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1.
J Exp Med ; 219(6)2022 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-35587822

RESUMEN

Evidence is emerging that immune responses not only play a part in the central nervous system (CNS) in diseases but may also be relevant for healthy conditions. We discovered a major role for the interleukin-4 (IL-4)/IL-4 receptor alpha (IL-4Rα) signaling pathway in synaptic processes, as indicated by transcriptome analysis in IL-4Rα-deficient mice and human neurons with/without IL-4 treatment. Moreover, IL-4Rα is expressed presynaptically, and locally available IL-4 regulates synaptic transmission. We found reduced synaptic vesicle pools, altered postsynaptic currents, and a higher excitatory drive in cortical networks of IL-4Rα-deficient neurons. Acute effects of IL-4 treatment on postsynaptic currents in wild-type neurons were mediated via PKCγ signaling release and led to increased inhibitory activity supporting the findings in IL-4Rα-deficient neurons. In fact, the deficiency of IL-4Rα resulted in increased network activity in vivo, accompanied by altered exploration and anxiety-related learning behavior; general learning and memory was unchanged. In conclusion, neuronal IL-4Rα and its presynaptic prevalence appear relevant for maintaining homeostasis of CNS synaptic function.


Asunto(s)
Interleucina-4 , Receptores de Interleucina-4 , Animales , Interleucina-4/metabolismo , Ratones , Ratones Noqueados , Neuronas/metabolismo , Receptores de Interleucina-4/metabolismo , Transducción de Señal
2.
Sci Transl Med ; 14(641): eabk0135, 2022 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-35442704

RESUMEN

Stroke penumbra injury caused by excess glutamate is an important factor in determining stroke outcome; however, several therapeutic approaches aiming to rescue the penumbra have failed, likely due to unspecific targeting and persistent excitotoxicity, which continued far beyond the primary stroke event. Synaptic lipid signaling can modulate glutamatergic transmission via presynaptic lysophosphatidic acid (LPA) 2 receptors modulated by the LPA-synthesizing molecule autotaxin (ATX) present in astrocytic perisynaptic processes. Here, we detected long-lasting increases in brain ATX concentrations after experimental stroke. In humans, cerebrospinal fluid ATX concentration was increased up to 14 days after stroke. Using astrocyte-specific deletion and pharmacological inhibition of ATX at different time points after experimental stroke, we showed that inhibition of LPA-related cortical excitability improved stroke outcome. In transgenic mice and in individuals expressing a single-nucleotide polymorphism that increased LPA-related glutamatergic transmission, we found dysregulated synaptic LPA signaling and subsequent negative stroke outcome. Moreover, ATX inhibition in the animal model ameliorated stroke outcome, suggesting that this approach might have translational potential for improving the outcome after stroke.


Asunto(s)
Excitabilidad Cortical , Accidente Cerebrovascular , Animales , Lisofosfolípidos/farmacología , Ratones , Ratones Transgénicos , Hidrolasas Diéster Fosfóricas , Receptores del Ácido Lisofosfatídico , Accidente Cerebrovascular/tratamiento farmacológico
3.
Cell Mol Neurobiol ; 40(8): 1327-1338, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32172457

RESUMEN

Neurons of the central nervous system (CNS) that project long axons into the spinal cord have a poor axon regenerative capacity compared to neurons of the peripheral nervous system. The corticospinal tract (CST) is particularly notorious for its poor regeneration. Because of this, traumatic spinal cord injury (SCI) is a devastating condition that remains as yet uncured. Based on our recent observations that direct neuronal interleukin-4 (IL-4) signaling leads to repair of axonal swellings and beneficial effects in neuroinflammation, we hypothesized that IL-4 acts directly on the CST. Here, we developed a tissue culture model for CST regeneration and found that IL-4 promoted new growth cone formation after axon transection. Most importantly, IL-4 directly increased the regenerative capacity of both murine and human CST axons, which corroborates its regenerative effects in CNS damage. Overall, these findings serve as proof-of-concept that our CST regeneration model is suitable for fast screening of new treatments for SCI.


Asunto(s)
Axones/metabolismo , Regeneración Nerviosa/fisiología , Neuronas/metabolismo , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/terapia , Animales , Humanos , Ratones Endogámicos C57BL , Regeneración Nerviosa/efectos de los fármacos , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/farmacología , Tractos Piramidales/efectos de los fármacos , Tractos Piramidales/fisiología , Recuperación de la Función/efectos de los fármacos , Traumatismos de la Médula Espinal/metabolismo
4.
J Clin Invest ; 130(2): 715-732, 2020 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-31661467

RESUMEN

Although the impact of Th17 cells on autoimmunity is undisputable, their pathogenic effector mechanism is still enigmatic. We discovered soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex proteins in Th17 cells that enable a vesicular glutamate release pathway that induces local intracytoplasmic calcium release and subsequent damage in neurons. This pathway is glutamine dependent and triggered by binding of ß1-integrin to vascular cell adhesion molecule 1 (VCAM-1) on neurons in the inflammatory context. Glutamate secretion could be blocked by inhibiting either glutaminase or KV1.3 channels, which are known to be linked to integrin expression and highly expressed on stimulated T cells. Although KV1.3 is not expressed in CNS tissue, intrathecal administration of a KV1.3 channel blocker or a glutaminase inhibitor ameliorated disability in experimental neuroinflammation. In humans, T cells from patients with multiple sclerosis secreted higher levels of glutamate, and cerebrospinal fluid glutamine levels were increased. Altogether, our findings demonstrate that ß1-integrin- and KV1.3 channel-dependent signaling stimulates glutamate release from Th17 cells upon direct cell-cell contact between Th17 cells and neurons.


Asunto(s)
Integrina beta1/inmunología , Canal de Potasio Kv1.3/inmunología , Esclerosis Múltiple/inmunología , Transducción de Señal/inmunología , Células Th17/inmunología , Animales , Comunicación Celular/genética , Comunicación Celular/inmunología , Ácido Glutámico/genética , Ácido Glutámico/inmunología , Humanos , Integrina beta1/genética , Canal de Potasio Kv1.3/genética , Ratones , Ratones Noqueados , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Proteínas SNARE/genética , Proteínas SNARE/inmunología , Transducción de Señal/genética , Células Th17/patología , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/inmunología
5.
Mol Psychiatry ; 25(11): 3108, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30602735

RESUMEN

Following the publication of this article the authors noted that Torfi Sigurdsson's name was misspelled. Instead of Sigrudsson it should be Sigurdsson. The PDF and HTML versions of the paper have been modified accordingly. The authors would like to apologise for this error and the inconvenience this may have caused.

6.
Mol Psychiatry ; 23(8): 1699-1710, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29743582

RESUMEN

Lysophosphatidic acid (LPA) is a synaptic phospholipid, which regulates cortical excitation/inhibition (E/I) balance and controls sensory information processing in mice and man. Altered synaptic LPA signaling was shown to be associated with psychiatric disorders. Here, we show that the LPA-synthesizing enzyme autotaxin (ATX) is expressed in the astrocytic compartment of excitatory synapses and modulates glutamatergic transmission. In astrocytes, ATX is sorted toward fine astrocytic processes and transported to excitatory but not inhibitory synapses. This ATX sorting, as well as the enzymatic activity of astrocyte-derived ATX are dynamically regulated by neuronal activity via astrocytic glutamate receptors. Pharmacological and genetic ATX inhibition both rescued schizophrenia-related hyperexcitability syndromes caused by altered bioactive lipid signaling in two genetic mouse models for psychiatric disorders. Interestingly, ATX inhibition did not affect naive animals. However, as our data suggested that pharmacological ATX inhibition is a general method to reverse cortical excitability, we applied ATX inhibition in a ketamine model of schizophrenia and rescued thereby the electrophysiological and behavioral schizophrenia-like phenotype. Our data show that astrocytic ATX is a novel modulator of glutamatergic transmission and that targeting ATX might be a versatile strategy for a novel drug therapy to treat cortical hyperexcitability in psychiatric disorders.


Asunto(s)
Fármacos del Sistema Nervioso Central/farmacología , Corteza Cerebral/efectos de los fármacos , Trastornos Mentales/tratamiento farmacológico , Inhibición Neural/efectos de los fármacos , Hidrolasas Diéster Fosfóricas/metabolismo , Sinapsis/efectos de los fármacos , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Células Cultivadas , Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Ácido Glutámico/metabolismo , Humanos , Ketamina , Lisofosfolípidos/farmacología , Trastornos Mentales/fisiopatología , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibición Neural/fisiología , Hidrolasas Diéster Fosfóricas/genética , Proteoglicanos/genética , Proteoglicanos/metabolismo , Psicotrópicos/farmacología , Sinapsis/fisiología , Técnicas de Cultivo de Tejidos , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
7.
Cereb Cortex ; 27(1): 131-145, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-27909001

RESUMEN

Altered synaptic bioactive lipid signaling has been recently shown to augment neuronal excitation in the hippocampus of adult animals by activation of presynaptic LPA2-receptors leading to increased presynaptic glutamate release. Here, we show that this results in higher postsynaptic Ca2+ levels and in premature onset of spontaneous neuronal activity in the developing entorhinal cortex. Interestingly, increased synchronized neuronal activity led to reduced axon growth velocity of entorhinal neurons which project via the perforant path to the hippocampus. This was due to Ca2+-dependent molecular signaling to the axon affecting stabilization of the actin cytoskeleton. The spontaneous activity affected the entire entorhinal cortical network and thus led to reduced overall axon fiber numbers in the mature perforant path that is known to be important for specific memory functions. Our data show that precise regulation of early cortical activity by bioactive lipids is of critical importance for proper circuit formation.


Asunto(s)
Axones/fisiología , Señalización del Calcio/fisiología , Ácido Glutámico/metabolismo , Redes y Vías Metabólicas/fisiología , Proyección Neuronal/fisiología , Fosfolípidos/metabolismo , Transmisión Sináptica/fisiología , Animales , Axones/ultraestructura , Calcio/metabolismo , Células Cultivadas , Ratones
8.
EMBO Mol Med ; 8(1): 25-38, 2016 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-26671989

RESUMEN

Loss of plasticity-related gene 1 (PRG-1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg-1 (R345T/mutPRG-1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss-of-PRG-1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG-1(+/-) mice, which are animal correlates of human PRG-1(+/mut) carriers, showed an altered cortical network function and stress-related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA-synthesizing molecule autotaxin. In line, EEG recordings in a human population-based cohort revealed an E/I balance shift in monoallelic mutPRG-1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress-related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate-dependent symptoms in psychiatric diseases.


Asunto(s)
Lisofosfolípidos/metabolismo , Polimorfismo de Nucleótido Simple , Proteoglicanos/genética , Transducción de Señal/genética , Sinapsis/metabolismo , Proteínas de Transporte Vesicular/genética , Animales , Electroencefalografía , Potenciales Evocados , Glicosilación , Células HEK293 , Humanos , Trastornos Mentales/genética , Trastornos Mentales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Técnicas de Placa-Clamp , Fosfopéptidos/análisis , Hidrolasas Diéster Fosfóricas/química , Hidrolasas Diéster Fosfóricas/metabolismo , Fosforilación , Proteoglicanos/metabolismo , Corteza Somatosensorial/metabolismo , Corteza Somatosensorial/patología , Proteínas de Transporte Vesicular/metabolismo
9.
J Neurosci ; 34(40): 13516-34, 2014 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-25274828

RESUMEN

GABA is the canonical inhibitory neurotransmitter in the CNS. This inhibitory action is largely mediated by GABA type A receptors (GABAARs). Among the many factors controlling GABAergic transmission, brain-derived neurotrophic factor (BDNF) appears to play a major role in regulating synaptic inhibition. Recent findings have demonstrated that BDNF can be released as a precursor (proBDNF). Although the role of mature BDNF on GABAergic synaptogenesis and maintenance has been well studied, an important question still unanswered is whether secreted proBDNF might affect GABAergic neurotransmission. Here, we have used 14 d in vitro primary culture of hippocampal neurons and ex vivo preparations from rats to study the function of proBDNF in regulation of GABAAR trafficking and activity. We demonstrate that proBDNF impairs GABAergic transmission by the activation of two distinct pathways: (1) a RhoA-Rock-PTEN pathway that decreases the phosphorylation levels of GABAAR, thus affecting receptor function and triggering endocytosis and degradation of internalized receptors, and (2) a JAK-STAT-ICER pathway leading to the repression of GABAARs synthesis. These effects lead to the diminution of GABAergic synapses and are correlated with a decrease in GABAergic synaptic currents. These results revealed new functions for proBDNF-p75 neurotrophin receptor signaling pathway in the control of the efficacy of GABAergic synaptic activity by regulating the trafficking and synthesis of GABAARs at inhibitory synapses.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/farmacología , Endocitosis/efectos de los fármacos , Neuronas/efectos de los fármacos , Receptores de GABA/metabolismo , Transmisión Sináptica/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismo , Animales , Animales Recién Nacidos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Endocitosis/fisiología , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/citología , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Quinoxalinas/farmacología , Ratas , Ratas Wistar , Bloqueadores de los Canales de Sodio/farmacología , Transmisión Sináptica/fisiología , Tetrodotoxina/farmacología , Valina/análogos & derivados , Valina/farmacología
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