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

Molecular Cause and Functional Impact of Altered Synaptic Lipid Signaling Due to a \u3cem\u3eprg-1\u3c/em\u3e 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

Presynaptically Localized Cyclic GMP-Dependent Protein Kinase 1 Is a Key Determinant of Spinal Synaptic Potentiation and Pain Hypersensitivity

Electrophysiological and behavioral experiments in mice reveal that a cGMP-dependent kinase amplifies neurotransmitter release from peripheral pain sensors, potentiates spinal synapses, and leads to exaggerated pain

Diagnostic Biopsy Does Not Commonly Induce Intratumoral CD8 T Cell Infiltration in Merkel Cell Carcinoma

<div><h3>Background</h3><p>Merkel cell carcinoma is a polyomavirus-associated cancer that is strongly linked with T lymphocyte immune suppression in epidemiologic studies. CD8+ T cell infiltration into MCC tumors (intratumoral) has recently been shown to be strongly predictive of improved survival. In contrast, the presence of CD8+ T cells at the border of the tumor (peritumoral) had no independent prognostic value. Spontaneous regression has been reported for MCC approximately one thousand times more often than would be expected given the frequency of this cancer. Many of these events began shortly after biopsy, and in some cases lymphocytic infiltration was described.</p> <h3>Methodology/Principal Findings</h3><p>To determine whether CD8+ lymphocyte infiltration in MCC tumors is commonly altered by biopsy.33 MCC patients who had microscopic confirmation of MCC on both an initial biopsy and a re-excision specimen were included in this study. Intratumoral and peritumoral CD8 lymphocyte infiltration was quantitated using immunohistochemistry and compared using the paired t-test in biopsy versus re-excision samples. There was a trend toward increased CD8 infiltration after biopsy in a peritumoral (‘stalled’) pattern (p = 0.08), however, biopsy was not associated with a significant increase in CD8 T cells in the clinically more important intratumoral location (p = 0.58).</p> <h3>Conclusions/Significance</h3><p>The initial diagnostic biopsy for MCC does not commonly alter intratumoral CD8+ T cell infiltration, suggesting it does not directly induce immunologic recognition of this cancer. Because CD8 infiltration is typically stable after biopsy, this parameter may be useful to assess the efficacy of future immune therapies for this virus-associated, immunogenic, often-lethal cancer.</p> </div

Peritumoral and intratumoral CD8 lymphocyte infiltration at biopsy and re-excision of a representative MCC tumor.

<p>Top row: Biopsy specimen stained with H/E (a) and á-CD8 (b) from case # w313. Bottom row: Re-excision section stained with H/E (c) and á-CD8 (d) from the same case. Peritumoral and intratumoral CD8 lymphocytic infiltrates were each scored on a 0 to 5 scale as described. These images correspond to peritumoral CD8 score of 3 and intratumoral CD8 score of 0 at biopsy, and peritumoral CD8 score of 4 and intratumoral CD8 score of 1 at re-excision. CD8 scores represent average peri-/intra-tumoral infiltration across many more fields than are visible in the figure. Importantly, CD8 cells that are in contact with stroma are not considered to be intratumoral. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041465#pone.0041465-Paulson1" target="_blank">[28]</a> The black dashed lines in á-CD8 images indicate the tumor/stromal interface (intratumoral: IT, peritumoral: PT). Brown cells indicated by arrows in panel d) are CD8+ cells in a true intra-tumoral location. Scalebar 100 uM. Abbreviations: H/E, hematoxylin and eosin.</p

CD8 cell infiltration of paired biopsy and re-excision specimens.

<p>Each circle represents a pair of specimens from an MCC patient. <b>Fig. 2a</b> shows the extent of peritumoral CD8 infiltration (n = 31), and <b>Fig. 2b</b> represents intratumoral CD8 infiltration (n = 33; two cases had insufficient tissue to evaluate peritumoral infiltration). Cases for which the two specimens were identical in CD8 infiltration are depicted along the diagonal that is not shaded (marked with “no change after Bx”). Cases that had an increase in infiltration after biopsy are in the top left (green shaded) area. Cases with a decrease in infiltration after biopsy are in the lower right (red shaded) area. Abbreviations: Bx, biopsy. There was no statistically significant difference in CD8 infiltration for either location, intratumoral (P-value = 0.08) or peritumoral (P-value = 0.58) via paired-t test.</p

Clinical and tumor characteristics among 33 study subjects.

<p>Stage was determined as per AJCC 2010 criteria.</p