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3. A team science approach to discover novel targets for infantile spasms (IS)

Author

Vezzani, Annamaria, Berg, Anne T, Lowenstein, Daniel H, Klitgaard, Henrik, Goodkin, Howard P, Rho, Jong M, Katsarou, Anna Maria, Pirone, Antonella, Galanopoulou, Aristea S, Dulla, Chris, Nordli, Douglas R, Iacobas, Dumitru A, Sherr, Elliott, Cloyd, James, Veliskova, Jana, Noebels, Jeff L, Millichap, John J, Swann, John W, Koh, Sookyung, Velisek, Libor, Coles, Lisa, Patel, Manisha, Siehr, Meagan S, Jacob, Michele, Seo, Ryan, Heischmann, Svenja, Moshe, Solomon L, Chachua, Tamar, Brima, Tufikameni, Mowrey, Wenzhu B, White, H Steve, Milder, Julie, Lubbers, Laura, and Iyengar, Sloka S

Subjects
Neurosciences, Brain Disorders, Neurodegenerative, Epilepsy, Clinical Research, Neurological, Electroencephalography, Humans, Infant, Interdisciplinary Research, Spasms, Infantile, Translational Research, Biomedical, CURE Infantile Spasms Consortium, CURE Staff, Citizens United for Research in Epilepsy, Hypsarhythmia, West syndrome, infantile spasms, team science
Abstract

Infantile spasms (IS) is a devastating epilepsy syndrome that typically begins in the first year of life. Symptoms consist of stereotypical spasms, developmental delay, and electroencephalogram (EEG) that may demonstrate Hypsarhythmia. Current therapeutic approaches are not always effective, and there is no reliable way to predict which patient will respond to therapy. Given this disorder's complexity and the potential impact of a disease-modifying approach, Citizens United for Research in Epilepsy (CURE) employed a "team science" approach to advance the understanding of IS pathology and explore therapeutic modalities that might lead to the development of new ways to potentially prevent spasms and Hypsarhythmia. This approach was a first-of-its-kind collaborative initiative in epilepsy. The IS initiative funded 8 investigative teams over the course of 1-3 years. Projects included the following: discovery on the basic biology of IS, discovery of novel therapeutic targets, cross-validation of targets, discovery of biomarkers, and prognosis and treatment of IS. The combined efforts of a strong investigative team led to numerous advances in understanding the neural pathways underlying IS, testing of small molecules in preclinical models of IS and generated preliminary data on potential biomarkers. Thus far, the initiative has resulted in over 19 publications and subsequent funding for several investigators. Investigators reported that the IS initiative generally affected their research positively due to its collaborative and iterative nature. It also provided a unique opportunity to mentor junior investigators with an interest in translational research. Learnings included the need for a dedicated project manager and more transparent and real-time communication with investigators. The CURE IS initiative represents a unique approach to fund scientific discoveries on epilepsy. It brought together an interdisciplinary group of investigators-who otherwise would not have collaborated-to find transformative therapies for IS. Learnings from this initiative are being utilized for subsequent initiatives at CURE.

Published
2021

10. Kir4.1 channels contribute to astrocyte CO2/H+-sensitivity and the drive to breathe

Author

Cleary, Colin M, Browning, Jack L, Armbruster, Moritz, Sobrinho, Cleyton R, Strain, Monica L, Jahanbani, Sarvin, Soto-Perez, Jaseph, Hawkins, Virginia E, Dulla, Chris G, Olsen, Michelle L, Mulkey, Daniel K, Cleary, Colin M, Browning, Jack L, Armbruster, Moritz, Sobrinho, Cleyton R, Strain, Monica L, Jahanbani, Sarvin, Soto-Perez, Jaseph, Hawkins, Virginia E, Dulla, Chris G, Olsen, Michelle L, and Mulkey, Daniel K

Abstract

Astrocytes in the retrotrapezoid nucleus (RTN) stimulate breathing in response to CO2/H+, however, it is not clear how these cells detect changes in CO2/H+. Considering Kir4.1/5.1 channels are CO2/H+-sensitive and important for several astrocyte-dependent processes, we consider Kir4.1/5.1 a leading candidate CO2/H+ sensor in RTN astrocytes. To address this, we show that RTN astrocytes express Kir4.1 and Kir5.1 transcripts. We also characterized respiratory function in astrocyte-specific inducible Kir4.1 knockout mice (Kir4.1 cKO); these mice breathe normally under room air conditions but show a blunted ventilatory response to high levels of CO2, which could be partly rescued by viral mediated re-expression of Kir4.1 in RTN astrocytes. At the cellular level, astrocytes in slices from astrocyte-specific inducible Kir4.1 knockout mice are less responsive to CO2/H+ and show a diminished capacity for paracrine modulation of respiratory neurons. These results suggest Kir4.1/5.1 channels in RTN astrocytes contribute to respiratory behavior.

Published
2024

11. Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model

Author

Bottom-Tanzer, Samantha, primary, Corella, Sofia, additional, Meyer, Jochen, additional, Sommer, Mary, additional, Bolaños, Luis, additional, Murphy, Timothy, additional, Quiñones, Sadi, additional, Heiney, Shane, additional, Shtrahman, Matthew, additional, Whalen, Michael, additional, Oren, Rachel, additional, Higley, Michael J, additional, Cardin, Jessica A, additional, Noubary, Farzad, additional, Armbruster, Moritz, additional, and Dulla, Chris, additional

Published
2024
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13. Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model

Author

Bottom-Tanzer, Samantha, primary, Corella, Sofia, additional, Meyer, Jochen, additional, Sommer, Mary, additional, Bolanos, Luis, additional, Murphy, Timothy, additional, Quinones, Sadi, additional, Heiney, Shane, additional, Shtrahman, Matthew, additional, Whalen, Michael, additional, Oren, Rachel, additional, Higley, Michael J, additional, Cardin, Jessica A, additional, Noubary, Farzad, additional, Armbruster, Moritz, additional, and Dulla, Chris, additional

Published
2023
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14. Cell type-specific gene expression dynamics during human brain maturation

Author

Steyn, Christina, primary, Mishi, Ruvimbo, additional, Fillmore, Stephanie, additional, Verhoog, Matthijs B., additional, More, Jessica, additional, Rohlwink, Ursula K., additional, Melvill, Roger, additional, Butler, James, additional, Enslin, Johannes M. N., additional, Jacobs, Muazzam, additional, Quiñones, Sadi, additional, Dulla, Chris G., additional, Raimondo, Joseph V., additional, Figaji, Anthony, additional, and Hockman, Dorit, additional

Published
2023
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15. Kir4.1 channels contribute to astrocyte CO2/H+-sensitivity and the drive to breathe.

Author

Cleary, Colin M., Browning, Jack L., Armbruster, Moritz, Sobrinho, Cleyton R., Strain, Monica L., Jahanbani, Sarvin, Soto-Perez, Jaseph, Hawkins, Virginia E., Dulla, Chris G., Olsen, Michelle L., and Mulkey, Daniel K.

Subjects
ASTROCYTES, KNOCKOUT mice, AIR conditioning, RESPIRATION
Abstract

Astrocytes in the retrotrapezoid nucleus (RTN) stimulate breathing in response to CO2/H+, however, it is not clear how these cells detect changes in CO2/H+. Considering Kir4.1/5.1 channels are CO2/H+-sensitive and important for several astrocyte-dependent processes, we consider Kir4.1/5.1 a leading candidate CO2/H+ sensor in RTN astrocytes. To address this, we show that RTN astrocytes express Kir4.1 and Kir5.1 transcripts. We also characterized respiratory function in astrocyte-specific inducible Kir4.1 knockout mice (Kir4.1 cKO); these mice breathe normally under room air conditions but show a blunted ventilatory response to high levels of CO2, which could be partly rescued by viral mediated re-expression of Kir4.1 in RTN astrocytes. At the cellular level, astrocytes in slices from astrocyte-specific inducible Kir4.1 knockout mice are less responsive to CO2/H+ and show a diminished capacity for paracrine modulation of respiratory neurons. These results suggest Kir4.1/5.1 channels in RTN astrocytes contribute to respiratory behavior. Inducible deletion of Kir4.1 channels from astrocytes blunts the CO2/H + -dependent drive to breathe at the cellular and whole animal level in mice [ABSTRACT FROM AUTHOR]

Published
2024
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20. Neuronal activity drives pathway-specific depolarization of peripheral astrocyte processes

Author

Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Armbruster, Moritz, Naskar, Saptarnab, Garcia, Jacqueline P, Sommer, Mary, Kim, Elliot, Adam, Yoav, Haydon, Philip G, Boyden, Edward S, Cohen, Adam E, Dulla, Chris G, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Armbruster, Moritz, Naskar, Saptarnab, Garcia, Jacqueline P, Sommer, Mary, Kim, Elliot, Adam, Yoav, Haydon, Philip G, Boyden, Edward S, Cohen, Adam E, and Dulla, Chris G

Abstract

Astrocytes are glial cells that interact with neuronal synapses via their distal processes, where they remove glutamate and potassium (K+) from the extracellular space following neuronal activity. Astrocyte clearance of both glutamate and K+ is voltage dependent, but astrocyte membrane potential (Vm) is thought to be largely invariant. As a result, these voltage dependencies have not been considered relevant to astrocyte function. Using genetically encoded voltage indicators to enable the measurement of Vm at peripheral astrocyte processes (PAPs) in mice, we report large, rapid, focal and pathway-specific depolarizations in PAPs during neuronal activity. These activity-dependent astrocyte depolarizations are driven by action potential-mediated presynaptic K+ efflux and electrogenic glutamate transporters. We find that PAP depolarization inhibits astrocyte glutamate clearance during neuronal activity, enhancing neuronal activation by glutamate. This represents a novel class of subcellular astrocyte membrane dynamics and a new form of astrocyte-neuron interaction.

Published
2023

27. Contributors

Author

Aiba, Isamu, primary, Andrade, Pedro, additional, Angamo, Eskedar A., additional, Aronica, Eleonora, additional, Auvin, Stéphane, additional, Baines, Richard A., additional, Balosso, Silvia, additional, Barker-Haliski, Melissa, additional, Bartolomei, Fabrice, additional, Bastar, Jeffrey, additional, Battaglia, Giorgio, additional, Benke, Tim, additional, Berdichevsky, Yevgeny, additional, Bernard, Christophe, additional, Bertoglio, Daniele, additional, Bertram, Edward H., additional, Buchanan, Gordon, additional, Buckmaster, Paul S., additional, Calas, Guilhem, additional, Carlen, Peter L., additional, Carmant, Lionel, additional, Cepeda, Carlos, additional, Cho, Frances S., additional, Clemente, Alexandra, additional, Cloyd, James C., additional, Colciaghi, Francesca, additional, Coles, Lisa D., additional, Conti, Valerio, additional, Copmans, Daniëlle, additional, Coulter, Douglas A., additional, Dal Bo, Gregory, additional, Dang, Louis T., additional, de Curtis, Marco, additional, de Witte, Peter A.M., additional, Dedeurwaerdere, Stefanie, additional, Deleye, Steven, additional, Dengler, Nora, additional, Depaulis, Antoine, additional, Deransart, Colin, additional, Dorandeu, Frederic, additional, Dudek, F. Edward, additional, Dulla, Chris G., additional, Dzhala, Volodya, additional, Ekstrand, Jeffrey, additional, Estrada-Sánchez, Ana M., additional, Eubanks, James H., additional, Faingold, Carl, additional, Fares, Raafat, additional, Ferland, R.J., additional, Ferraro, T.N., additional, Finardi, Adele, additional, Friedman, Alon, additional, Gabriel, Siegrun, additional, Galanopoulou, Aristea S., additional, Giachello, Carlo N.G., additional, Glykys, Joseph, additional, Gnatkovsky, Vadym, additional, Goldman, Alica M., additional, Goodman, Jeffrey, additional, Gorter, Jan A., additional, Gröhn, Olli, additional, Guerrini, Renzo, additional, Guillemain, Isabelle, additional, Halasz, Peter, additional, Heinemann, Uwe, additional, Henshall, David C., additional, Holden, Stephanie, additional, Holmes, Gregory L., additional, Hovens, Chris, additional, Ivanov, Anton I., additional, Jansen, Laura A., additional, Jarre, Guillaume, additional, Jarvis, Paul R., additional, Jefferys, John G.R., additional, Jensen, Frances E., additional, Jeong, Anna, additional, Jin, Xiaoming, additional, Jin, Yishi, additional, Köhling, Rüdiger, additional, Kadam, Shilpa D., additional, Kaufer, Daniela, additional, Kelly, Kevin M., additional, Kelly, Mary E., additional, Klang, Andrea, additional, Klitgaard, Henrik, additional, Kneissl, Sibylle, additional, Kostopoulos, George K., additional, Kotloski, Robert J., additional, Kuker, Marie, additional, Kyyriäinen, Jenni, additional, Löscher, Wolfgang, additional, Lau, Lauren A., additional, Lehmann, Thomas-Nicolas, additional, Leppik, Ilo E., additional, Levine, Michael S., additional, Librizzi, Laura, additional, Lillis, Kyle, additional, Lin, Dean D., additional, Lin, Wei-Hsiang, additional, Mühlebner, Angelika, additional, Marchi, Nicola, additional, Mazarati, Andrey M., additional, Milikovsky, Dan Z., additional, Modolo, Julien, additional, Moshé, Solomon L., additional, N’Gouemo, Prosper, additional, Ndode-Ekane, Xavier Ekolle, additional, Nehlig, Astrid, additional, Newton, Jamila, additional, Nobili, Paola, additional, Noebels, Jeffrey L., additional, O’Brien, Terence J., additional, O’Leary, Heather, additional, Pakozdy, Akos, additional, Parent, Jack M., additional, Pasanen, Lotta, additional, Patel, Dipan C., additional, Patterson, Edward N., additional, Paz, Jeanne T., additional, Petrou, Steve, additional, Ping, Xingjie, additional, Pitkänen, Asla, additional, Potschka, Heidrun, additional, Raikov, Ivan, additional, Ravizza, Teresa, additional, Reddy, Doodipala S., additional, Richards, Kay L., additional, Roper, Steven N., additional, Salar, Seda, additional, Salinas, Felipe S., additional, Sanon, Nathalie T., additional, Shakarjian, Michael P., additional, Shaker, Tarek, additional, Shultz, Sandy, additional, Siekierska, Aleksandra, additional, Soltesz, Ivan, additional, Spampanato, Jay G., additional, Staley, Kevin J., additional, Stewart, Mark, additional, Sun, Hongyu, additional, Sutula, Thomas P., additional, Szabó, Charles Á., additional, Takayanagi-Kiya, Seika, additional, Tanila, Heikki, additional, Tannenbaum, Jerrold, additional, Tupal, Srinivasan, additional, Uva, Laura, additional, van Vliet, Erwin A., additional, Velíšek, Libor, additional, Velíšková, Jana, additional, Walker, Matthew C., additional, Wendling, Fabrice, additional, White, H. Steve, additional, Wilcox, Karen S., additional, Wong, Michael, additional, Wykes, Robert C., additional, Zayachkivsky, Andrew, additional, Zhang, Liang, additional, and Zheng, Ping, additional

Published
2017
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33. Epilepsy Benchmarks Area I: Understanding the Causes of the Epilepsies and Epilepsy-Related Neurologic, Psychiatric, and Somatic Conditions

Author

Chang, Bernard S., Krishnan, Vaishnav, Dulla, Chris G., Jette, Nathalie, Marsh, Eric D., Dacks, Penny A., Whittemore, Vicky, and Poduri, Annapurna

Subjects
0301 basic medicine, NINDS Benchmarks for Epilepsy Research, Reviews, what causes seizures, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, causes of epilepsy, epilepsy comorbidities, Neurology (clinical), progress in epilepsy research, epilepsy benchmarks, 030217 neurology & neurosurgery, causes of the epilepsies
Abstract

The 2014 NINDS Benchmarks for Epilepsy Research included area I: Understand the causes of the epilepsies and epilepsy-related neurologic, psychiatric, and somatic conditions. In preparation for the 2020 Curing Epilepsies Conference, where the Benchmarks will be revised, this review will cover scientific progress toward that Benchmark, with emphasize on studies since 2016.

Published
2020
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39. Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

Author

Rimmele, Theresa S., Li, Shaomin, Andersen, Jens Velde, Westi, Emil W., Rotenberg, Alexander, Wang, Jianlin, Aldana, Blanca Irene, Selkoe, Dennis J., Aoki, Chiye J., Dulla, Chris G., Rosenberg, Paul Allen, Rimmele, Theresa S., Li, Shaomin, Andersen, Jens Velde, Westi, Emil W., Rotenberg, Alexander, Wang, Jianlin, Aldana, Blanca Irene, Selkoe, Dennis J., Aoki, Chiye J., Dulla, Chris G., and Rosenberg, Paul Allen

Abstract

GLT-1, the major glutamate transporter in the mammalian central nervous system, is expressed in presynaptic terminals that use glutamate as a neurotransmitter, in addition to astrocytes. It is widely assumed that glutamate homeostasis is regulated primarily by glutamate transporters expressed in astrocytes, leaving the function of GLT-1 in neurons relatively unexplored. We generated conditional GLT-1 knockout (KO) mouse lines to understand the cell-specific functions of GLT-1. We found that stimulus-evoked field extracellular postsynaptic potentials (fEPSPs) recorded in the CA1 region of the hippocampus were normal in the astrocytic GLT-1 KO but were reduced and often absent in the neuronal GLT-1 KO at 40 weeks. The failure of fEPSP generation in the neuronal GLT-1 KO was also observed in slices from 20 weeks old mice but not consistently from 10 weeks old mice. Using an extracellular FRET-based glutamate sensor, we found no difference in stimulus-evoked glutamate accumulation in the neuronal GLT-1 KO, suggesting a postsynaptic cause of the transmission failure. We hypothesized that excitotoxicity underlies the failure of functional recovery of slices from the neuronal GLT-1 KO. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist MK801, when present in the ACSF during the recovery period following cutting of slices, promoted full restoration of fEPSP generation. The inclusion of an enzymatic glutamate scavenging system in the ACSF conferred partial protection. Excitotoxicity might be due to excess release or accumulation of excitatory amino acids, or to metabolic perturbation resulting in increased vulnerability to NMDA receptor activation. Previous studies have demonstrated a defect in the utilization of glutamate by synaptic mitochondria and aspartate production in the synGLT-1 KO in vivo, and we found evidence for similar metabolic perturbations in the slice preparation. In addition, mitochondrial cristae density was higher in synapti

Published
2021

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