L-DOPA-Induced Dyskinesia and Abnormal Signaling in Striatal Medium Spiny Neurons: Focus on Dopamine D1 Receptor-Mediated Transmission

Dyskinesia is a serious motor complication caused by prolonged administration of l-DOPA to patients affected by Parkinson’s disease. Accumulating evidence indicates that l-DOPA-induced dyskinesia (LID) is primarily caused by the development of sensitized dopamine D1 receptor (D1R) transmission in the medium spiny neurons (MSNs) of the striatum. This phenomenon, combined with chronic administration of l-DOPA, leads to persistent and intermittent hyper-activation of the cAMP signaling cascade. Activation of cAMP signaling results in increased activity of the cAMP-dependent protein kinase (PKA) and of the dopamine- and cAMP-dependent phosphoprotein of 32 kDa (DARPP-32), which regulate several downstream effector targets implicated in the control of the excitability of striatal MSNs. Dyskinesia is also accompanied by augmented activity of the extracellular signal-regulated kinases (ERK) and the mammalian target of rapamycin complex 1 (mTORC1), which are involved in the control of transcriptional and translational efficiency. Pharmacological or genetic interventions aimed at reducing abnormal signal transduction at the level of these various intracellular cascades have been shown to attenuate LID in different animal models. For instance, LID is reduced in mice deficient for DARPP-32, or following inhibition of PKA. Blockade of ERK obtained genetically or using specific inhibitors is also able to attenuate dyskinetic behavior in rodents and non-human primates. Finally, administration of rapamycin, a drug which blocks mTORC1, results in a strong reduction of LID. This review focuses on the abnormalities in signaling affecting the D1R-expressing MSNs and on their potential relevance for the design of novel anti-dyskinetic therapies

Dall'esperimento alla realtà. La macchina borghese alla prova di un tempo di crisi. Il silenzio della ragione

La prima metà del Novecento tra tanti e noti tragici eventi ci ha lasciato anche testimonianze di disagio. Attraverso le voci di S. Zweig, K. Jaspers e H. Fallada in questo saggio si cerca di mettere a fuoco la contraddizione tra il processo di normalizzazione della vita umana e la condizione di sofferenza degli individui. Una sorta di rovesciamento del rapporto tra normale e patologico in cui viene alla luce il peso ideologico e performativo del significato di benessere e salute della vita umana. La crisi rimette in gioco la necessità di un esercizio critico verso un "presente" che vuole assolutizzarsi a prezzo della perdita della dinamica "forma umana della vita".From Experiment to reality. Bourgeoisie in times of crisis. The silence of reason.Among many famous and tragic events, the first half of the XX century has left us many accounts of malaise. This essay focuses on the contradiction between the normalization of human life and the suffering of individuals, as highlighted by the writings of S. Zweig, K. Jaspers, and H. Fallada. This is a reversal of the order of normal and pathological, which emphasizes the meaning, ideological or otherwise, of wellbeing and health. This crisis urges for an exercise of critical thinking towards a present of absolutism that threatens the dynamism of human life form

Deciphering the Actions of Antiparkinsonian and Antipsychotic Drugs on cAMP/DARPP-32 Signaling

The basal ganglia are affected by several neuropsychiatric and neurodegenerative diseases, many of which are treated with drugs acting on the dopamine system. For instance, the loss of dopaminergic input to the striatum, which is the main pathological feature of Parkinson’s disease, is counteracted by administering the dopamine precursor, L-DOPA. Furthermore, psychotic disorders, including schizophrenia, are treated with drugs that act as antagonists at the D2-type of dopamine receptor (D2R). The use of L-DOPA and typical antipsychotic drugs, such as haloperidol, is limited by the emergence of motor side-effects, particularly after prolonged use. Striatal medium spiny neurons (MSNs) represent an ideal tool to investigate the molecular changes implicated in these conditions. MSNs receive a large glutamatergic innervation from cortex, thalamus, and limbic structures, and are controlled by dopaminergic projections originating in the midbrain. There are two large populations of striatal MSNs, which differ based on their connectivity to the output nuclei of the basal ganglia and on their ability to express dopamine D1 receptors (D1Rs) or D2Rs. Administration of L-DOPA promotes cAMP signaling and activates the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) in the D1R-expressing MSNs, which form the striatonigral, or direct pathway. Conversely, haloperidol activates the cAMP/DARPP-32 cascade in D2R-expressing MSNs, which form the striatopallidal, or indirect pathway. This review describes the effects produced on downstream effector proteins by stimulation of cAMP/DARPP-32 signaling in these two groups of MSNs. Particular emphasis is given to the regulation of the GluR1 subunit of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor, the extracellular signal-regulated protein kinases 1 and 2, focusing on functional role and potential pathological relevance

Capacità e possibilità. Una riflessione sulle implicazioni della libertà individuale tra diritti e norme

Abstract not availabl

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio