Interactions neurogliales en physiopathologie cérébrale / Neuroglial interactions in cerebral physiopathology

Recherche Page web : https://www.college-de-france.fr/site/en-cirb/rouach.htm. The main goal of our group is to determine whether and how the underexplored glial cells, which are the very abundant non neuronal but yet active cells of the brain, play a role in brain information processing. We investigate the molecular modalities and functional outcomes of neuroglial interactions in physiological and pathological conditions, focusing ex vivo or in vivo on neuronal excitability, synaptic transmi..

Nanoscale molecular architecture controls calcium diffusion and ER replenishment in dendritic spines.

Dendritic spines are critical components of neuronal synapses as they receive and transform synaptic inputs into a succession of calcium-regulated biochemical events. The spine apparatus (SA), an extension of smooth endoplasmic reticulum, regulates slow and fast calcium dynamics in spines. Calcium release events deplete SA calcium ion reservoir rapidly, yet the next cycle of signaling requires its replenishment. How spines achieve this replenishment without triggering calcium release remains unclear. Using computational modeling, calcium and STED superresolution imaging, we show that the SA replenishment involves the store-operated calcium entry pathway during spontaneous calcium transients. We identified two main conditions for SA replenishment without depletion: a small amplitude and a slow timescale for calcium influx, and a close proximity between SA and plasma membranes. Thereby, spine’s nanoscale organization separates SA replenishment from depletion. We further conclude that spine’s receptor organization also determines the calcium dynamics during the induction of long-term synaptic changes

Synapse Geometry and Receptor Dynamics Modulate Synaptic Strength

Synaptic transmission relies on several processes, such as the location of a released vesicle, the number and type of receptors, trafficking between the postsynaptic density (PSD) and extrasynaptic compartment, as well as the synapse organization. To study the impact of these parameters on excitatory synaptic transmission, we present a computational model for the fast AMPA-receptor mediated synaptic current. We show that in addition to the vesicular release probability, due to variations in their release locations and the AMPAR distribution, the postsynaptic current amplitude has a large variance, making a synapse an intrinsic unreliable device. We use our model to examine our experimental data recorded from CA1 mice hippocampal slices to study the differences between mEPSC and evoked EPSC variance. The synaptic current but not the coefficient of variation is maximal when the active zone where vesicles are released is apposed to the PSD. Moreover, we find that for certain type of synapses, receptor trafficking can affect the magnitude of synaptic depression. Finally, we demonstrate that perisynaptic microdomains located outside the PSD impacts synaptic transmission by regulating the number of desensitized receptors and their trafficking to the PSD. We conclude that geometrical modifications, reorganization of the PSD or perisynaptic microdomains modulate synaptic strength, as the mechanisms underlying long-term plasticity

Interactions neurogliales en physiopathologie cérébrale

    Responsable : Nathalie Rouach Recherche Les interactions neurogliales participent activement à l’activité cérébrale. Cependant, les mécanismes physiologiques et moléculaires sous-jacents restent mal compris. Nos travaux récents ont montré que : 1) les canaux potassiques Kir4.1 astrocytaires sous-tendent la majorité des courants astrocytaires induits synaptiquement, régulent la plasticité synaptique à court terme des neurones hippocampiques (Sibille et al., 2014), et jouent un rôle crucial..

Interactions neurogliales en physiopathologie cérébrale / Neuroglial interactions in cerebral physiopathology

    Responsable : Nathalie Rouach Recherche The main goal of our group is to assess whether and how the underexplored glial cells play a direct role in information processing. In the last years we investigated the role of astrocytes in both neurophysiology and neuropathology in situ in brain slices and human tissues as well as in vivo in mice. We particularly explored the molecular modalities and functional outcomes of neuroglial interactions, focusing ex vivo or in vivo on neuronal excitabil..

Interactions neurogliales en physiopathologie cérébrale / Neuroglial interactions in cerebral physiopathology

    Responsable : Nathalie Rouach Recherche Astrocytes play critical roles in brain development, activity and disorders through dynamic interactions with neurons. However, comprehensive molecular description of such modulations is still limited. This last year we investigated the role of several astroglial properties in neurotransmission, including their network organization mediated by gap junction channels (1), potassium uptake by Kir4.1 channels (2) and calcium signaling (3). 1) We have in..

Astroglial networking contributes to neurometabolic coupling

International audienceThe strategic position of astrocytic processes between blood capillaries and neurons, provided the early insight that astrocytes play a key role in supplying energy substrates to neurons in an activity-dependent manner. The central role of astrocytes in neurometabolic coupling has been first established at the level of single cell. Since then, exciting recent work based on cellular imaging and electrophysiological recordings has provided new mechanistic insights into this phenomenon, revealing the crucial role of gap junction (GJ)-mediated networks of astrocytes. Indeed, astrocytes define the local availability of energy substrates by regulating blood flow. Subsequently, in order to efficiently reach distal neurons, these substrates can be taken up, and distributed through networks of astrocytes connected by GJs, a process modulated by neuronal activity. Astrocytic networks can be morphologically and/or functionally altered in the course of various pathological conditions, raising the intriguing possibility of a direct contribution from these networks to neuronal dysfunction. The present review upgrades the current view of neuroglial metabolic coupling, by including the recently unravelled properties of astroglial metabolic networks and their potential contribution to normal and pathological neuronal activity

Astrocytes as new targets to improve cognitive functions

International audienceAstrocytes are now viewed as key elements of brain wiring as well as neuronal communication. Indeed, they not only bridge the gap between metabolic supplies by blood vessels and neurons, but also allow fine control of neurotransmission by providing appropriate signaling molecules and insulation through a tight enwrapping of synapses. Recognition that astroglia is essential to neuronal communication is nevertheless fairly recent and the large body of evidence dissecting such role has focused on the synaptic level by identifying neuro- and gliotransmitters uptaken and released at synaptic or extrasynaptic sites. Yet, more integrated research deciphering the impact of astroglial functions on neuronal network activity have led to the reasonable assumption that the role of astrocytes in supervising synaptic activity translates in influencing neuronal processing and cognitive functions. Several investigations using recent genetic tools now support this notion by showing that inactivating or boosting astroglial function directly affects cognitive abilities. Accordingly, brain diseases resulting in impaired cognitive functions have seen their physiopathological mechanisms revisited in light of this primary protagonist of brain processing. We here provide a review of the current knowledge on the role of astrocytes in cognition and in several brain diseases including neurodegenerative disorders, psychiatric illnesses, as well as other conditions such as epilepsy. Potential astroglial therapeutic targets are also discussed