Thomas Papouin, Ph.D.

Assistant Professor
Neuroscience

Neurosciences Program

Research Abstract:

Since its inception, neuroscience has focused on neurons as the single most relevant cellular component of the nervous system for understanding its inner workings. Yet, neurons only account for ~20% of all cells in the mammalian cortex, while the remaining 80% is composed of non-neuronal cells called glial cells. The overarching goal of the Papouin lab is to understand the role played by astrocytes, a type of glial cells, in brain computation, at the molecular scale, circuit level, all the way to behavior.

ASTROCYTES AND NEUROMODULATION
While what astrocytes can do at synapses has been profusely studied, much less is known about the endogenous determinants and principles that govern astrocyte-to-neuron signaling. The focus of our lab is on understanding the local and temporal cues that drive astrocytes to release specific sets of signaling molecules at synapses, in order to achieve a detailed comprehension and functional map of the neuron-glia interface. We turn our attention to the role of neuromodulatory substances due to recent evidence from us and others that astrocytes act as a signaling node that transforms neuromodulation into synaptic information. Therefore, we investigate how neuromodulation shapes neuron-astrocyte interactions and helps reconfigure neuronal circuits in a brain state-dependent manner by tackling five major aspects 1) how does the neuromodulatory environment affect the activity of astrocytes? 2) do specific neuromodulators drive specific gliotransmitter pathways, and what are the rules and mechanisms of such coupling? 3) how does this impact synaptic properties and the rules of synaptic integration? 4) what are the spatial boundaries of such local relay of state-dependent information by astrocytes (i.e. is it brain region-specific or restricted to astrocytic networks?) and 5) does this contribute to cognitive functions and behavioral performance?

NEUROPSYCHIATRIC DISORDERS
Our line of research is inherently relevant to several brain disorders and our projects also aim at elucidating the contribution of astrocytes to neuropsychiatric conditions, such as schizophrenia and depression, and cognitive disorders associated with sleep loss. We are interested in understanding how the molecular determinants of the neuron-glia interactions can explain, mitigate or ameliorate current pharmacotherapies and whether this can this lead to a new generation of therapeutics that are glia-centric.

NMDAR AND D-SERINE
A major model that we have used to tackle these great questions is the N-methyl D-aspartate receptor (NMDAR) and its control by the astrocyte-derived co-agonist D-serine. Indeed, the activation of NMDARs requires the binding of D-serine on their co-agonist binding site; and D-serine is a gliotransmitter synthesized and released by astrocytes. Therefore, the NMDAR/D-serine duo is not only an interesting system to study in and of itself, it is also an ideal molecular model to investigate reciprocal interactions between neurons and astrocytes at synapses. Ultimately, because NMDARs are central to many developmental, physiological and pathological processes of the nervous system, the study of the NMDAR/D-serine system is highly translatable to many grand aspects of neuroscience including synaptic plasticity, learning and memory, excitotoxicity and multiple brain disorders.

Mentorship and Commitment to Diversity Statement:
Life in our lab is governed by core principles:
- Expectations are clearly stated
- Efficient and direct mentoring is in place
- Our work environment is stimulating

This framework helps us cultivate an environment that fosters a positive and engaging experience for everyone on the team, and values mentorship and personal development in hope that each member will reach their full potential.

We wish to work with people who share our work ethic and understand both its importance and its rationale.

A safe and inclusive workplace for all:
The Papouin Lab welcomes you no matter your skin color, country of origin, cultural background, last name, age, gender and sexual orientations. What matters to us is what’s in your head. Literally and figuratively!

We’ll only judge you by your ideas, your work and your work ethics. Whether you want to visit, apply, work in, collaborate with or otherwise be part of the Papouin lab: simply reach out!

Selected Publications:

Henneberger, C., Papouin, T., Oliet, S.H.R., and Rusakov, D.A. (2010). Long-term potentiation depends on the
release of D-serine from astrocytes. Nature. 463, 232-236.

Papouin, T., Ladépêche, L., Ruel, J., Sacchi, S., Labasque, M., Hanini, M., Groc, L., Pollegioni, L., Mothet, L-P., and Oliet, S.H.R. (2012). Synaptic and extrasynaptic NMDA receptors are gated by different endogenous co-agonists. Cell. 150, 633-646.

Papouin, T., Dunphy, J., Tolman, M., Dineley, K, and Haydon, P.G. (2017). Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness. Neuron. 94, 1-15.
CellPress Video Abstract: http://bit.ly/PapouinVideoAbstract

Smith SE, Chen X, Brier LM, Bumstead JR, Rensing NR, Ringel AE, Shin H, Oldenborg A, Crowley JR, Bice AR, Dikranian K, Ippolito JE, Haigis MC, Papouin T, Zhao G, Wong M, Culver JP, Bonni A. Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway. Nat Commun. 2020 Dec 2;11(1):6164

Christian DL, Wu DY, Martin JR, Moore JR, Liu YR, Clemens AW, Nettles SA, Kirkland NM, Papouin T, Hill CA, Wozniak DF, Dougherty JD, Gabel HW. DNMT3A Haploinsufficiency Results in Behavioral Deficits and Global Epigenomic Dysregulation Shared across Neurodevelopmental Disorders. Cell Rep. 2020 Nov 24;33(8):108416.

Ozawa M, Davis P, Ni J, Maguire J, Papouin T, Reijmers L. Experience-dependent resonance in amygdalo-cortical circuits supports fear memory retrieval following extinction. Nat Commun. 2020 Aug 31;11(1):4358.

Manno R, Witte J, Papouin T. A Modular Setup to Run a Large Line of Behavioral Testing in Mice in a Single Space. Curr Protoc Neurosci. 2020 Sep;93(1):e102.

Last Updated: 3/22/2021 1:52:01 PM

Astrocytes transform cholinergic neuromodulation into D-serine tone at synapses. This provides a mechanistic link between the two focal points in the research of the etiology and treatment of schizophrenia: the cholinergic system and the NMDA receptor. Credit: adapted from Papouin et al., Neuron 2017
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