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, parts of the mammalian brain are only comprised of 10-20% of neurons. Our research explores the role played by the remaining 80-90% of “non-neuronal” cells, called glial cells, in brain function.
A central goal of cellular neuroscience is to understand how the different cells of the central nervous system function together to process, integrate, store, and use information that allows cognition and behavior. While neurons are exquisitely equipped to receive and transmit information in the millisecond time scale, the rest of the mammalian brain is made of glial cells that process information over a much slower time scale. In particular, astrocytes influence synaptic properties by releasing signaling molecules known as gliotransmitters, but the time frame of such signaling is unfitted to respond to the millisecond-operated flow of neuronal information. This is a major drawback in our current conceptualization of the role of astrocytes in brain circuits. This is, however, highly adequate in the context of brain states that involve slow and long-lasting biochemical changes in the brain. Therefore, we are interested in understanding the role of astrocytes in brain function from the perspective of brain states.
Astrocytes and Neuromodulation
We focus on astrocytes, a sub-class of glial cells that has the ability to respond to different forms of brain activity and release signaling molecules to influence neuronal function. The goal of the Papouin lab is to understand how the network of astrocytes contributes to information processing in the brain, at the molecular scale, circuit level, all the way to behavior.
Rather than studying astrocytes as a standalone entity, our lab studies the place they occupy in brain circuitry, and the role they play in brain computation, from the perspective of brain states. Mounting evidence suggests that astrocytes sense and respond to slow, volume-transmitted neuromodulators. This is interesting because these signals are released in the brain during specific vigilance states, such as wakefulness, or behavioral states, such as attention. In parallel, it has also become clear that a single astrocyte can influence hundreds of neurons and thousands of synapses in its territory, by releasing molecules known as gliotransmitters. But the determinants that govern this secretory activity are ill-defined and its temporal dynamics are surprisingly slow. In the Papouin lab, we explore the idea that astrocytes are a conditioning entity that shapes the underlying neuronal network, via gliotransmitter release, to the ongoing brain context – a concept we coined “contextual guidance”. Therefore, we study the interplay between neuromodulation and gliotransmission 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?
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 if 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 glio-centric.
Astrocytes and NMDA receptors
A major model that we have used to tackle these 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 its 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 major aspects of neuroscience including synaptic plasticity, learning and memory, excitotoxicity and neuropsychiatric disorders.
