Mechanisms of neuron-glia interactions in health and disease
The overarching goal of the Papouin lab is to understand the cellular and molecular mechanisms of neuron-glia interactions and their contribution to information processing at the synaptic and behavioral levels. 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 neuromodulators shape neuron-astrocyte interactions and help reconfigure neuronal circuits in a brain state-dependent manner. To examine these aspects, we mainly employ molecular genetics, analytical chemistry, electrophysiology, optogenetics and behavioral approaches.
The main model that we use 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.
Our overall line of research is inherently relevant to neuropsychiatric diseases and our lab is particularly interested in schizophrenia, depression and the cognitive impairments associated with chronic sleep loss. Notably, by mechanistically linking NMDAR function and cholinergic signaling via astrocytes, the scope of our research reconciles two historical hypotheses for the etiology and treatment of schizophrenic disorders.