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Lysophosphatidic acids (LPAs) evoke nociception and itch in mice and humans. In this study, we assessed the signaling paths. Hydroxychloroquine was injected intradermally to evoke itch in mice, which evoked an increase of LPAs in the skin and in the thalamus, suggesting that peripheral and central LPA receptors (LPARs) were involved in HCQ-evoked pruriception. To unravel the signaling paths, we assessed the localization of candidate genes and itching behavior in knockout models addressing LPAR5, LPAR2, autotaxin/ENPP2 and the lysophospholipid phosphatases, as well as the plasticity-related genes Prg1/LPPR4 and Prg2/LPPR3. LacZ reporter studies and RNAscope revealed LPAR5 in neurons of the dorsal root ganglia (DRGs) and in skin keratinocytes, LPAR2 in cortical and thalamic neurons, and Prg1 in neuronal structures of the dorsal horn, thalamus and SSC. HCQ-evoked scratching behavior was reduced in sensory neuron-specific Advillin-LPAR5-/- mice (peripheral) but increased in LPAR2-/- and Prg1-/- mice (central), and it was not affected by deficiency of glial autotaxin (GFAP-ENPP2-/-) or Prg2 (PRG2-/-). Heat and mechanical nociception were not affected by any of the genotypes. The behavior suggested that HCQ-mediated itch involves the activation of peripheral LPAR5, which was supported by reduced itch upon treatment with an LPAR5 antagonist and autotaxin inhibitor. Further, HCQ-evoked calcium fluxes were reduced in primary sensory neurons of Advillin-LPAR5-/- mice. The results suggest that LPA-mediated itch is primarily mediated via peripheral LPAR5, suggesting that a topical LPAR5 blocker might suppress "non-histaminergic" itch.
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Hidroxicloroquina , Ratones Noqueados , Prurito , Receptores del Ácido Lisofosfatídico , Animales , Receptores del Ácido Lisofosfatídico/metabolismo , Receptores del Ácido Lisofosfatídico/genética , Prurito/inducido químicamente , Prurito/metabolismo , Prurito/genética , Prurito/tratamiento farmacológico , Ratones , Hidroxicloroquina/farmacología , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Masculino , Hidrolasas Diéster Fosfóricas/metabolismo , Hidrolasas Diéster Fosfóricas/genética , Lisofosfolípidos/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacosRESUMEN
Decoding human speech requires the brain to segment the incoming acoustic signal into meaningful linguistic units, ranging from syllables and words to phrases. Integrating these linguistic constituents into a coherent percept sets the root of compositional meaning and hence understanding. One important cue for segmentation in natural speech is prosodic cues, such as pauses, but their interplay with higher-level linguistic processing is still unknown. Here, we dissociate the neural tracking of prosodic pauses from the segmentation of multi-word chunks using magnetoencephalography (MEG). We find that manipulating the regularity of pauses disrupts slow speech-brain tracking bilaterally in auditory areas (below 2 Hz) and in turn increases left-lateralized coherence of higher-frequency auditory activity at speech onsets (around 25-45 Hz). Critically, we also find that multi-word chunks-defined as short, coherent bundles of inter-word dependencies-are processed through the rhythmic fluctuations of low-frequency activity (below 2 Hz) bilaterally and independently of prosodic cues. Importantly, low-frequency alignment at chunk onsets increases the accuracy of an encoding model in bilateral auditory and frontal areas while controlling for the effect of acoustics. Our findings provide novel insights into the neural basis of speech perception, demonstrating that both acoustic features (prosodic cues) and abstract linguistic processing at the multi-word timescale are underpinned independently by low-frequency electrophysiological brain activity in the delta frequency range.
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Comprensión , Magnetoencefalografía , Percepción del Habla , Humanos , Percepción del Habla/fisiología , Comprensión/fisiología , Masculino , Femenino , Adulto , Adulto Joven , Habla/fisiología , Ritmo Delta/fisiología , Encéfalo/fisiología , LingüísticaRESUMEN
Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1R345T/WT). Prg-1R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders.
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Importance: Biological psychiatry aims to understand mental disorders in terms of altered neurobiological pathways. However, for one of the most prevalent and disabling mental disorders, major depressive disorder (MDD), no informative biomarkers have been identified. Objective: To evaluate whether machine learning (ML) can identify a multivariate biomarker for MDD. Design, Setting, and Participants: This study used data from the Marburg-Münster Affective Disorders Cohort Study, a case-control clinical neuroimaging study. Patients with acute or lifetime MDD and healthy controls aged 18 to 65 years were recruited from primary care and the general population in Münster and Marburg, Germany, from September 11, 2014, to September 26, 2018. The Münster Neuroimaging Cohort (MNC) was used as an independent partial replication sample. Data were analyzed from April 2022 to June 2023. Exposure: Patients with MDD and healthy controls. Main Outcome and Measure: Diagnostic classification accuracy was quantified on an individual level using an extensive ML-based multivariate approach across a comprehensive range of neuroimaging modalities, including structural and functional magnetic resonance imaging and diffusion tensor imaging as well as a polygenic risk score for depression. Results: Of 1801 included participants, 1162 (64.5%) were female, and the mean (SD) age was 36.1 (13.1) years. There were a total of 856 patients with MDD (47.5%) and 945 healthy controls (52.5%). The MNC replication sample included 1198 individuals (362 with MDD [30.1%] and 836 healthy controls [69.9%]). Training and testing a total of 4 million ML models, mean (SD) accuracies for diagnostic classification ranged between 48.1% (3.6%) and 62.0% (4.8%). Integrating neuroimaging modalities and stratifying individuals based on age, sex, treatment, or remission status does not enhance model performance. Findings were replicated within study sites and also observed in structural magnetic resonance imaging within MNC. Under simulated conditions of perfect reliability, performance did not significantly improve. Analyzing model errors suggests that symptom severity could be a potential focus for identifying MDD subgroups. Conclusion and Relevance: Despite the improved predictive capability of multivariate compared with univariate neuroimaging markers, no informative individual-level MDD biomarker-even under extensive ML optimization in a large sample of diagnosed patients-could be identified.
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Trastorno Depresivo Mayor , Humanos , Femenino , Masculino , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/patología , Imagen de Difusión Tensora , Estudios de Cohortes , Reproducibilidad de los Resultados , Imagen por Resonancia Magnética , BiomarcadoresRESUMEN
Up to 70% of patients with major depressive disorder present with psychomotor disturbance (PmD), but at the present time understanding of its pathophysiology is limited. In this study, we capitalized on a large sample of patients to examine the neural correlates of PmD in depression. This study included 820 healthy participants and 699 patients with remitted (n = 402) or current (n = 297) depression. Patients were further categorized as having psychomotor retardation, agitation, or no PmD. We compared resting-state functional connectivity (ROI-to-ROI) between nodes of the cerebral motor network between the groups, including primary motor cortex, supplementary motor area, sensory cortex, superior parietal lobe, caudate, putamen, pallidum, thalamus, and cerebellum. Additionally, we examined network topology of the motor network using graph theory. Among the currently depressed 55% had PmD (15% agitation, 29% retardation, and 11% concurrent agitation and retardation), while 16% of the remitted patients had PmD (8% retardation and 8% agitation). When compared with controls, currently depressed patients with PmD showed higher thalamo-cortical and pallido-cortical connectivity, but no network topology alterations. Currently depressed patients with retardation only had higher thalamo-cortical connectivity, while those with agitation had predominant higher pallido-cortical connectivity. Currently depressed patients without PmD showed higher thalamo-cortical, pallido-cortical, and cortico-cortical connectivity, as well as altered network topology compared to healthy controls. Remitted patients with PmD showed no differences in single connections but altered network topology, while remitted patients without PmD did not differ from healthy controls in any measure. We found evidence for compensatory increased cortico-cortical resting-state functional connectivity that may prevent psychomotor disturbance in current depression, but may perturb network topology. Agitation and retardation show specific connectivity signatures. Motor network topology is slightly altered in remitted patients arguing for persistent changes in depression. These alterations in functional connectivity may be addressed with non-invasive brain stimulation.
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The Phospholipid Phosphatase Related 4 gene (PLPPR4, *607813) encodes the Plasticity-Related-Gene-1 (PRG-1) protein. This cerebral synaptic transmembrane-protein modulates cortical excitatory transmission on glutamatergic neurons. In mice, homozygous Prg-1 deficiency causes juvenile epilepsy. Its epileptogenic potential in humans was unknown. Thus, we screened 18 patients with infantile epileptic spasms syndrome (IESS) and 98 patients with benign familial neonatal/infantile seizures (BFNS/BFIS) for the presence of PLPPR4 variants. A girl with IESS had inherited a PLPPR4-mutation (c.896C > G, NM_014839; p.T299S) from her father and an SCN1A-mutation from her mother (c.1622A > G, NM_006920; p.N541S). The PLPPR4-mutation was located in the third extracellular lysophosphatidic acid-interacting domain and in-utero electroporation (IUE) of the Prg-1p.T300S construct into neurons of Prg-1 knockout embryos demonstrated its inability to rescue the electrophysiological knockout phenotype. Electrophysiology on the recombinant SCN1Ap.N541S channel revealed partial loss-of-function. Another PLPPR4 variant (c.1034C > G, NM_014839; p.R345T) that was shown to result in a loss-of-function aggravated a BFNS/BFIS phenotype and also failed to suppress glutamatergic neurotransmission after IUE. The aggravating effect of Plppr4-haploinsufficiency on epileptogenesis was further verified using the kainate-model of epilepsy: double heterozygous Plppr4-/+|Scn1awt|p.R1648H mice exhibited higher seizure susceptibility than either wild-type, Plppr4-/+, or Scn1awt|p.R1648H littermates. Our study shows that a heterozygous PLPPR4 loss-of-function mutation may have a modifying effect on BFNS/BFIS and on SCN1A-related epilepsy in mice and humans.
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Epilepsia , Convulsiones , Animales , Femenino , Humanos , Ratones , Epilepsia/metabolismo , Hipocampo/metabolismo , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Fenotipo , Convulsiones/genética , Convulsiones/metabolismoRESUMEN
When we attentively listen to an individual's speech, our brain activity dynamically aligns to the incoming acoustic input at multiple timescales. Although this systematic alignment between ongoing brain activity and speech in auditory brain areas is well established, the acoustic events that drive this phase-locking are not fully understood. Here, we use magnetoencephalographic recordings of 24 human participants (12 females) while they were listening to a 1 h story. We show that whereas speech-brain coupling is associated with sustained acoustic fluctuations in the speech envelope in the theta-frequency range (4-7 Hz), speech tracking in the low-frequency delta (below 1 Hz) was strongest around onsets of speech, like the beginning of a sentence. Crucially, delta tracking in bilateral auditory areas was not sustained after onsets, proposing a delta tracking during continuous speech perception that is driven by speech onsets. We conclude that both onsets and sustained components of speech contribute differentially to speech tracking in delta- and theta-frequency bands, orchestrating sampling of continuous speech. Thus, our results suggest a temporal dissociation of acoustically driven oscillatory activity in auditory areas during speech tracking, providing valuable implications for orchestration of speech tracking at multiple time scales.
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Corteza Auditiva , Percepción del Habla , Femenino , Humanos , Habla , Estimulación Acústica/métodos , Magnetoencefalografía/métodos , Percepción AuditivaRESUMEN
The systematic alignment of low-frequency brain oscillations with the acoustic speech envelope signal is well established and has been proposed to be crucial for actively perceiving speech. Previous studies investigating speech-brain coupling in source space are restricted to univariate pairwise approaches between brain and speech signals, and therefore speech tracking information in frequency-specific communication channels might be lacking. To address this, we propose a novel multivariate framework for estimating speech-brain coupling where neural variability from source-derived activity is taken into account along with the rate of envelope's amplitude change (derivative). We applied it in magnetoencephalographic (MEG) recordings while human participants (male and female) listened to one hour of continuous naturalistic speech, showing that a multivariate approach outperforms the corresponding univariate method in low- and high frequencies across frontal, motor, and temporal areas. Systematic comparisons revealed that the gain in low frequencies (0.6 - 0.8 Hz) was related to the envelope's rate of change whereas in higher frequencies (from 0.8 to 10 Hz) it was mostly related to the increased neural variability from source-derived cortical areas. Furthermore, following a non-negative matrix factorization approach we found distinct speech-brain components across time and cortical space related to speech processing. We confirm that speech envelope tracking operates mainly in two timescales (δ and θ frequency bands) and we extend those findings showing shorter coupling delays in auditory-related components and longer delays in higher-association frontal and motor components, indicating temporal differences of speech tracking and providing implications for hierarchical stimulus-driven speech processing.
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Corteza Auditiva , Percepción del Habla , Estimulación Acústica , Femenino , Humanos , Magnetoencefalografía , Masculino , Análisis Multivariante , HablaRESUMEN
Phospholipid levels are influenced by peripheral metabolism. Within the central nervous system, synaptic phospholipids regulate glutamatergic transmission and cortical excitability. Whether changes in peripheral metabolism affect brain lipid levels and cortical excitability remains unknown. Here, we show that levels of lysophosphatidic acid (LPA) species in the blood and cerebrospinal fluid are elevated after overnight fasting and lead to higher cortical excitability. LPA-related cortical excitability increases fasting-induced hyperphagia, and is decreased following inhibition of LPA synthesis. Mice expressing a human mutation (Prg-1R346T) leading to higher synaptic lipid-mediated cortical excitability display increased fasting-induced hyperphagia. Accordingly, human subjects with this mutation have higher body mass index and prevalence of type 2 diabetes. We further show that the effects of LPA following fasting are under the control of hypothalamic agouti-related peptide (AgRP) neurons. Depletion of AgRP-expressing cells in adult mice decreases fasting-induced elevation of circulating LPAs, as well as cortical excitability, while blunting hyperphagia. These findings reveal a direct influence of circulating LPAs under the control of hypothalamic AgRP neurons on cortical excitability, unmasking an alternative non-neuronal route by which the hypothalamus can exert a robust impact on the cortex and thereby affect food intake.
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Diabetes Mellitus Tipo 2 , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Conducta Alimentaria/fisiología , Humanos , Hiperfagia/metabolismo , Lisofosfolípidos/metabolismo , Lisofosfolípidos/farmacología , Ratones , Neuronas/metabolismo , Sinapsis/metabolismoRESUMEN
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.
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Excitabilidad Cortical , Accidente Cerebrovascular , Animales , Lisofosfolípidos/farmacología , Ratones , Ratones Transgénicos , Hidrolasas Diéster Fosfóricas , Receptores del Ácido Lisofosfatídico , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2-/- mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2-/- mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2-/- mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2-/- mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2-/- were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2-/- phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions.
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Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Neuronas/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Envejecimiento , Animales , Encéfalo/metabolismo , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/genética , Cromatografía Líquida de Alta Presión , Giro Dentado/metabolismo , Análisis Discriminante , Familia de Proteínas EGF/deficiencia , Familia de Proteínas EGF/genética , Femenino , Hígado/metabolismo , Potenciación a Largo Plazo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Componente Principal , Receptores del Ácido Lisofosfatídico/antagonistas & inhibidores , Receptores del Ácido Lisofosfatídico/deficiencia , Receptores del Ácido Lisofosfatídico/genética , Espectrometría de Masas en TándemRESUMEN
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.
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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/metabolismoRESUMEN
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.
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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.
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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/metabolismoRESUMEN
Ongoing axonal degeneration is thought to underlie disability in chronic neuroinflammation, such as multiple sclerosis (MS), especially during its progressive phase. Upon inflammatory attack, axons undergo pathological swelling, which can be reversible. Because we had evidence for beneficial effects of T helper 2 lymphocytes in experimental neurotrauma and discovered interleukin-4 receptor (IL-4R) expressed on axons in MS lesions, we aimed at unraveling the effects of IL-4 on neuroinflammatory axon injury. We demonstrate that intrathecal IL-4 treatment during the chronic phase of several experimental autoimmune encephalomyelitis models reversed disease progression without affecting inflammation. Amelioration of disability was abrogated upon neuronal deletion of IL-4R. We discovered direct neuronal signaling via the IRS1-PI3K-PKC pathway underlying cytoskeletal remodeling and axonal repair. Nasal IL-4 application, suitable for clinical translation, was equally effective in improving clinical outcome. Targeting neuronal IL-4 signaling may offer new therapeutic strategies to halt disability progression in MS and possibly also neurodegenerative conditions.
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Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/metabolismo , Receptores de Interleucina-4/metabolismo , Administración Intranasal , Animales , Axones/efectos de los fármacos , Axones/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-4/administración & dosificación , Interleucina-4/uso terapéutico , Locomoción/efectos de los fármacos , Masculino , Ratones , Esclerosis Múltiple , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
Plasticity related gene 1 (PRG-1) is a neuron specific membrane protein located at the postsynaptic density of glutamatergic synapses. PRG-1 modulates signaling pathways of phosphorylated lipid substrates such as lysophosphatidic acid (LPA). Deletion of PRG-1 increases presynaptic glutamate release probability leading to neuronal over-excitation. However, due to its cortical expression, PRG-1 deficiency leading to increased glutamatergic transmission is supposed to also affect motor pathways. We therefore analyzed the effects of PRG-1 function on exploratory and motor behavior using homozygous PRG-1 knockout (PRG-1-/-) mice and PRG-1/LPA2-receptor double knockout (PRG-1-/-/LPA2-/-) mice in two open field settings of different size and assessing motor behavior in the Rota Rod test. PRG-1-/- mice displayed significantly longer path lengths and higher running speed in both open field conditions. In addition, PRG-1-/- mice spent significantly longer time in the larger open field and displayed rearing and self-grooming behavior. Furthermore PRG-1-/- mice displayed stereotypical behavior resembling phenotypes of psychiatric disorders in the smaller sized open field arena. Altogether, this behavior is similar to the stereotypical behavior observed in animal models for psychiatric disease of autistic spectrum disorders which reflects a disrupted balance between glutamatergic and GABAergic synapses. These differences indicate an altered excitation/inhibition balance in neuronal circuits in PRG-1-/- mice as recently shown in the somatosensory cortex [38]. In contrast, PRG-1-/-/LPA2-/- did not show significant changes in behavior in the open field suggesting that these specific alterations were abolished when the LPA2-receptor was lacking. Our findings indicate that PRG-1 deficiency led to over-excitability caused by an altered LPA/LPA2-R signaling inducing a behavioral phenotype typically observed in animal models for psychiatric disorders.
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Proteínas de Unión a Calmodulina/deficiencia , Conducta Exploratoria/fisiología , Hipercinesia/metabolismo , Lisofosfolípidos/metabolismo , Trastornos Mentales/metabolismo , Proteínas del Tejido Nervioso/deficiencia , Receptores del Ácido Lisofosfatídico/metabolismo , Sinapsis/metabolismo , Animales , Proteínas de Unión a Calmodulina/genética , Proteínas de Unión a Calmodulina/metabolismo , Femenino , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , Hipercinesia/genética , Hipercinesia/fisiopatología , Hipercinesia/psicología , Trastornos Mentales/genética , Trastornos Mentales/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/patología , Neuronas/fisiología , Receptores del Ácido Lisofosfatídico/genética , Transducción de Señal , Corteza Somatosensorial/metabolismo , Sinapsis/genéticaRESUMEN
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.
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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 , RatonesRESUMEN
Precise connection of thalamic barreloids with their corresponding cortical barrels is critical for processing of vibrissal sensory information. Here, we show that PRG-2, a phospholipid-interacting molecule, is important for thalamocortical axon guidance. Developing thalamocortical fibers both in PRG-2 full knockout (KO) and in thalamus-specific KO mice prematurely entered the cortical plate, eventually innervating non-corresponding barrels. This misrouting relied on lost axonal sensitivity toward lysophosphatidic acid (LPA), which failed to repel PRG-2-deficient thalamocortical fibers. PRG-2 electroporation in the PRG-2-/- thalamus restored the aberrant cortical innervation. We identified radixin as a PRG-2 interaction partner and showed that radixin accumulation in growth cones and its LPA-dependent phosphorylation depend on its binding to specific regions within the C-terminal region of PRG-2. In vivo recordings and whisker-specific behavioral tests demonstrated sensory discrimination deficits in PRG-2-/- animals. Our data show that bioactive phospholipids and PRG-2 are critical for guiding thalamic axons to their proper cortical targets.
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Orientación del Axón/fisiología , Corteza Cerebral/crecimiento & desarrollo , Proteínas del Citoesqueleto/fisiología , Lisofosfolípidos/fisiología , Proteínas de la Membrana/fisiología , Transducción de Señal/fisiología , Tálamo/crecimiento & desarrollo , Animales , Corteza Cerebral/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Discriminación en Psicología/fisiología , Conos de Crecimiento/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiología , Fosforilación , Tálamo/metabolismoRESUMEN
Alterations in dendritic spine numbers are linked to deficits in learning and memory. While we previously revealed that postsynaptic plasticity-related gene 1 (PRG-1) controls lysophosphatidic acid (LPA) signaling at glutamatergic synapses via presynaptic LPA receptors, we now show that PRG-1 also affects spine density and synaptic plasticity in a cell-autonomous fashion via protein phosphatase 2A (PP2A)/ß1-integrin activation. PRG-1 deficiency reduces spine numbers and ß1-integrin activation, alters long-term potentiation (LTP), and impairs spatial memory. The intracellular PRG-1 C terminus interacts in an LPA-dependent fashion with PP2A, thus modulating its phosphatase activity at the postsynaptic density. This results in recruitment of adhesome components src, paxillin, and talin to lipid rafts and ultimately in activation of ß1-integrins. Consistent with these findings, activation of PP2A with FTY720 rescues defects in spine density and LTP of PRG-1-deficient animals. These results disclose a mechanism by which bioactive lipid signaling via PRG-1 could affect synaptic plasticity and memory formation.
Asunto(s)
Espinas Dendríticas/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Integrina beta1/metabolismo , Lisofosfolípidos/metabolismo , Plasticidad Neuronal/fisiología , Proteína Fosfatasa 2/metabolismo , Sinapsis/fisiología , Animales , Células Cultivadas , Espinas Dendríticas/genética , Adhesiones Focales/fisiología , Factores de Intercambio de Guanina Nucleótido/genética , Hipocampo/citología , Hipocampo/metabolismo , Integrina beta1/genética , Potenciación a Largo Plazo , Microdominios de Membrana/metabolismo , Ratones , Ratones Noqueados , Proteína Fosfatasa 2/genética , Factores de Intercambio de Guanina Nucleótido Rho , Transducción de SeñalRESUMEN
Plasticity-related gene-1 (PRG-1) is a brain-specific protein that modulates glutamatergic synaptic transmission. Here we investigated the functional role of PRG-1 in adolescent and adult mouse barrel cortex both in vitro and in vivo. Compared with wild-type (WT) animals, PRG-1-deficient (KO) mice showed specific behavioral deficits in tests assessing sensorimotor integration and whisker-based sensory discrimination as shown in the beam balance/walking test and sandpaper tactile discrimination test, respectively. At P25-31, spontaneous network activity in the barrel cortex in vivo was higher in KO mice compared with WT littermates, but not at P16-19. At P16-19, sensory evoked cortical responses in vivo elicited by single whisker stimulation were comparable in KO and WT mice. In contrast, at P25-31 evoked responses were smaller in amplitude and longer in duration in WT animals, whereas KO mice revealed no such developmental changes. In thalamocortical slices from KO mice, spontaneous activity was increased already at P16-19, and glutamatergic thalamocortical inputs to Layer 4 spiny stellate neurons were potentiated. We conclude that genetic ablation of PRG-1 modulates already at P16-19 spontaneous and evoked excitability of the barrel cortex, including enhancement of thalamocortical glutamatergic inputs to Layer 4, which distorts sensory processing in adulthood.