Aude Panatier

Surface diffusion of astrocytic glutamate transporters shapes synaptic transmission

Control of the glutamate time course in the synapse is crucial for excitatory transmission. This process is mainly ensured by astrocytic transporters, high expression of which is essential to compensate for their slow transport cycle. Although molecular mechanisms regulating transporter intracellular trafficking have been identified, the relationship between surface transporter dynamics and synaptic function remains unexplored. We found that GLT-1 transporters were highly mobile on rat astrocytes. Surface diffusion of GLT-1 was sensitive to neuronal and glial activities and was strongly reduced in the vicinity of glutamatergic synapses, favoring transporter retention. Notably, glutamate uncaging at synaptic sites increased GLT-1 diffusion, displacing transporters away from this compartment. Functionally, impairing GLT-1 membrane diffusion through cross-linking in vitro and in vivo slowed the kinetics of excitatory postsynaptic currents, indicative of a prolonged time course of synaptic glutamate. These data provide, to the best of our knowledge, the first evidence for a physiological role of GLT-1 surface diffusion in shaping synaptic transmission.

Neuron-glia interactions in the hypothalamus.

The supraoptic (SON) and paraventricular (PVN) magnocellular nuclei of the hypothalamus undergo reversible anatomical remodeling under conditions of intense secretion of neurohypophysial hormones, such as lactation and chronic dehydration. This morphological plasticity is characterized by a pronounced reduction in astrocytic coverage of neurons, which results in an increased number and extent of directly juxtaposed somatic and dendritic surfaces. As a consequence, astrocyte-mediated clearance of glutamate from the extracellular space is altered, which causes an increased concentration and range of action of the excitatory amino acid in the extracellular space. This leads to a reduction of synaptic efficacy at excitatory and inhibitory inputs through the activation of presynaptic metabotropic glutamate receptors. By contrast, the action of glio transmitters released from astrocytes and acting on adjacent magnocellular neurons is limited during such anatomical remodeling. This includes glia derived ATP mediating potentiation of glutamatergic transmission, a process compromised by the neuronal-glial reorganization.Together, these studies on hypothalamic magnocellular nuclei provide new insights on the contribution of glial cells on neuronal activity.

Astrocytic IP3Rs: Contribution to Ca2+signalling and hippocampal LTP: Astrocytic IP3Rs: Ca2+Signalling and LTP

Astrocytes regulate hippocampal synaptic plasticity by the Ca2+ dependent release of the N‐methyl d‐aspartate receptor (NMDAR) co‐agonist d‐serine. Previous evidence indicated that d‐serine release would be regulated by the intracellular Ca2+ release channel IP3 receptor (IP3R), however, genetic deletion of IP3R2, the putative astrocytic IP3R subtype, had no impact on synaptic plasticity or transmission. Although IP3R2 is widely believed to be the only functional IP3R in astrocytes, three IP3R subtypes (1, 2, and 3) have been identified in vertebrates. Therefore, to better understand gliotransmission, we investigated the functionality of IP3R and the contribution of the three IP3R subtypes to Ca2+ signalling. As a proxy for gliotransmission, we found that long‐term potentiation (LTP) was impaired by dialyzing astrocytes with the broad IP3R blocker heparin, and rescued by exogenous d‐serine, indicating that astrocytic IP3Rs regulate d‐serine release. To explore which IP3R subtypes are functional in astrocytes, we used pharmacology and two‐photon Ca2+ imaging of hippocampal slices from transgenic mice (IP3R2−/− and IP3R2−/−;3−/−). This approach revealed that underneath IP3R2‐mediated global Ca2+ events are an overlooked class of IP3R‐mediated local events, occurring in astroglial processes. Notably, multiple IP3Rs were recruited by high frequency stimulation of the Schaffer collaterals, a classical LTP induction protocol. Together, these findings show the dependence of LTP and gliotransmission on Ca2+ release by astrocytic IP3Rs. GLIA 2017;65:502–513

Astrocytic IP3Rs: Contribution to Ca2+ signalling and hippocampal LTP

Astrocytes regulate hippocampal synaptic plasticity by the Ca2+ dependent release of the N‐methyl d‐aspartate receptor (NMDAR) co‐agonist d‐serine. Previous evidence indicated that d‐serine release would be regulated by the intracellular Ca2+ release channel IP3 receptor (IP3R), however, genetic deletion of IP3R2, the putative astrocytic IP3R subtype, had no impact on synaptic plasticity or transmission. Although IP3R2 is widely believed to be the only functional IP3R in astrocytes, three IP3R subtypes (1, 2, and 3) have been identified in vertebrates. Therefore, to better understand gliotransmission, we investigated the functionality of IP3R and the contribution of the three IP3R subtypes to Ca2+ signalling. As a proxy for gliotransmission, we found that long‐term potentiation (LTP) was impaired by dialyzing astrocytes with the broad IP3R blocker heparin, and rescued by exogenous d‐serine, indicating that astrocytic IP3Rs regulate d‐serine release. To explore which IP3R subtypes are functional in astrocytes, we used pharmacology and two‐photon Ca2+ imaging of hippocampal slices from transgenic mice (IP3R2−/− and IP3R2−/−;3−/−). This approach revealed that underneath IP3R2‐mediated global Ca2+ events are an overlooked class of IP3R‐mediated local events, occurring in astroglial processes. Notably, multiple IP3Rs were recruited by high frequency stimulation of the Schaffer collaterals, a classical LTP induction protocol. Together, these findings show the dependence of LTP and gliotransmission on Ca2+ release by astrocytic IP3Rs. GLIA 2017;65:502–513

The Soothing Touch: Microglial Contact Influences Neuronal Excitability

Resting microglial cells in the brain scan their environment with their processes, primed to react to injury and disease. In this issue of Developmental Cell, Li and colleagues (2012) report that resting microglia also react to physiological neuronal activity, sending their processes toward highly active neurons to regulate their excitability.

Astrocytic IP3 Rs: Contribution to Ca(2+) signalling and hippocampal LTP.

Astrocytes regulate hippocampal synaptic plasticity by the Ca2+ dependent release of the N‐methyl d‐aspartate receptor (NMDAR) co‐agonist d‐serine. Previous evidence indicated that d‐serine release would be regulated by the intracellular Ca2+ release channel IP3 receptor (IP3R), however, genetic deletion of IP3R2, the putative astrocytic IP3R subtype, had no impact on synaptic plasticity or transmission. Although IP3R2 is widely believed to be the only functional IP3R in astrocytes, three IP3R subtypes (1, 2, and 3) have been identified in vertebrates. Therefore, to better understand gliotransmission, we investigated the functionality of IP3R and the contribution of the three IP3R subtypes to Ca2+ signalling. As a proxy for gliotransmission, we found that long‐term potentiation (LTP) was impaired by dialyzing astrocytes with the broad IP3R blocker heparin, and rescued by exogenous d‐serine, indicating that astrocytic IP3Rs regulate d‐serine release. To explore which IP3R subtypes are functional in astrocytes, we used pharmacology and two‐photon Ca2+ imaging of hippocampal slices from transgenic mice (IP3R2−/− and IP3R2−/−;3−/−). This approach revealed that underneath IP3R2‐mediated global Ca2+ events are an overlooked class of IP3R‐mediated local events, occurring in astroglial processes. Notably, multiple IP3Rs were recruited by high frequency stimulation of the Schaffer collaterals, a classical LTP induction protocol. Together, these findings show the dependence of LTP and gliotransmission on Ca2+ release by astrocytic IP3Rs. GLIA 2017;65:502–513

Activity-Dependent Neuroplasticity Induced by an Enriched Environment Reverses Cognitive Deficits in Scribble Deficient Mouse

Abstract Planar cell polarity (PCP) signaling is well known to play a critical role during prenatal brain development; whether it plays specific roles at postnatal stages remains rather unknown. Here, we investigated the role of a key PCP‐associated gene scrib in CA1 hippocampal structure and function at postnatal stages. We found that Scrib is required for learning and memory consolidation in the Morris water maze as well as synaptic maturation and NMDAR‐dependent bidirectional plasticity. Furthermore, we unveiled a direct molecular interaction between Scrib and PP1/PP2A phosphatases whose levels were decreased in postsynaptic density of conditional knock‐out mice. Remarkably, exposure to enriched environment (EE) preserved memory formation in CaMK‐Scrib−/− mice by recovering synaptic plasticity and maturation. Thus, Scrib is required for synaptic function involved in memory formation and EE has beneficiary therapeutic effects. Our results demonstrate a distinct new role for a PCP‐associated protein, beyond embryonic development, in cognitive functions during adulthood.

Astrocytes detect and upregulate transmission at inhibitory synapses of somatostatin interneurons onto pyramidal cells

Astrocytes are important regulators of excitatory synaptic networks. However, astrocytes regulation of inhibitory synaptic systems remains ill defined. This is particularly relevant since GABAergic interneurons regulate the activity of excitatory cells and shape network function. To address this issue, we combined optogenetics and pharmacological approaches, two-photon confocal imaging and whole-cell recordings to specifically activate hippocampal somatostatin or paravalbumin-expressing interneurons (SOM-INs or PV-INs), while monitoring inhibitory synaptic currents in pyramidal cells and Ca2+ responses in astrocytes. We found that astrocytes detect SOM-IN synaptic activity via GABABR and GAT-3-dependent Ca2+ signaling mechanisms, the latter triggering the release of ATP. In turn, ATP is converted into adenosine, activating A1Rs and upregulating SOM-IN synaptic inhibition of pyramidal cells, but not PV-IN inhibition. Our findings uncover functional interactions between a specific subpopulation of interneurons, astrocytes and pyramidal cells, involved in positive feedback autoregulation of dendritic inhibition of pyramidal cells.Astrocytes have been shown to regulate glutamatergic transmission in the brain. Here, the authors show that astrocytes also detect and modulate GABAergic transmission from somatostatin but not parvalbumin-positive interneurons, thus regulating dendritic inhibition via a feedback loop.

Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer's disease.

Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer’s disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies.Here, we used cell type-specific approaches in vivo and identified the JAK2-STAT3 pathway, as necessary and sufficient for the induction and maintenance of astrocyte reactivity. Modulation of this cascade by viral gene transfer in mouse astrocytes efficiently controlled several morphological and molecular features of reactivity. Inhibition of this pathway in mouse models of Alzheimer’s disease improved three key pathological hallmarks by reducing amyloid deposition, improving spatial learning and restoring synaptic deficits.In conclusion, the JAK2-STAT3 cascade operates as a master regulator of astrocyte reactivity in vivo. Its inhibition offers new therapeutic opportunities for Alzheimer’s disease.