How astrocytes close a critical period
During the visual critical period, brain circuits are rewired to adjust to sensory input. Closure of the critical period stabilizes the circuits. Looking at ...development in the mouse visual cortex, Ribot
et al.
found that astrocytes increase their expression of the gap junction channel subunit connexin 30, which in turn inhibits expression of a matrix-degrading enzyme (see the Perspective by Kofuji and Araque). As the matrix stabilizes, inhibitory interneurons mature, and the unusual flexibility of the critical period comes to an end.
Science
, abf5273, this issue p.
77
; see also abj6745, p.
29
By controlling enzymes that degrade the extracellular matrix, astrocytes regulate interneuron maturation and closure of the visual critical period.
Brain postnatal development is characterized by critical periods of experience-dependent remodeling of neuronal circuits. Failure to end these periods results in neurodevelopmental disorders. The cellular processes defining critical-period timing remain unclear. Here, we show that in the mouse visual cortex, astrocytes control critical-period closure. We uncover the underlying pathway, which involves astrocytic regulation of the extracellular matrix, allowing interneuron maturation. Unconventional astrocyte connexin signaling hinders expression of extracellular matrix–degrading enzyme matrix metalloproteinase 9 (MMP9) through RhoA–guanosine triphosphatase activation. Thus, astrocytes not only influence the activity of single synapses but also are key elements in the experience-dependent wiring of brain circuits.
Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder, characterized by normal post-natal development followed by a sudden deceleration in brain growth with progressive loss of acquired ...motor and language skills, stereotypic hand movements and severe cognitive impairment. Mutations in the methyl-CpG-binding protein 2 (MECP2) cause more than 95% of classic cases. Recently, it has been shown that the loss of Mecp2 from glia negatively influences neurons in a non-cell-autonomous fashion, and that in Mecp2-null mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern and greatly prolonged lifespan compared with globally null mice. We now report that microtubule (MT)-dependent vesicle transport is altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared with control wild-type littermates. Similar observation has been made in human MECP2 p.Arg294* iPSC-derived astrocytes. Importantly, administration of Epothilone D, a brain-penetrant MT-stabilizing natural product, was found to restore MT dynamics in Mecp2-deficient astrocytes and in MECP2 p.Arg294* iPSC-derived astrocytes in vitro. Finally, we report that relatively low weekly doses of Epothilone D also partially reversed the impaired exploratory behavior in Mecp2(308/y) male mice. These findings represent a first step toward the validation of an innovative treatment for RTT.
Mutations and deletions of the
(
) gene, located on the X chromosome, are associated with intellectual disability (ID) and autism spectrum disorder (ASD). IL1RAPL1 protein is located at the ...postsynaptic compartment of excitatory synapses and plays a role in synapse formation and stabilization. Here, using primary neuronal cultures and
-KO mice, we characterized the role of IL1RAPL1 in regulating dendrite morphology. In
-KO mice we identified an increased number of dendrite branching points in CA1 and CA2 hippocampal neurons associated to hippocampal cognitive impairment. Similarly, induced pluripotent stem cell-derived neurons from a patient carrying a null mutation of the
gene had more dendrites. In hippocampal neurons, the overexpression of full-length IL1RAPL1 and mutants lacking part of C-terminal domains leads to simplified neuronal arborization. This effect is abolished when we overexpressed mutants lacking part of N-terminal domains, indicating that the IL1RAPL1 extracellular domain is required for regulating dendrite development. We also demonstrate that PTPδ interaction is not required for this activity, while IL1RAPL1 mediates the activity of IL-1β on dendrite morphology. Our data reveal a novel specific function for IL1RAPL1 in regulating dendrite morphology that can help clarify how changes in IL1RAPL1-regulated pathways can lead to cognitive disorders in humans.
Abnormalities in the architecture of dendrites have been observed in a variety of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. Here we show that the X-linked intellectual disability protein interleukin-1 receptor accessory protein like 1 (IL1RAPL1) regulates dendrite morphology of mice hippocampal neurons and induced pluripotent stem cell-derived neurons from a patient carrying a null mutation of
gene. We also found that the extracellular domain of IL1RAPL1 is required for this effect, independently of the interaction with PTPδ, but IL1RAPL1 mediates the activity of IL-1β on dendrite morphology. Our data reveal a novel specific function for IL1RAPL1 in regulating dendrite morphology that can help clarify how changes in IL1RAPL1-regulated pathways can lead to cognitive disorders in humans.
Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and ...downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.
Display omitted
•IL-38-deficient mice display delayed resolution of imiquimod-induced psoriasis•IL-38 suppresses IL-17A production by γδ T cells•Inhibition of IL-17A production by γδ T cells requires IL1RAPL1•IL1RAPL1-deficient mice show decreased γδ T cell activation during psoriasis
Han et al. report that genetic depletion of IL-38 in mice delays the resolution of imiquimod-induced psoriasis by increasing the production of the inflammatory cytokine IL-17A by skin-infiltrating T cells. Depleting these T cells or the receptor that is targeted by IL-38 reduces psoriatic skin inflammation.
Cajal-Retzius cells (CRs) are a class of transient neurons in the mammalian cortex that play a critical role in cortical development. Neocortical CRs undergo almost complete elimination in the first ...two postnatal weeks in rodents and the persistence of CRs during postnatal life has been detected in pathological conditions related to epilepsy. However, it is unclear whether their persistence is a cause or consequence of these diseases. To decipher the molecular mechanisms involved in CR death, we investigated the contribution of the PI3K/AKT/mTOR pathway as it plays a critical role in cell survival. We first showed that this pathway is less active in CRs after birth before massive cell death. We also explored the spatio-temporal activation of both AKT and mTOR pathways and reveal area-specific differences along both the rostro-caudal and medio-lateral axes. Next, using genetic approaches to maintain an active pathway in CRs, we found that the removal of either PTEN or TSC1, two negative regulators of the pathway, lead to differential CR survivals, with a stronger effect in the
model. Persistent cells in this latter mutant are still active. They express more Reelin and their persistence is associated with an increase in the duration of kainate-induced seizures in females. Altogether, we show that the decrease in PI3K/AKT/mTOR activity in CRs primes these cells to death by possibly repressing a survival pathway, with the mTORC1 branch contributing less to the phenotype.
Abstract Oligophrenin-1 (OPHN1) is a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID). How loss of function of Ophn1 affects neuronal development is only ...partly understood. Here we have exploited adult hippocampal neurogenesis to dissect the steps of neuronal differentiation that are affected by Ophn1 deletion. We found that mice lacking Ophn1 display a reduction in the number of newborn neurons in the dentate gyrus. A significant fraction of the Ophn1-deficient newly generated neurons failed to extend an axon towards CA3, and showed an altered density of dendritic protrusions. Since Ophn1-deficient mice display overactivation of Rho-associated protein kinase (ROCK) and protein kinase A (PKA) signaling, we administered a clinically approved ROCK/PKA inhibitor (fasudil) to correct the neurogenesis defects. While administration of fasudil was not effective in rescuing axon formation, the same treatment completely restored spine density to control levels, and enhanced the long-term survival of adult-born neurons in mice lacking Ophn1. These results identify specific neurodevelopmental steps that are impacted by Ophn1 deletion, and indicate that they may be at least partially corrected by pharmacological treatment.
Oligophrenin-1 (OPHN1) is a Rho-GTPase-activating protein (RhoGAP), whose mutations are associated with X-linked intellectual disability (XLID). OPHN1 is enriched at the synapse in both pre- and ...postsynaptic compartments, where it regulates the RhoA/ROCK/MLC2 signaling pathway, playing a critical role in cytoskeleton remodeling and vesicle recycling.
knockout (KO) adult mice display some behavioral deficits in multiple tasks, reminiscent of some symptoms in the human pathology. We also previously reported a reduction in dendritic spine density in the adult hippocampus of KO mice. Yet the nature of the deficits occurring in these mice during postnatal development remains elusive. Here, we show that juvenile KO mice present normal basal synaptic transmission, but altered synaptic plasticity, with a selective impairment in long-term depression, but no change in long-term potentiation. This contrasts with the functional deficits that these mice display at the adult stage, as we found that both basal synaptic transmission and long-term potentiation are reduced at later stages, due to presynaptic alterations. In addition, the number of excitatory synapses in adult is increased, suggesting some unsuccessful compensation. Altogether, these results suggest that OPHN1 function at synapses is differentially affected during maturation of the brain, which provides some therapeutic opportunities for early intervention.
The Rho family of small GTPases has been analyzed in cardiac physiology and pathophysiology including myocardial infarction (MI) in the last years. Contradictory results show either a protective or a ...declined effect of RhoA and the RhoA effector Rho-associated protein kinase (ROCK) in myocardial ischemia and reperfusion injury that is associated with cardiomyocyte survival and caspase-3 activation. Cardiac-specific deletion of Rac1 reduced ischemia reperfusion injury in diabetic hearts, whereas cardiomyocyte specific overexpression of active Rac1 predisposes the heart to increased myocardial injury with enhanced contractile dysfunction. GTPase-activating proteins (GAPs) control the activation of Rho proteins through stimulation of GTP hydrolysis. However, the impact of GAPs in myocardial ischemia and reperfusion injury remains elusive. Here we analyzed the role of oligophrenin1 (OPHN1), a RhoGAP with Bin/Amphiphysin/Rvs (BAR) domain known to regulate the activity of RhoA, Rac1 and Cdc42 in MI. The expression of Ophn1, RhoA and Rac1 is strongly upregulated 24h after myocardial ischemia. Loss of OPHN1 induced enhanced activity of Rho effector molecules leading to elevated cardiomyocyte apoptosis and increased migration of inflammatory cells into the infarct border zone of OPHN1 deficient mice. Consequently, echocardiography 24h after myocardial ischemia revealed declined left ventricle function in OPHN1 deficient mice. Our results indicate that OPHN1 mediated regulation of RhoA, Rac1 and Cdc42 is crucial for the preservation of cardiac function after myocardial injury.
•Ophn1 expression is upregulated upon myocardial ischemia and reperfusion injury (I/R).•Loss of OPHN1 results in enhanced activation of Rho effectors in the heart after I/R.•Increased inflammatory cell migration and cardiomyocyte apoptosis 24h after I/R•Declined cardiac LV function 24h after myocardial ischemia in OPHN1 deficient mice•These results point to a new role for OPHN1 as an important regulator of LV function after I/R.
Loss of oligophrenin1 (OPHN1) function in human causes X-linked mental retardation associated with cerebellar hypoplasia and, in some cases, with lateral ventricle enlargement. In vitro studies ...showed that ophn1 regulates dendritic spine through the control of Rho GTPases, but its in vivo function remains unknown. We generated a mouse model of ophn1 deficiency and showed that it mimics the ventricles enlargement without affecting the cerebellum morphoanatomy. The ophn1 knock-out mice exhibit behavioral defects in spatial memory together with impairment in social behavior, lateralization, and hyperactivity. Long-term potentiation and mGluR-dependent long-term depression are normal in the CA1 hippocampal area of ophn1 mutant, whereas paired-pulse facilitation is reduced. This altered short-term plasticity that reflects changes in the release of neurotransmitters from the presynaptic processes is associated with normal synaptic density together with a reduction in mature dendritic spines. In culture, inactivation of ophn1 function increases the density and proportion of immature spines. Using a conditional model of loss of ophn1 function, we confirmed this immaturity defect and showed that ophn1 is required at all the stages of the development. These studies show that, depending of the context, ophn1 controls the maturation of dendritic spines either by maintaining the density of mature spines or by limiting the extension of new filopodia. Altogether, these observations indicate that cognitive impairment related to OPHN1 loss of function is associated with both presynaptic and postsynaptic alterations.
The patho-physiological hypothesis of mental retardation caused by the deficiency of the RhoGAP Oligophrenin1 (OPHN1), relies on the well-known functions of Rho GTPases on neuronal morphology, i.e. ...dendritic spine structure. Here, we describe a new function of this Bin/Amphiphysin/Rvs domain containing protein in the control of clathrin-mediated endocytosis (CME). Through interactions with Src homology 3 domain containing proteins involved in CME, OPHN1 is concentrated to endocytic sites where it down-regulates the RhoA/ROCK signaling pathway and represses the inhibitory function of ROCK on endocytosis. Indeed disruption of Ophn1 in mice reduces the endocytosis of synaptic vesicles and the post-synaptic α-amino-3-hydroxy-5-methylisoazol-4-propionate (AMPA) receptor internalization, resulting in almost a complete loss of long-term depression in the hippocampus. Finally, pharmacological inhibition of this pathway by ROCK inhibitors fully rescued not only the CME deficit in OPHN1 null cells but also synaptic plasticity in the hippocampus from Ophn1 null model. Altogether, we uncovered a new patho-physiological mechanism for intellectual disabilities associated to mutations in RhoGTPases linked genes and also opened new directions for therapeutic approaches of congenital mental retardation.
PDF
