---
_id: '14363'
abstract:
- lang: eng
  text: Mitochondrial networks remodel their connectivity, content, and subcellular
    localization to support optimized energy production in conditions of increased
    environmental or cellular stress. Microglia rely on mitochondria to respond to
    these stressors, however our knowledge about mitochondrial networks and their
    adaptations in microglia in vivo is limited. Here, we generate a mouse model that
    selectively labels mitochondria in microglia. We identify that mitochondrial networks
    are more fragmented with increased content and perinuclear localization in vitro
    vs. in vivo. Mitochondrial networks adapt similarly in microglia closest to the
    injury site after optic nerve crush. Preventing microglial UCP2 increase after
    injury by selective knockout induces cellular stress. This results in mitochondrial
    hyperfusion in male microglia, a phenotype absent in females due to circulating
    estrogens. Our results establish the foundation for mitochondrial network analysis
    of microglia in vivo, emphasizing the importance of mitochondrial-based sex effects
    of microglia in other pathologies.
acknowledged_ssus:
- _id: Bio
- _id: LifeSc
- _id: PreCl
acknowledgement: We thank the Scientific Service Units (SSU) of ISTA through resources
  provided by the Imaging and Optics Facility (IOF), the Lab Support Facility (LSF),
  and the Pre-Clinical Facility (PCF) team, specifically Sonja Haslinger and Michael
  Schunn for excellent mouse colony management and support. This research was supported
  by the FWF Sonderforschungsbereich F83 (to E.E.P). We thank Bálint Nagy, Ryan John
  A. Cubero, Marco Benevento and all members of the Siegert group for constant feedback
  on the project and article.
article_number: '107780'
article_processing_charge: Yes
article_type: original
author:
- first_name: Margaret E
  full_name: Maes, Margaret E
  id: 3838F452-F248-11E8-B48F-1D18A9856A87
  last_name: Maes
  orcid: 0000-0001-9642-1085
- first_name: Gloria
  full_name: Colombo, Gloria
  id: 3483CF6C-F248-11E8-B48F-1D18A9856A87
  last_name: Colombo
  orcid: 0000-0001-9434-8902
- first_name: Florianne E
  full_name: Schoot Uiterkamp, Florianne E
  id: 3526230C-F248-11E8-B48F-1D18A9856A87
  last_name: Schoot Uiterkamp
- first_name: Felix
  full_name: Sternberg, Felix
  last_name: Sternberg
- first_name: Alessandro
  full_name: Venturino, Alessandro
  id: 41CB84B2-F248-11E8-B48F-1D18A9856A87
  last_name: Venturino
  orcid: 0000-0003-2356-9403
- first_name: Elena E.
  full_name: Pohl, Elena E.
  last_name: Pohl
- first_name: Sandra
  full_name: Siegert, Sandra
  id: 36ACD32E-F248-11E8-B48F-1D18A9856A87
  last_name: Siegert
  orcid: 0000-0001-8635-0877
citation:
  ama: Maes ME, Colombo G, Schoot Uiterkamp FE, et al. Mitochondrial network adaptations
    of microglia reveal sex-specific stress response after injury and UCP2 knockout.
    <i>iScience</i>. 2023;26(10). doi:<a href="https://doi.org/10.1016/j.isci.2023.107780">10.1016/j.isci.2023.107780</a>
  apa: Maes, M. E., Colombo, G., Schoot Uiterkamp, F. E., Sternberg, F., Venturino,
    A., Pohl, E. E., &#38; Siegert, S. (2023). Mitochondrial network adaptations of
    microglia reveal sex-specific stress response after injury and UCP2 knockout.
    <i>IScience</i>. Elsevier. <a href="https://doi.org/10.1016/j.isci.2023.107780">https://doi.org/10.1016/j.isci.2023.107780</a>
  chicago: Maes, Margaret E, Gloria Colombo, Florianne E Schoot Uiterkamp, Felix Sternberg,
    Alessandro Venturino, Elena E. Pohl, and Sandra Siegert. “Mitochondrial Network
    Adaptations of Microglia Reveal Sex-Specific Stress Response after Injury and
    UCP2 Knockout.” <i>IScience</i>. Elsevier, 2023. <a href="https://doi.org/10.1016/j.isci.2023.107780">https://doi.org/10.1016/j.isci.2023.107780</a>.
  ieee: M. E. Maes <i>et al.</i>, “Mitochondrial network adaptations of microglia
    reveal sex-specific stress response after injury and UCP2 knockout,” <i>iScience</i>,
    vol. 26, no. 10. Elsevier, 2023.
  ista: Maes ME, Colombo G, Schoot Uiterkamp FE, Sternberg F, Venturino A, Pohl EE,
    Siegert S. 2023. Mitochondrial network adaptations of microglia reveal sex-specific
    stress response after injury and UCP2 knockout. iScience. 26(10), 107780.
  mla: Maes, Margaret E., et al. “Mitochondrial Network Adaptations of Microglia Reveal
    Sex-Specific Stress Response after Injury and UCP2 Knockout.” <i>IScience</i>,
    vol. 26, no. 10, 107780, Elsevier, 2023, doi:<a href="https://doi.org/10.1016/j.isci.2023.107780">10.1016/j.isci.2023.107780</a>.
  short: M.E. Maes, G. Colombo, F.E. Schoot Uiterkamp, F. Sternberg, A. Venturino,
    E.E. Pohl, S. Siegert, IScience 26 (2023).
date_created: 2023-09-24T22:01:11Z
date_published: 2023-10-20T00:00:00Z
date_updated: 2023-12-13T12:27:30Z
day: '20'
ddc:
- '570'
department:
- _id: SaSi
doi: 10.1016/j.isci.2023.107780
external_id:
  isi:
  - '001080403500001'
  pmid:
  - '37731609'
file:
- access_level: open_access
  checksum: be1a560efdd96d20712311f4fc54aac2
  content_type: application/pdf
  creator: dernst
  date_created: 2023-11-07T08:53:21Z
  date_updated: 2023-11-07T08:53:21Z
  file_id: '14497'
  file_name: 2023_iScience_Maes.pdf
  file_size: 8197935
  relation: main_file
  success: 1
file_date_updated: 2023-11-07T08:53:21Z
has_accepted_license: '1'
intvolume: '        26'
isi: 1
issue: '10'
language:
- iso: eng
month: '10'
oa: 1
oa_version: Published Version
pmid: 1
publication: iScience
publication_identifier:
  eissn:
  - 2589-0042
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: Mitochondrial network adaptations of microglia reveal sex-specific stress response
  after injury and UCP2 knockout
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 26
year: '2023'
...
---
_id: '9642'
abstract:
- lang: eng
  text: Perineuronal nets (PNNs), components of the extracellular matrix, preferentially
    coat parvalbumin-positive interneurons and constrain critical-period plasticity
    in the adult cerebral cortex. Current strategies to remove PNN are long-lasting,
    invasive, and trigger neuropsychiatric symptoms. Here, we apply repeated anesthetic
    ketamine as a method with minimal behavioral effect. We find that this paradigm
    strongly reduces PNN coating in the healthy adult brain and promotes juvenile-like
    plasticity. Microglia are critically involved in PNN loss because they engage
    with parvalbumin-positive neurons in their defined cortical layer. We identify
    external 60-Hz light-flickering entrainment to recapitulate microglia-mediated
    PNN removal. Importantly, 40-Hz frequency, which is known to remove amyloid plaques,
    does not induce PNN loss, suggesting microglia might functionally tune to distinct
    brain frequencies. Thus, our 60-Hz light-entrainment strategy provides an alternative
    form of PNN intervention in the healthy adult brain.
acknowledged_ssus:
- _id: Bio
- _id: PreCl
acknowledgement: We thank the scientific service units at IST Austria, especially
  the IST bioimaging facility, the preclinical facility, and, specifically, Michael
  Schunn and Sonja Haslinger for excellent support; Plexxikon for the PLX food; the
  Csicsvari group for advice and equipment for in vivo recording; Jürgen Siegert for
  the light-entrainment design; Marco Benevento, Soledad Gonzalo Cogno, Pat King,
  and all Siegert group members for constant feedback on the project and manuscript;
  Lorena Pantano (PILM Bioinformatics Core) for assisting with sample-size determination
  for OD plasticity experiments; and Ana Morello from MIT for technical assistance
  with VEPs recordings. This research was supported by a DOC Fellowship from the Austrian
  Academy of Sciences at the Institute of Science and Technology Austria to R.S.,
  from the European Union Horizon 2020 research and innovation program under the Marie
  Skłodowska-Curie Actions program (grants 665385 to G.C.; 754411 to R.J.A.C.), the
  European Research Council (grant 715571 to S.S.), and the National Eye Institute
  of the National Institutes of Health under award numbers R01EY029245 (to M.F.B.)
  and R01EY023037 (diversity supplement to H.D.J-C.).
article_number: '109313'
article_processing_charge: No
article_type: original
author:
- first_name: Alessandro
  full_name: Venturino, Alessandro
  id: 41CB84B2-F248-11E8-B48F-1D18A9856A87
  last_name: Venturino
  orcid: 0000-0003-2356-9403
- first_name: Rouven
  full_name: Schulz, Rouven
  id: 4C5E7B96-F248-11E8-B48F-1D18A9856A87
  last_name: Schulz
  orcid: 0000-0001-5297-733X
- first_name: Héctor
  full_name: De Jesús-Cortés, Héctor
  last_name: De Jesús-Cortés
- first_name: Margaret E
  full_name: Maes, Margaret E
  id: 3838F452-F248-11E8-B48F-1D18A9856A87
  last_name: Maes
  orcid: 0000-0001-9642-1085
- first_name: Balint
  full_name: Nagy, Balint
  id: 93C65ECC-A6F2-11E9-8DF9-9712E6697425
  last_name: Nagy
- first_name: Francis
  full_name: Reilly-Andújar, Francis
  last_name: Reilly-Andújar
- first_name: Gloria
  full_name: Colombo, Gloria
  id: 3483CF6C-F248-11E8-B48F-1D18A9856A87
  last_name: Colombo
  orcid: 0000-0001-9434-8902
- first_name: Ryan J
  full_name: Cubero, Ryan J
  id: 850B2E12-9CD4-11E9-837F-E719E6697425
  last_name: Cubero
  orcid: 0000-0003-0002-1867
- first_name: Florianne E
  full_name: Schoot Uiterkamp, Florianne E
  id: 3526230C-F248-11E8-B48F-1D18A9856A87
  last_name: Schoot Uiterkamp
- first_name: Mark F.
  full_name: Bear, Mark F.
  last_name: Bear
- first_name: Sandra
  full_name: Siegert, Sandra
  id: 36ACD32E-F248-11E8-B48F-1D18A9856A87
  last_name: Siegert
  orcid: 0000-0001-8635-0877
citation:
  ama: Venturino A, Schulz R, De Jesús-Cortés H, et al. Microglia enable mature perineuronal
    nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment
    in the healthy brain. <i>Cell Reports</i>. 2021;36(1). doi:<a href="https://doi.org/10.1016/j.celrep.2021.109313">10.1016/j.celrep.2021.109313</a>
  apa: Venturino, A., Schulz, R., De Jesús-Cortés, H., Maes, M. E., Nagy, B., Reilly-Andújar,
    F., … Siegert, S. (2021). Microglia enable mature perineuronal nets disassembly
    upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain.
    <i>Cell Reports</i>. Elsevier. <a href="https://doi.org/10.1016/j.celrep.2021.109313">https://doi.org/10.1016/j.celrep.2021.109313</a>
  chicago: Venturino, Alessandro, Rouven Schulz, Héctor De Jesús-Cortés, Margaret
    E Maes, Balint Nagy, Francis Reilly-Andújar, Gloria Colombo, et al. “Microglia
    Enable Mature Perineuronal Nets Disassembly upon Anesthetic Ketamine Exposure
    or 60-Hz Light Entrainment in the Healthy Brain.” <i>Cell Reports</i>. Elsevier,
    2021. <a href="https://doi.org/10.1016/j.celrep.2021.109313">https://doi.org/10.1016/j.celrep.2021.109313</a>.
  ieee: A. Venturino <i>et al.</i>, “Microglia enable mature perineuronal nets disassembly
    upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain,”
    <i>Cell Reports</i>, vol. 36, no. 1. Elsevier, 2021.
  ista: Venturino A, Schulz R, De Jesús-Cortés H, Maes ME, Nagy B, Reilly-Andújar
    F, Colombo G, Cubero RJ, Schoot Uiterkamp FE, Bear MF, Siegert S. 2021. Microglia
    enable mature perineuronal nets disassembly upon anesthetic ketamine exposure
    or 60-Hz light entrainment in the healthy brain. Cell Reports. 36(1), 109313.
  mla: Venturino, Alessandro, et al. “Microglia Enable Mature Perineuronal Nets Disassembly
    upon Anesthetic Ketamine Exposure or 60-Hz Light Entrainment in the Healthy Brain.”
    <i>Cell Reports</i>, vol. 36, no. 1, 109313, Elsevier, 2021, doi:<a href="https://doi.org/10.1016/j.celrep.2021.109313">10.1016/j.celrep.2021.109313</a>.
  short: A. Venturino, R. Schulz, H. De Jesús-Cortés, M.E. Maes, B. Nagy, F. Reilly-Andújar,
    G. Colombo, R.J. Cubero, F.E. Schoot Uiterkamp, M.F. Bear, S. Siegert, Cell Reports
    36 (2021).
date_created: 2021-07-11T22:01:16Z
date_published: 2021-07-06T00:00:00Z
date_updated: 2023-08-10T14:09:39Z
day: '06'
ddc:
- '570'
department:
- _id: SaSi
doi: 10.1016/j.celrep.2021.109313
ec_funded: 1
external_id:
  isi:
  - '000670188500004'
  pmid:
  - '34233180'
file:
- access_level: open_access
  checksum: f056255f6d01fd9a86b5387635928173
  content_type: application/pdf
  creator: cziletti
  date_created: 2021-07-19T13:32:17Z
  date_updated: 2021-07-19T13:32:17Z
  file_id: '9693'
  file_name: 2021_CellReports_Venturino.pdf
  file_size: 56388540
  relation: main_file
  success: 1
file_date_updated: 2021-07-19T13:32:17Z
has_accepted_license: '1'
intvolume: '        36'
isi: 1
issue: '1'
language:
- iso: eng
month: '07'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 2564DBCA-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '665385'
  name: International IST Doctoral Program
- _id: 260C2330-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '754411'
  name: ISTplus - Postdoctoral Fellowships
- _id: 25D4A630-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '715571'
  name: Microglia action towards neuronal circuit formation and function in health
    and disease
publication: Cell Reports
publication_identifier:
  eissn:
  - '22111247'
publication_status: published
publisher: Elsevier
quality_controlled: '1'
related_material:
  link:
  - description: News on IST Homepage
    relation: press_release
    url: https://ist.ac.at/en/news/the-twinkle-and-the-brain/
scopus_import: '1'
status: public
title: Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine
  exposure or 60-Hz light entrainment in the healthy brain
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 36
year: '2021'
...
---
_id: '7880'
abstract:
- lang: eng
  text: 'Following its evoked release, dopamine (DA) signaling is rapidly terminated
    by presynaptic reuptake, mediated by the cocaine-sensitive DA transporter (DAT).
    DAT surface availability is dynamically regulated by endocytic trafficking, and
    direct protein kinase C (PKC) activation acutely diminishes DAT surface expression
    by accelerating DAT internalization. Previous cell line studies demonstrated that
    PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases
    a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT.
    However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis
    in DAergic terminals or whether there are region- and/or sex-dependent differences
    in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls
    PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important
    questions. Ex vivo studies revealed that PKC activation acutely decreased DAT
    surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated,
    conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular
    distribution in DAergic terminals from female ventral, but not dorsal, striatum.
    Further, Rit2 was required for PKC-stimulated DAT internalization in both male
    and female ventral striatum. FRET and surface pulldown studies in cell lines revealed
    that PKC activation drives DAT-Rit2 surface dissociation and that the DAT N terminus
    is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization.
    Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate
    PKC-stimulated DAT endocytosis. Together, our data provide greater insight into
    mechanisms that mediate PKC-regulated DAT internalization and reveal unexpected
    region-specific differences in PKC-stimulated DAT trafficking in bona fide DAergic
    terminals. '
article_processing_charge: No
article_type: original
author:
- first_name: Rita R.
  full_name: Fagan, Rita R.
  last_name: Fagan
- first_name: Patrick J.
  full_name: Kearney, Patrick J.
  last_name: Kearney
- first_name: Carolyn G.
  full_name: Sweeney, Carolyn G.
  last_name: Sweeney
- first_name: Dino
  full_name: Luethi, Dino
  last_name: Luethi
- first_name: Florianne E
  full_name: Schoot Uiterkamp, Florianne E
  id: 3526230C-F248-11E8-B48F-1D18A9856A87
  last_name: Schoot Uiterkamp
- first_name: Klaus
  full_name: Schicker, Klaus
  last_name: Schicker
- first_name: Brian S.
  full_name: Alejandro, Brian S.
  last_name: Alejandro
- first_name: Lauren C.
  full_name: O'Connor, Lauren C.
  last_name: O'Connor
- first_name: Harald H.
  full_name: Sitte, Harald H.
  last_name: Sitte
- first_name: Haley E.
  full_name: Melikian, Haley E.
  last_name: Melikian
citation:
  ama: 'Fagan RR, Kearney PJ, Sweeney CG, et al. Dopamine transporter trafficking
    and Rit2 GTPase: Mechanism of action and in vivo impact. <i>Journal of Biological
    Chemistry</i>. 2020;295(16):5229-5244. doi:<a href="https://doi.org/10.1074/jbc.RA120.012628">10.1074/jbc.RA120.012628</a>'
  apa: 'Fagan, R. R., Kearney, P. J., Sweeney, C. G., Luethi, D., Schoot Uiterkamp,
    F. E., Schicker, K., … Melikian, H. E. (2020). Dopamine transporter trafficking
    and Rit2 GTPase: Mechanism of action and in vivo impact. <i>Journal of Biological
    Chemistry</i>. ASBMB Publications. <a href="https://doi.org/10.1074/jbc.RA120.012628">https://doi.org/10.1074/jbc.RA120.012628</a>'
  chicago: 'Fagan, Rita R., Patrick J. Kearney, Carolyn G. Sweeney, Dino Luethi, Florianne
    E Schoot Uiterkamp, Klaus Schicker, Brian S. Alejandro, Lauren C. O’Connor, Harald
    H. Sitte, and Haley E. Melikian. “Dopamine Transporter Trafficking and Rit2 GTPase:
    Mechanism of Action and in Vivo Impact.” <i>Journal of Biological Chemistry</i>.
    ASBMB Publications, 2020. <a href="https://doi.org/10.1074/jbc.RA120.012628">https://doi.org/10.1074/jbc.RA120.012628</a>.'
  ieee: 'R. R. Fagan <i>et al.</i>, “Dopamine transporter trafficking and Rit2 GTPase:
    Mechanism of action and in vivo impact,” <i>Journal of Biological Chemistry</i>,
    vol. 295, no. 16. ASBMB Publications, pp. 5229–5244, 2020.'
  ista: 'Fagan RR, Kearney PJ, Sweeney CG, Luethi D, Schoot Uiterkamp FE, Schicker
    K, Alejandro BS, O’Connor LC, Sitte HH, Melikian HE. 2020. Dopamine transporter
    trafficking and Rit2 GTPase: Mechanism of action and in vivo impact. Journal of
    Biological Chemistry. 295(16), 5229–5244.'
  mla: 'Fagan, Rita R., et al. “Dopamine Transporter Trafficking and Rit2 GTPase:
    Mechanism of Action and in Vivo Impact.” <i>Journal of Biological Chemistry</i>,
    vol. 295, no. 16, ASBMB Publications, 2020, pp. 5229–44, doi:<a href="https://doi.org/10.1074/jbc.RA120.012628">10.1074/jbc.RA120.012628</a>.'
  short: R.R. Fagan, P.J. Kearney, C.G. Sweeney, D. Luethi, F.E. Schoot Uiterkamp,
    K. Schicker, B.S. Alejandro, L.C. O’Connor, H.H. Sitte, H.E. Melikian, Journal
    of Biological Chemistry 295 (2020) 5229–5244.
date_created: 2020-05-24T22:00:59Z
date_published: 2020-04-17T00:00:00Z
date_updated: 2023-08-21T06:26:22Z
day: '17'
department:
- _id: SaSi
doi: 10.1074/jbc.RA120.012628
external_id:
  isi:
  - '000530288000006'
  pmid:
  - '32132171'
intvolume: '       295'
isi: 1
issue: '16'
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://escholarship.umassmed.edu/oapubs/4187
month: '04'
oa: 1
oa_version: Submitted Version
page: 5229-5244
pmid: 1
publication: Journal of Biological Chemistry
publication_identifier:
  eissn:
  - 1083351X
  issn:
  - '00219258'
publication_status: published
publisher: ASBMB Publications
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and
  in vivo impact'
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 295
year: '2020'
...