Département de Biologie

Fine control of neuronal activity is crucial to rapidly adjust to subtle changes of the environment. This fine-tuning was thought to be purely neuronal until the discovery that astrocytes are active players of synaptic transmission. In the adult hippocampus, microglia are the other major glial cell-type. Microglia are highly dynamic and are closely associated with neurons and astrocytes. They react rapidly to modifications of their environment and are able to release molecules known to control neuronal function and synaptic transmission. Therefore, microglia display functional features of synaptic partners, but their involvement in the regulation of synaptic transmission has not yet been addressed. We have used a combination of pharmacological approaches with electrophysiological analysis on acute hippocampal slices and ATP assays in purified cell cultures, to demonstrate that activation of microglia induces a rapid increase of spontaneous excitatory post-synaptic currents (EPSC). We found that this modulation is mediated by binding of ATP to P2Y1R located on astrocytes and is independent of TNFα or NOS2. Our data indicates that upon activation, microglia rapidly release small amount of ATP and astrocytes in turn amplified this release. Finally, P2Y1 stimulation of astrocytes increased EPSC frequency through an mGlur5-dependent mechanism. These results reveal for the first time microglia as a genuine regulator of neurotransmission and place microglia as an upstream partner of astrocytes. Because pathological activation of microglia and alteration of neurotransmission are two early symptoms of most brain diseases, our work also provides a basis for understanding synaptic dysfunction in neuronal diseases.

Figure 1

Microglia (in green) are closely aposed to neurons (in gold). Pascual et al. have now shown that stimulation of microglia rapidly modulate AMPAergic synapses via astrocytes.

Brain connectivity relies on axonal responses to combinations of guidance cues

A joint collaboration from IBENS researchers and the INA (Alicante, Spain) has found a key mechanism that ensures the development of a major axonal connection in the brain.

Figure 1. The Corridor Is a Guidance Decision Point for Thalamocortical Axon Topography

(A) Coronal section of an E14.5 brain after DiI injection in the thalamus (Th) shows that labeled thalamocortical axons (TCAs) in the subpallium are encom- passed within a 45° plane of section (45° corridor angle), which is used in the following panels. (B and B0 ) 45° corridor angle sections after DiI and DiA injections at E15.5 in the caudolateral (cTh) and rostromedial thalamus (rTh) show distinct positioning of caudal (red, DiI) and rostral (green, DiA) axons (arrowhead) within the corridor (dotted line). (c) Schema of the topographical arrangement of TCAs in the corridor. (D) Experimental paradigm used to test the presence of guidance information in the corridor. The corridor (co, red dotted line) was transiently labeled on 45° co-LacZ E13.5 live sections using a fluorescent substrate of b-galactosidase activity and subsequently cut for a control incision or a rostrocaudal flip. Thalamic (Th) explants of either rostral (Th1/2) or intermediate (Th3) levels from a Gfp transgenic mouse were then grafted at the tip of the corridor. (E and F) Th1/2 grow rostrally (black arrowhead) in controls but mostly caudally (white arrowhead) after the corridor flip [n(Th1/2)control = 9 ; n(Th1/2)flip = 10]. Dotted lines indicate the explants and the boundary delineating rostral and caudal quadrants (see Supplemental Experimental Procedures). Inserts show low-magnification images of the entire slices where the red dotted line indicates the corridor/striatum boundary. (G) Quantification of (E) and (F). **p < 0.005 by Student's t test. (H and I) Th3 grow rostrointermediate in the controls (black arrowhead) but caudointermediate after the corridor flip [n(Th3)control = 8 ; n(Th3)flip = 9]. Dotted lines indicate the explants and the boundary delineating rostral and caudal quadrants (see Supplemental Experimental Procedures). Inserts show low- magnification images of the entire slices where the red dotted line indicates the corridor/striatum boundary. (J) Quantification of (H) and (I). ***p < 0.001 by Student's t test. The following abbreviations are used : c, caudal ; L, lateral ; Ncx, neocortex ; Str, striatum ; GP, globus pallidus ; r/R, rostral. Scale bars represent 250 mm. Data in (G) and (J) are presented as mean 6 standard error of the mean (SEM).

The functioning of the nervous system relies on the establishment of axonal tracts that follow complex trajectories. However, how guidance cues are integrated during the formation of these axonal tracts remains largely unknown. Thalamocortical axons, which convey sensory and motor information to the neocortex, have a rostrocaudal topographic organization initially established within the ventral telencephalon. In this study the authors show that this topography is set in a small hub, the corridor, which contains gradients guidance cues such as Slit1 and Netrin 1. Using in vitro and in vivo experiments, these authors found that Slit1 is a rostral repellent that positions intermediate thalamocortical axons. For rostral axons, while Slit1 is also repulsive and Netrin 1 has no chemotactic activity, the two factors combined generate attraction. These results show that Slit1 has a dual context-dependent role in thalamocortical pathfinding and furthermore reveals that a combination of cues produces an emergent activity that neither of them has alone. This study thus provides a novel framework to explain how a limited set of guidance cues can generate a vast diversity of axonal responses necessary for proper wiring of the nervous system.