, Untranslated/genetics ; RNA, Untranslated/metabolism ; Tamoxifen/pharmacology
    Chemical Substances Ascl1 protein, mouse ; Basic Helix-Loop-Helix Transcription Factors ; Calbindin 1 ; Estrogen Antagonists ; Excitatory Amino Acid Transporter 1 ; Gt(ROSA)26Sor non-coding RNA, mouse ; Nerve Tissue Proteins ; RNA, Untranslated ; Slc1a3 protein, mouse ; Tamoxifen (094ZI81Y45) ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
    Language English
    Publishing date 2015-11-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.2345-15.2015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1668: Show issues Location:
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  4. Article ; Online: Dynamic role of adult-born dentate granule cells in memory processing.

    Kropff, Emilio / Yang, Sung M / Schinder, Alejandro F

    Current opinion in neurobiology

    2015  Volume 35, Page(s) 21–26

    Abstract: Throughout the adult life of all mammals including humans, new neurons are incorporated to the dentate gyrus of the hippocampus. During a critical window that lasts about two weeks, adult-born immature neurons are more excitable and plastic than mature ... ...

    Abstract Throughout the adult life of all mammals including humans, new neurons are incorporated to the dentate gyrus of the hippocampus. During a critical window that lasts about two weeks, adult-born immature neurons are more excitable and plastic than mature ones, and they respond to a wider range of inputs. In apparent contradiction, new neurons have been shown to be crucial to solve behavioral tasks that involve the discrimination of very similar situations, which would instead require high input specificity. We propose that immature neurons are initially unspecific because their task is to identify novel elements inside a high dimensional input space. With maturation, they would specialize to represent details of these novel inputs, favoring discrimination.
    MeSH term(s) Adult ; Animals ; Dentate Gyrus/cytology ; Dentate Gyrus/physiology ; Humans ; Memory/physiology ; Nerve Net/physiology ; Neural Networks (Computer) ; Neurogenesis/physiology ; Neurons/cytology ; Neurons/physiology
    Language English
    Publishing date 2015-12
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1078046-4
    ISSN 1873-6882 ; 0959-4388
    ISSN (online) 1873-6882
    ISSN 0959-4388
    DOI 10.1016/j.conb.2015.06.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3260: Show issues Location:
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  5. Article ; Online: Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells.

    Temprana, Silvio G / Mongiat, Lucas A / Yang, Sung M / Trinchero, Mariela F / Alvarez, Diego D / Kropff, Emilio / Giacomini, Damiana / Beltramone, Natalia / Lanuza, Guillermo M / Schinder, Alejandro F

    Neuron

    2015  Volume 85, Issue 1, Page(s) 116–130

    Abstract: Developing granule cells (GCs) of the adult dentate gyrus undergo a critical period of enhanced activity and synaptic plasticity before becoming mature. The impact of developing GCs on the activity of preexisting dentate circuits remains unknown. Here we  ...

    Abstract Developing granule cells (GCs) of the adult dentate gyrus undergo a critical period of enhanced activity and synaptic plasticity before becoming mature. The impact of developing GCs on the activity of preexisting dentate circuits remains unknown. Here we combine optogenetics, acute slice electrophysiology, and in vivo chemogenetics to activate GCs at different stages of maturation to study the recruitment of local target networks. We show that immature (4-week-old) GCs can efficiently drive distal CA3 targets but poorly activate proximal interneurons responsible for feedback inhibition (FBI). As new GCs transition toward maturity, they reliably recruit GABAergic feedback loops that restrict spiking of neighbor GCs, a mechanism that would promote sparse coding. Such inhibitory loop impinges only weakly in new cohorts of young GCs. A computational model reveals that the delayed coupling of new GCs to FBI could be crucial to achieve a fine-grain representation of novel inputs in the dentate gyrus.
    MeSH term(s) Animals ; CA3 Region, Hippocampal/metabolism ; Dentate Gyrus/cytology ; Dentate Gyrus/growth & development ; Dentate Gyrus/metabolism ; Feedback, Physiological/physiology ; GABAergic Neurons/metabolism ; Interneurons/metabolism ; Mice ; Neuronal Plasticity/physiology ; Neurons/cytology ; Neurons/metabolism ; Optogenetics ; Parvalbumins/metabolism ; Patch-Clamp Techniques
    Chemical Substances Parvalbumins
    Language English
    Publishing date 2015-01-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2014.11.023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MG 92: Show issues

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