TY - JOUR AB - SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility. Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in humans with intellectual disability and autism spectrum disorder. AU - Deliu, Elena AU - Arecco, Niccoló AU - Morandell, Jasmin AU - Dotter, Christoph AU - Contreras, Ximena AU - Girardot, Charles AU - Käsper, Eva AU - Kozlova, Alena AU - Kishi, Kasumi AU - Chiaradia, Ilaria AU - Noh, Kyung AU - Novarino, Gaia ID - 3 IS - 12 JF - Nature Neuroscience TI - Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition VL - 21 ER - TY - JOUR AB - The pituitary adenylyl cyclase-activating polypeptide (PACAP) and its G protein-coupled receptors, PAC1, VPAC1 and VPAC2 form a system involved in a variety of biological processes. Although some sympathetic stimulatory effects of this system have been reported, its central cardiovascular regulatory properties are poorly characterized. VPAC1 receptors are expressed in the nucleus ambiguus (nAmb), a key center controlling cardiac parasympathetic tone. In this study, we report that selective VPAC1 activation in rhodamine-labeled cardiac vagal preganglionic neurons of the rat nAmb produces inositol 1,4,5-trisphosphate receptor-mediated Ca2+ mobilization, membrane depolarization and activation of P/Q-type Ca2+ channels. In vivo, this pathway converges onto transient reduction in heart rate of conscious rats. Therefore we demonstrate a VPAC1-dependent mechanism in the central parasympathetic regulation of the heart rate, adding to the complexity of PACAP-mediated cardiovascular modulation. AU - Gherghina, Florin L AU - Tica, Andrei A AU - Elena Deliu AU - Abood, Mary E AU - Brailoiu, G. Christina AU - Brǎiloiu, Eugen ID - 529 JF - Brain Research TI - Effects of VPAC1 activation in nucleus ambiguus neurons VL - 1657 ER - TY - CHAP AB - As autism spectrum disorder (ASD) is largely regarded as a neurodevelopmental condition, long-time consensus was that its hallmark features are irreversible. However, several studies from recent years using defined mouse models of ASD have provided clear evidence that in mice neurobiological and behavioural alterations can be ameliorated or even reversed by genetic restoration or pharmacological treatment either before or after symptom onset. Here, we review findings on genetic and pharmacological reversibility of phenotypes in mouse models of ASD. Our review should give a comprehensive overview on both aspects and encourage future studies to better understand the underlying molecular mechanisms that might be translatable from animals to humans. AU - Schroeder, Jan AU - Deliu, Elena AU - Novarino, Gaia AU - Schmeisser, Michael ED - Schmeisser, Michael ED - Boekers, Tobias ID - 634 T2 - Translational Anatomy and Cell Biology of Autism Spectrum Disorder TI - Genetic and pharmacological reversibility of phenotypes in mouse models of autism spectrum disorder VL - 224 ER - TY - JOUR AB - Background HIV-1 infection and drug abuse are frequently co-morbid and their association greatly increases the severity of HIV-1-induced neuropathology. While nucleus accumbens (NAcc) function is severely perturbed by drugs of abuse, little is known about how HIV-1 infection affects NAcc. Methods We used calcium and voltage imaging to investigate the effect of HIV-1 trans-activator of transcription (Tat) on rat NAcc. Based on previous neuronal studies, we hypothesized that Tat modulates intracellular Ca2+ homeostasis of NAcc neurons. Results We provide evidence that Tat triggers a Ca2+ signaling cascade in NAcc medium spiny neurons (MSN) expressing D1-like dopamine receptors leading to neuronal depolarization. Firstly, Tat induced inositol 1,4,5-trisphsophate (IP3) receptor-mediated Ca2+ release from endoplasmic reticulum, followed by Ca2+ and Na+ influx via transient receptor potential canonical channels. The influx of cations depolarizes the membrane promoting additional Ca2+ entry through voltage-gated P/Q-type Ca2+ channels and opening of tetrodotoxin-sensitive Na+ channels. By activating this mechanism, Tat elicits a feed-forward depolarization increasing the excitability of D1-phosphatidylinositol-linked NAcc MSN. We previously found that cocaine targets NAcc neurons directly (independent of the inhibition of dopamine transporter) only when IP3-generating mechanisms are concomitantly initiated. When tested here, cocaine produced a dose-dependent potentiation of the effect of Tat on cytosolic Ca2+. Conclusion We describe for the first time a HIV-1 Tat-triggered Ca2+ signaling in MSN of NAcc involving TRPC and depolarization and a potentiation of the effect of Tat by cocaine, which may be relevant for the reward axis in cocaine-abusing HIV-1-positive patients. AU - Brailoiu, Gabriela AU - Deliu, Elena AU - Barr, Jeffrey AU - Console Bram, Linda AU - Ciuciu, Alexandra AU - Abood, Mary AU - Unterwald, Ellen AU - Brǎiloiu, Eugen ID - 714 JF - Drug and Alcohol Dependence SN - 03768716 TI - HIV Tat excites D1 receptor-like expressing neurons from rat nucleus accumbens VL - 178 ER - TY - JOUR AB - Bradykinin (BK), a component of the kallikrein-kininogen-kinin system exerts multiple effects via B1 and B2 receptor activation. In the cardiovascular system, bradykinin has cardioprotective and vasodilator properties. We investigated the effect of BK on cardiac-projecting neurons of nucleus ambiguus, a key site for the parasympathetic cardiac regulation. BK produced a dose-dependent increase in cytosolic Ca2+ concentration. Pretreatment with HOE140, a B2 receptor antagonist, but not with R715, a B1 receptor antagonist, abolished the response to BK. A selective B2 receptor agonist, but not a B1 receptor agonist, elicited an increase in cytosolic Ca2+ similarly to BK. Inhibition of N-type voltage-gated Ca2+ channels with ω-conotoxin GVIA had no effect on the Ca2+ signal produced by BK, while pretreatment with ω-conotoxin MVIIC, a blocker of P/Q-type of Ca2+ channels, significantly diminished the effect of BK. Pretreatment with xestospongin C and 2-aminoethoxydiphenyl borate, antagonists of inositol 1,4,5-trisphosphate receptors, abolished the response to BK. Inhibition of ryanodine receptors reduced the BK-induced Ca2+ increase, while disruption of lysosomal Ca2+ stores with bafilomycin A1 did not affect the response. BK produced a dose-dependent depolarization of nucleus ambiguus neurons, which was prevented by the B2 receptor antagonist. In vivo studies indicate that microinjection of BK into nucleus ambiguus elicited bradycardia in conscious rats via B2 receptors. In summary, in cardiac vagal neurons of nucleus ambiguus, BK activates B2 receptors promoting Ca2+ influx and Ca2+ release from endoplasmic reticulum, and membrane depolarization; these effects are translated in vivo by bradycardia. AU - Brǎiloiu, Eugen AU - Mcguire, Matthew AU - Shuler, Shadaria AU - Deliu, Elena AU - Barr, Jeffrey AU - Abood, Mary AU - Brailoiu, Gabriela ID - 747 JF - Neuroscience SN - 03064522 TI - Modulation of cardiac vagal tone by bradykinin acting on nucleus ambiguus VL - 365 ER - TY - JOUR AB - Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function. AU - Tarlungeanu, Dora-Clara AU - Deliu, Elena AU - Dotter, Christoph AU - Kara, Majdi AU - Janiesch, Philipp AU - Scalise, Mariafrancesca AU - Galluccio, Michele AU - Tesulov, Mateja AU - Morelli, Emanuela AU - Sönmez, Fatma AU - Bilgüvar, Kaya AU - Ohgaki, Ryuichi AU - Kanai, Yoshikatsu AU - Johansen, Anide AU - Esharif, Seham AU - Ben Omran, Tawfeg AU - Topcu, Meral AU - Schlessinger, Avner AU - Indiveri, Cesare AU - Duncan, Kent AU - Caglayan, Ahmet AU - Günel, Murat AU - Gleeson, Joseph AU - Novarino, Gaia ID - 1183 IS - 6 JF - Cell TI - Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder VL - 167 ER -