Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders.

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.

NECAB2 is an endosomal protein important for striatal function.

Synaptic signaling depends on ATP generated by mitochondria. Dysfunctional mitochondria shift the redox balance towards a more oxidative environment. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction. We found that neuronal calcium-binding protein 2 (NECAB2) plays a role in striatal function and mitochondrial homeostasis. NECAB2 is a predominantly endosomal striatal protein which partially colocalizes with mitochondria. This colocalization is enhanced by mild oxidative stress. Global knockout of Necab2 in the mouse results in increased superoxide levels, increased DNA oxidation and reduced levels of the antioxidant glutathione which correlates with an altered mitochondrial shape and function. Striatal mitochondria from Necab2 knockout mice are more abundant and smaller and characterized by a reduced spare capacity suggestive of intrinsic uncoupling respectively mitochondrial dysfunction. In line with this, we also found an altered stress-induced interaction of endosomes with mitochondria in Necab2 knockout striatal cultures. The predominance of dysfunctional mitochondria and the pro-oxidative redox milieu correlates with a loss of striatal synapses and behavioral changes characteristic of striatal dysfunction like reduced motivation and altered sensory gating. Together this suggests an involvement of NECAB2 in an endosomal pathway of mitochondrial stress response important for striatal function.

AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids.

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.

The K63 deubiquitinase CYLD modulates autism-like behaviors and hippocampal plasticity by regulating autophagy and mTOR signaling.

Nondegradative ubiquitin chains attached to specific targets via Lysine 63 (K63) residues have emerged to play a fundamental role in synaptic function. The K63-specific deubiquitinase CYLD has been widely studied in immune cells and lately also in neurons. To better understand if CYLD plays a role in brain and synapse homeostasis, we analyzed the behavioral profile of CYLD-deficient mice. We found that the loss of CYLD results in major autism-like phenotypes including impaired social communication, increased repetitive behavior, and cognitive dysfunction. Furthermore, the absence of CYLD leads to a reduction in hippocampal network excitability, long-term potentiation, and pyramidal neuron spine numbers. By providing evidence that CYLD can modulate mechanistic target of rapamycin (mTOR) signaling and autophagy at the synapse, we propose that synaptic K63-linked ubiquitination processes could be fundamental in understanding the pathomechanisms underlying autism spectrum disorder.

Correction: Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders.

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.

Ultrasound power and irrigation volume in different lens opacity grades: comparison of femtosecond laser-assisted cataract surgery and conventional phacoemulsification.

OBJECTIVES: To compare the amount of ultrasound energy and irrigation volume in conventional phacoemulsification cataract surgery versus femtosecond laser-assisted phacoemulsification at different nuclear-cortical cataract grades. METHOD: This was a prospective, consecutive, investigator-masked nonrandomized parallel cohort study. Patients were divided into 4 groups (Phaco1, Phaco2, Femto1 and Femto2) according to the surgical technique (conventional phacoemulsification [Group Phaco] or femtosecond laser-assisted cataract surgery [Group Femto]) and the Lens Opacity Classification System III (LOCS) grade (LOCS<11 [group 1] or LOCS≥11 [group 2]). The measured outcomes were effective phacoemulsification time (EPT), indicating the ultrasound energy, and balanced salt solution (BSS) use, indicating the irrigation volume, to indirectly estimate the damage to the corneal endothelium caused by the cataract surgery. RESULTS: A total of 160 eyes from 109 patients were included: 87 eyes in Group Phaco, 73 eyes in Group Femto, 76 eyes in group 1 and 84 eyes in group 2. The EPT mean in Femto1 was 53% less (2.73±1.88, 0.1 to 8.65) than that in Phaco1 (5.80±2.86) (p=0.00) and in Femto2 (8.38±9.32) was 33% less than that in Phaco2 (12.55±8.38) (p=0.00). No significant differences in mean LOCS grades between the Phaco1 (8.21±1.44) and Femto1 (7.90±1.90) groups (p=0.73) or between the Phaco2 (13.15±2.55) and Femto2 (12.72±2.18) groups (p=0.95) were found. There were no significant differences in the mean BSS use between the Phaco1 (55.73±12.45) and Femto1 (59.37±10.93) groups (p=0.48) or between the Phaco2 (64.34±21.00) and Femto2 (65.71±17.60) groups (p=0.47). CONCLUSIONS: Compared to conventional phacoemulsification at different nuclear-cortical cataract grades, femtosecond laser-assisted cataract surgery provides an EPT reduction but does not influence the BSS use.

Ultrasound power and irrigation volume in different lens opacity grades: comparison of femtosecond laser-assisted cataract surgery and conventional phacoemulsification

OBJECTIVES: To compare the amount of ultrasound energy and irrigation volume in conventional phacoemulsification cataract surgery versus femtosecond laser-assisted phacoemulsification at different nuclear-cortical cataract grades. METHOD: This was a prospective, consecutive, investigator-masked nonrandomized parallel cohort study. Patients were divided into 4 groups (Phaco1, Phaco2, Femto1 and Femto2) according to the surgical technique (conventional phacoemulsification [Group Phaco] or femtosecond laser-assisted cataract surgery [Group Femto]) and the Lens Opacity Classification System III (LOCS) grade (LOCS<11 [group 1] or LOCS≥11 [group 2]). The measured outcomes were effective phacoemulsification time (EPT), indicating the ultrasound energy, and balanced salt solution (BSS) use, indicating the irrigation volume, to indirectly estimate the damage to the corneal endothelium caused by the cataract surgery. RESULTS: A total of 160 eyes from 109 patients were included: 87 eyes in Group Phaco, 73 eyes in Group Femto, 76 eyes in group 1 and 84 eyes in group 2. The EPT mean in Femto1 was 53% less (2.73±1.88, 0.1 to 8.65) than that in Phaco1 (5.80±2.86) (p=0.00) and in Femto2 (8.38±9.32) was 33% less than that in Phaco2 (12.55±8.38) (p=0.00). No significant differences in mean LOCS grades between the Phaco1 (8.21±1.44) and Femto1 (7.90±1.90) groups (p=0.73) or between the Phaco2 (13.15±2.55) and Femto2 (12.72±2.18) groups (p=0.95) were found. There were no significant differences in the mean BSS use between the Phaco1 (55.73±12.45) and Femto1 (59.37±10.93) groups (p=0.48) or between the Phaco2 (64.34±21.00) and Femto2 (65.71±17.60) groups (p=0.47). CONCLUSIONS: Compared to conventional phacoemulsification at different nuclear-cortical cataract grades, femtosecond laser-assisted cataract surgery provides an EPT reduction but does not influence the BSS use.

Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders.

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.

Neurovascular EGFL7 regulates adult neurogenesis in the subventricular zone and thereby affects olfactory perception.

Adult neural stem cells reside in a specialized niche in the subventricular zone (SVZ). Throughout life they give rise to adult-born neurons in the olfactory bulb (OB), thus contributing to neural plasticity and pattern discrimination. Here, we show that the neurovascular protein EGFL7 is secreted by endothelial cells and neural stem cells (NSCs) of the SVZ to shape the vascular stem-cell niche. Loss of EGFL7 causes an accumulation of activated NSCs, which display enhanced activity and re-entry into the cell cycle. EGFL7 pushes activated NSCs towards quiescence and neuronal progeny towards differentiation. This is achieved by promoting Dll4-induced Notch signalling at the blood vessel-stem cell interface. Fewer inhibitory neurons form in the OB of EGFL7-knockout mice, which increases the absolute signal conducted from the mitral cell layer of the OB but decreases neuronal network synchronicity. Consequently, EGFL7-knockout mice display severe physiological defects in olfactory behaviour and perception.

PRG-1 Regulates Synaptic Plasticity via Intracellular PP2A/ß1-Integrin Signaling.

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.

Plasticity-Related Gene 1 Affects Mouse Barrel Cortex Function via Strengthening of Glutamatergic Thalamocortical Transmission.

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.

Molecular cause and functional impact of altered synaptic lipid signaling due to a prg-1 gene SNP.

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.

Avaliaçäo da intoxicaçäo profissional por chumbo em industria de acumuladores elétricos na grande Belo Horizonte / Evaluation of occupational lead poisoning in industries of electric accumulations in Great Belo Horizonte

A DRT-MG, atuando como órgäo de prevençäo primária na área de doenças profissionais, realizou, por meio de médicos de trabalho, levantamento em 79 indústrias de reforma ou fabricaçäo de acumuladores elétricos na Grande Belo Horizonte. Ficou evidenciado nesse trabalho a quase total desinformaçäo sobre a intoxicaçäo profissional pelo chumbo e também sobre quaisquer métodos prevencionistas, havendo sido constatados ambientes de trabalho em péssimas condiçöes de higiene industrial e a total ausência de controle médico da saúde do trabalhador exposto ao agente. Foi constatada, através de avaliaçäo clínica e laboratorial, intoxicaçäo profissional por chumbo em 51,9% dos empregados avaliados, deixando patente a urgente necessidade de modificaçöes para controle ambiental e de uma conscientizaçäo efetiva dos indivíduos envolvidos nessa atividade

Avaliaçäo da intoxicaçäo profissional por chumbo em indústrias de acumuladores elétricos na grande Belo Horizonte

A DRT-MG, atuando como órgäo de prevençäo primária na área de doenças profissionais, realizou, através de médicos do trabalho, levantamento em 79 indústrias de reforma ou fabricaçäo de acumuladores elétricos na Grande Belo Horizonte. Ficou evidenciado nesse trabalho a quase total desinformaçäo sobre a intoxicaçäo profissional pelo chumbo e também sobre quaisquer métodos prevencionistas, havendo sido constatados ambientes de trabalho em péssimas condiçöes de higiene industrial e a total ausência de controle médico da saúde do trabalhador exposto ao agente. Foi constatada, através de avaliaçäo clínica e laboratorial, a intoxicaçäo profissional pelo chumbo em 51,9% dos empregados avaliados, deixando patente a urgente necessidade de modificaçöes para controle ambiental e de uma conscientizaçäo efetiva dos indivíduos envolvidos nessa atividade