60 research outputs found
Endocannabinoid-mediated long-term depression of excitability and synaptic transmission in the neocortex
No full textNel sistema nervoso centrale, gli endocannabinoidi sono rappresentati principalmente da due lipidi: l’anandamide, l’etanolamide dell’acido arachidonico, e il 2-arachidonilglicerolo (2-AG). E’ accertato che gli endocannabinoidi inibiscono in modo retrogrado il rilascio presinaptico di trasmettitori; è peraltro dimostrato il loro coinvolgimento nel fenomeno inibitorio detto slow self-inhibition (SSI) in interneuroni low-threshold spiking (LTS) della corteccia somatosensoriale. L’SSI è indotta in seguito a treni di potenziali d’azione ripetuti in cellule LTS, che esprimono colecistochinina o somatostatina. La SSI è generata dall’attivazione prolungata di un canale K+ ed è associata ad iperpolarizzazione nella stessa cellula. La sintesi di entrambi i cannabinoidi è dipendente dall’aumento della [Ca2+]i come accade durante una elevata attività neuronale. Per verificare se il 2-AG media la SSI in modo autocrino in cellule LTS, abbiamo bloccato la sua biosintesi a partire dalla fosfolipasi C (PLC) e da diacil-glicerolo lipasi (DAGLs). Queste manipolazioni hanno impedito l’insorgenza della SSI. Inoltre, l’attivazione di PLC mediata da recettori metabotropici del glutammato ha prodotto una prolungata iperpolarizzazione, la quale è stata inibita dall’antagonista del recettore cannabinoide di tipo 1 (CB1R) AM-251, e dagli inibitori di PLC e DAGL. La scomparsa della SSI in presenza di bloccanti intracellulari della DAGL conferma che la produzione di endocannabinoidi avviene nello stesso interneurone che va incontro a persistente iperpolarizzazione. Poiché le DAGLs non producono cannabinoidi se non 2-AG, questi risultati identificano tale composto come il mediatore autocrino responsabile della slow self-inhibition postsinaptica in interneuroni corticali LTS.
Abbiamo inoltre dimostrato che la SSI è espressa anche da una significativa percentuale (~30%) di neuroni piramidali glutamatergici dello strato II/III della neocorteccia. La SSI è asssente in presenza di AM-251 e in topi CB-/-. Allo stesso modo, la somministrazione esogena di cannabinoidi mima la SSI in una percentuale equivalente di neuroni piramidali, provando un’espressione funzionale somatodendritica di CB1R in cellule glutammatergiche. Questa modulazione autoindotta dell’eccitabilità di neuroni piramidali è generata da un’azione autocrina di endocannabinoidi, poiché la SSI è inibita dal blocco intracellulare della loro sintesi.
E’ interessante osservare che i neuroni piramidali che esprimono SSI mostrano un dendrite apicale più lungo e meno ramificato, suggerendo che la SSI può identificare un sottogruppo anatomicamente distinto di neuroni piramidali neocorticali. Risultati preliminari indicano l’esistenza della SSI anche in una frazione di neuroni piramidali dello strato V, e suggeriscono una bidirezionale plasticità a lungo termine della trasmissione sinpatica GABAergica perisomatica in neuroni piramidali corticali dello strato II/III in confronto a quelli dello strato V.
In conclusione, i nostri risultati suggeriscono un’autoregolazione omeostatica di una rete di neuroni glutammatergici all’interno dei circuiti corticali, con possibili implicazioni che sono rilevanti per l’attività della neocorteccia sia in condizioni normali che patologiche.In the central nervous system (CNS), endocannabinoids are identified mainly as two endogenous lipids: anandamide, the ethanolamide of arachidonic acid, and 2-arachidonoylglycerol (2-AG). Endocannabinoids are known to retrogradely inhibit presynaptic transmitter release; however it is demonstrated that they are also involved in slow self-inhibition (SSI) of layer V low-threshold spiking (LTS) interneurons in somatosensory cortex. SSI is induced by repetitive firing in LTS cells, which can express either cholecystokinin or somatostatin. SSI is triggered by an endocannabinoid-dependent activation of a prolonged somatodendritic K+ conductance and associated hyperpolarization in the same cell. The synthesis of both endocannabinoids is dependent on elevated [Ca2+]i such as occurs during sustained neuronal activity. To establish whether 2-AG mediates autocrine LTS-SSI, we blocked its biosynthesis from phospholipase C (PLC) and diacylglycerol lipases (DAGLs), preventing the SSI. Moreover, metabotropic glutamate receptor-dependent activation of PLC produced a long-lasting hyperpolarization which was prevented by the cannabinoid receptor type 1 (CB1R) antagonist AM-251, as well as byPLC and DAGL inhibitors. The loss of SSI in the presence of intracellular DAGL blockers confirms that endocannabinoid production occurs in the same interneuron undergoing the persistent hyperpolarization. Since DAGLs produce no endocannabinoid other than 2-AG, these results identify this compound as the autocrine mediator responsible for the postsynaptic slow self-inhibition of neocortical LTS interneurons.
Moreover, here we show that SSI also occurs in a significant percentage (~30%) of neocortical layer II/III glutamatergic pyramidal neurons. SSI was prevented by AM-251 and in CB1-/- mice. Similarly, exogenously application of cannabinoids mimicked SSI in a corresponding percentage of pyramidal neurons, proving functional somatodendritic CB1R expression in glutamatergic cells. This self-induced endocannabinoid modulation of pyramidal neuron excitability resulted from an autocrine action of endocannabinoids, as SSI was prevented by intracellular blockade of endocannabinoid synthesis. Interestingly, pyramidal neurons exhibiting SSI showed a significant less branched and longer apical dendrite than SSI-negative neurons, suggesting that endocannabinoid-mediated SSI can identify an anatomical subtype of pyramidal neocortical neurons. Preliminary results indicate the existence of SSI also in a fraction of neocortical layer V pyramidal neurons, and suggest a bidirectional long-term plasticity of GABAergic perisomatic inhibition in neocortical layer II/III vs layer V pyramidal neurons.
In conclusion, our results suggest a homeostatic self-regulation of a glutamatergic network within cortical circuits, with important possible implications for normal and pathological operations of the neocortex
On the Tuber magnatum, Tuber albidum and Tuber rufum author name: Picco vs Pico
No full textThis article presents the results of a research that has been conducted on the surname of the author of the three truffle species Tuber magnatum, T. albidum and T. rufum who in the nomenclatural databases of fungi is listed as “Picco” rather than “Pico” (how he is usually indicated). Drawing upon official documents from the Turin State and University Archives the claim is made that the surname Picco is the correct version. This name can also be found in a contemporary review of the book Melethemata Inauguralia (Picco 1788), as well as in a biographic dictionary of Piedmontese physicians dated back to 1825. Therefore, the officially used indication since Stafleu and Cowan (1983) can be considered to be correct
JCB912405 Supplemental Material1 - Supplemental material for Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo
No full textSupplemental material, JCB912405 Supplemental Material1 for Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo by Igor Giarretta, Carmelo L Sturiale, Ilaria Gatto, Simone Pacioni, Eleonora Gaetani, Angelo Porfidia, Alfredo Puca, Ivana Palucci, Paolo Tondi, Alessandro Olivi, Roberto Pallini and Roberto Pola in Journal of Cerebral Blood Flow & Metabolism</p
JCB912405 Supplemental Material3 - Supplemental material for Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo
No full textSupplemental material, JCB912405 Supplemental Material3 for Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo by Igor Giarretta, Carmelo L Sturiale, Ilaria Gatto, Simone Pacioni, Eleonora Gaetani, Angelo Porfidia, Alfredo Puca, Ivana Palucci, Paolo Tondi, Alessandro Olivi, Roberto Pallini and Roberto Pola in Journal of Cerebral Blood Flow & Metabolism</p
JCB912405 Supplemental Material2 - Supplemental material for Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo
No full textSupplemental material, JCB912405 Supplemental Material2 for Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo by Igor Giarretta, Carmelo L Sturiale, Ilaria Gatto, Simone Pacioni, Eleonora Gaetani, Angelo Porfidia, Alfredo Puca, Ivana Palucci, Paolo Tondi, Alessandro Olivi, Roberto Pallini and Roberto Pola in Journal of Cerebral Blood Flow & Metabolism</p
Indagare i quartieri settentrionali di Aquileia: l’insula della Casa delle Bestie ferite
No full textEndothelial trans-differentiation in glioblastoma recurring after radiotherapy
No full textWe hypothesized that in glioblastoma recurring after radiotherapy, a condition whereby the brain endothelium undergoes radiation-induced senescence, tumor cells with endothelial phenotype may be relevant for tumor neovascularization. Matched glioblastoma samples obtained at primary surgery and at surgery for tumor recurrence after radiotherapy, all expressing epidermal growth factor receptor variant III (EGFRvIII), were assessed by a technique that combines fluorescent in situ hybridization (FISH) for the EGFR/CEP7 chromosomal probe with immunostaining for endothelial cells (CD31) and activated pericytes (α Smooth Muscle Actin). Five EGFRvIII-expressing paired primary/recurrent glioblastoma samples, in which the tumor cells showed EGFR/CEP7 amplification, were then assessed by CD31 and α Smooth Muscle Actin immunofluorescence. In glomeruloid bodies, the ratio between CD31+ cells with amplified EGFR/CEP7 signal and the total CD31+ cells was 0.23 ± 0.09 (mean ± sem) and 0.63 ± 0.07 in primary tumors and in recurrent ones, respectively (p < 0.002, Student-t test). In capillaries, the ratio of CD31+ cells with amplified EGFR/CEP7 over the total CD31+ cells lining the capillary lumen was 0.21 ± 0.06 (mean ± sem) and 0.42 ± 0.07 at primary surgery and at recurrence, respectively (p < 0.005, Student-t test). Expression of α Smooth Muscle Actin by cells with EGFR/CEP7 amplification was not observed. Then, in glioblastoma recurring after radiotherapy, where the brain endothelium suffers from radiation-induced cell senescence, tumor-derived endothelium plays a role in neo-vascularization
Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1
No full textBevacizumab, a VEGF-targeting monoclonal antibody, may trigger an infiltrative growth pattern in glioblastoma. We investigated this pattern using both a human specimen and rat models. In the human specimen, a substantial fraction of infiltrating tumor cells were located along perivascular spaces in close relationship with endothelial cells. Brain xenografts of U87MG cells treated with bevacizumab were smaller than controls (p = 0.0055; Student t-test), however, bands of tumor cells spread through the brain farther than controls (p < 0.001; Student t-test). Infiltrating tumor Cells exhibited tropism for vascular structures and propensity to form tubules and niches with endothelial cells. Molecularly, bevacizumab triggered an epithelial to mesenchymal transition with over-expression of the receptor Plexin Domain Containing 1 (PLXDC1). These results were validated using brain xenografts of patient-derived glioma stem-like cells. Enforced expression of PLXDC1 in U87MG cells promoted brain infiltration along perivascular spaces. Importantly, PLXDC1 inhibition prevented perivascular infiltration and significantly increased the survival of bevacizumab-treated rats. Our study indicates that bevacizumab-induced brain infiltration is driven by vascular endothelium and depends on PLXDC1 activation of tumor cells
Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo
No full textAbnormalities in arterial versus venous endothelial cell identity and dysregulation of angiogenesis are deemed important in the pathophysiology of brain arteriovenous malformations (AVMs). The Sonic hedgehog (Shh) pathway is crucial for both angiogenesis and arterial versus venous differentiation of endothelial cells, through its dual role on the vascular endothelial growth factor/Notch signaling and the nuclear orphan receptor COUP-TFII. In this study, we show that Shh, Gli1 (the main transcription factor of the Shh pathway), and COUP-TFII (a target of the non-canonical Shh pathway) are aberrantly expressed in human brain AVMs. We also show that implantation of pellets containing Shh in the cornea of Efnb2/LacZ mice induces growth of distinct arteries and veins, interconnected by complex sets of arteriovenous shunts, without an interposed capillary bed, as seen in AVMs. We also demonstrate that injection in the rat brain of a plasmid containing the human Shh gene induces the growth of tangles of tortuous and dilated vessels, in part positive and in part negative for the arterial marker αSMA, with direct connections between αSMA-positive and -negative vessels. In summary, we show that the Shh pathway is active in human brain AVMs and that Shh-induced angiogenesis has characteristics reminiscent of those seen in AVMs in humans
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