Where Ideas Grow

ABOUT

Astrocytes are the major glial cell type in the mammalian brain and physically interact with neurons at synapse, thereby influencing synaptic transmission and information flow in the central nervous system (CNS). We are interested in understanding the mechanisms responsible for formation and function of this so-called ‘tripartite’ synapse.

 

RESEARCH

Although it is well established that all brain regions contain multiple neuronal subtypes with different functions, astrocytes have traditionally been thought to be homogenous. However, recent evidence from our lab and others has shown that astrocytes in the mammalian CNS display a high degree of anatomical, molecular and functional diversity, dependent on their position in the brain. A potential advantage of specialized astrocyte subtypes would be their capacity to regulate local synapse development and/or function. We have chosen to focus our research on exploring fundamental differences in astrocyte-neuron interactions at excitatory and inhibitory synapses. Maintaining correct excitation/inhibition (E/I) balance is central to key CNS processes, such as learning and memory: likewise, imbalances in E/I are hypothesized to contribute to several serious CNS diseases.

Research in our group is currently focused on the following topics:

  1. Identifying differential molecular mechanisms responsible for excitatory and inhibitory tripartite synapse assembly and function.
  2. Understanding the relationship between aberrant tripartite synapses and human disease, specifically epilepsy.

 

To answer these questions, we use a multi-disciplinary approach, encompassing advanced molecular and biochemical techniques to identify candidate proteins involved in synapse formation and function, mouse genetics and viral vector systems to manipulate proteins levels, and simultaneous slice electrophysiology with imaging to assess the effects on synaptic transmission.

As astrocytes show profound changes in response to injury and disease, a major effort of the group has been in the design and exploitation of novel blood-brain barrier crossing viral vector systems for genetic manipulation of the CNS with minimal physical damage. Our group has shown that these systems possess tremendous translational potential, as they allow sustained local production and secretion of therapeutics from CNS cells – the so-called ‘biopharmacy’ concept, an approach being pursued in close collaboration with Aila Biotech.

Schematic of known astrocyte-neuron interaction networks at excitatory and inhibitory tripartite synapses (adapted from Takano and Soderling, Neurosci Res, 2021). Note the disparity in what is known about the molecular mechanisms involved in excitatory versus inhibitory synaptogenesis.

Team

Selected Publications

Wahis J., Hennes M., Arckens L., Holt M.G.,
Star power: the emerging role of astrocytes as neuronal partners during cortical plasticity. Current Opinion in Neurobiology67:174-182, 2021. [Journal: Review] [CI: 9] [IF: 7,1]
DOI: 10.1016/j.conb.2020.12.001 SCOPUS: 85098074813

Escartin C., Galea E., Lakatos A., O’Callaghan J.P., Petzold G.C., Serrano-Pozo A., Steinhäuser C., Volterra A., Carmignoto G., Agarwal A., Allen N.J., Araque A., Barbeito L., Barzilai A., Bergles D.E., Bonvento G., Butt A.M., Chen W.T., Cohen-Salmon M., Cunningham C., Deneen B., De Strooper B., Díaz-Castro B., Farina C., Freeman M., Gallo V., Goldman J.E., Goldman S.A., Götz M., Gutiérrez A., Haydon P.G., Heiland D.H., Hol E.M., Holt M.G., Iino M., Kastanenka K.V., Kettenmann H., Khakh B.S., Koizumi S., Lee C.J., Liddelow S.A., MacVicar B.A., Magistretti P., Messing A., Mishra A., Molofsky A.V., Murai K.K., Norris C.M., Okada S., Oliet S.H.R., Oliveira J.F., Panatier A., Parpura V., Pekna M., Pekny M., Pellerin L., Perea G., Pérez-Nievas B.G., Pfrieger F.W., Poskanzer K.E., Quintana F.J., Ransohoff R.M., Riquelme-Perez M., Robel S., Rose C.R., Rothstein J.D., Rouach N., Rowitch D.H., Semyanov A., Sirko S., Sontheimer H., Swanson R.A., Vitorica J., Wanner I.B., Wood L.B., Wu J., Zheng B., Zimmer E.R., Zorec R., Sofroniew M.V., Verkhratsky A.,
Reactive astrocyte nomenclature, definitions, and future directions. Nature Neuroscience24(3):312-325, 2021. [Journal: Review] [CI: 419] [IF: 28,8]
DOI: 10.1038/s41593-020-00783-4 SCOPUS: 85100133612

Bayraktar O.A., Bartels T., Holmqvist S., Kleshchevnikov V., Martirosyan A., Polioudakis D., Ben Haim L., Young A.M.H., Batiuk M.Y., Prakash K., Brown A., Roberts K., Paredes M.F., Kawaguchi R., Stockley J.H., Sabeur K., Chang S.M., Huang E., Hutchinson P., Ullian E.M., Hemberg M., Coppola G., Holt M.G., Geschwind D.H., Rowitch D.H.,
Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map. Nature Neuroscience23(4):500-509, 2020. [Journal: Article] [CI: 148] [IF: 24,9]
DOI: 10.1038/s41593-020-0602-1 SCOPUS: 85081379147

Batiuk M.Y., Martirosyan A., Wahis J., de Vin F., Marneffe C., Kusserow C., Koeppen J., Viana J.F., Oliveira J.F., Voet T., Ponting C.P., Belgard T.G., Holt M.G.,
Identification of region-specific astrocyte subtypes at single cell resolution. Nature Communications11(1):, 2020. [Journal: Article] [CI: 219] [IF: 14,9]
DOI: 10.1038/s41467-019-14198-8 SCOPUS: 85081389044

Slezak M., Kandler S., Van Veldhoven P.P., Van den Haute C., Bonin V., Holt M.G.,
Distinct Mechanisms for Visual and Motor-Related Astrocyte Responses in Mouse Visual Cortex. Current Biology29(18):3120-3127.e5, 2019. [Journal: Article] [CI: 19] [IF: 9,6]
DOI: 10.1016/j.cub.2019.07.078 SCOPUS: 85072241720

Batiuk M.Y., De Vin F., Duqué S.I., Li C., Saito T., Saido T., Fiers M., Belgard T.G., Holt M.G.,
An immunoaffinity-based method for isolating ultrapure adult astrocytes based on ATP1B2 targeting by the ACSA-2 antibody. Journal of Biological Chemistry292(21):8874-8891, 2017. [Journal: Article] [CI: 42] [IF: 4]
DOI: 10.1074/jbc.M116.765313 SCOPUS: 85019654835