Serotonin drives a novel GABAergic synaptic current recorded in rat cerebellar purkinje cells: a lugaro cell to purkinje cell synapse

We recorded a novel fast GABAergic synaptic current in cerebellar Purkinje cells in rat brain slices using patch-clamp techniques. Because of a relatively low sensitivity to bicuculline, these currents can be recorded under conditions in which basket and stellate cell inputs are blocked. The observations that the novel synaptic currents occur spontaneously only in the presence of serotonin, and the specific limited positions in the slice from which they can be electrically evoked, suggest that the presynaptic cell is the Lugaro cell. Cell-attached recordings confirm that the Lugaro cell is the only interneuron in the cerebellar cortex with firing behavior consistent with the spontaneous activity recorded in Purkinje cells. The input shows a strong presynaptic modulation mediated by GABAA receptors, resulting in a dynamic range from almost 0 to >90% release probability. Modeling GABAA receptor responses to different GABA transients suggests that the relatively low sensitivity of the synaptic currents to bicuculline, compared with the higher affinity GABAA receptor antagonist SR-95531 (2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl) pyridazinium), is attributable to an unusually long GABA dwell time and/or high GABA concentration in the synaptic cleft. The significance of this novel input is discussed in relation to other GABAergic synapses impinging on Purkinje cells. We suggest that the release of GABA onto Purkinje cells from Lugaro cells would primarily occur during motor activity under conditions in which the activity of basket and stellate cells might be inhibited

Serotonin drives a novel GABAergic synaptic current recorded in rat cerebellar purkinje cells: a lugaro cell to Purkinje cell synapse

We recorded a novel fast GABAergic synaptic current in cerebellar Purkinje cells in rat brain slices using patch-clamp techniques. Because of a relatively low sensitivity to bicuculline, these currents can be recorded under conditions in which basket and stellate cell inputs are blocked. The observations that the novel synaptic currents occur spontaneously only in the presence of serotonin, and the specific limited positions in the slice from which they can be electrically evoked, suggest that the presynaptic cell is the Lugaro cell. Cell-attached recordings confirm that the Lugaro cell is the only interneuron in the cerebellar cortex with firing behavior consistent with the spontaneous activity recorded in Purkinje cells. The input shows a strong presynaptic modulation mediated by GABAA receptors, resulting in a dynamic range from almost 0 to >90% release probability. Modeling GABAA receptor responses to different GABA transients suggests that the relatively low sensitivity of the synaptic currents to bicuculline, compared with the higher affinity GABAA receptor antagonist SR-95531 (2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl) pyridazinium), is attributable to an unusually long GABA dwell time and/or high GABA concentration in the synaptic cleft. The significance of this novel input is discussed in relation to other GABAergic synapses impinging on Purkinje cells. We suggest that the release of GABA onto Purkinje cells from Lugaro cells would primarily occur during motor activity under conditions in which the activity of basket and stellate cells might be inhibited

Smoothness of the truncated display functor

We show that to every p-divisible group over a p-adic ring one can associate a display by crystalline Dieudonne theory. For an appropriate notion of truncated displays, this induces a functor from truncated Barsotti-Tate groups to truncated displays, which is a smooth morphism of smooth algebraic stacks. As an application we obtain a new proof of the equivalence between infinitesimal p-divisible groups and nilpotent displays over p-adic rings, and a new proof of the equivalence due to Berthelot and Gabber between commutative finite flat group schemes of p-power order and Dieudonne modules over perfect rings.Comment: 38 page

Primary Biliary Cirrhosis Associated with Systemic Sclerosis: Diagnostic and Clinical Challenges

Patients with primary biliary cirrhosis (PBC) often have concurrent limited systemic sclerosis (SSc). Conversely, up to one-fourth of SSc patients are positive for PBC-specific antimitochondrial antibodies (AMA). The mechanisms responsible for the co-occurrence of these diseases are largely unknown. Genetic, epigenetic, environmental, and infectious factors appear to be important for the pathogenesis of the disease, but the hierarchy of events are not well defined. Patients with SSc and PBC have an increased morbidity and mortality compared with the general population, but whether the presence of both diseases in an affected individual worsens the prognosis and/or outcome of either disease is not clear. Some case reports suggested that the presence of SSc in PBC patents is associated with a more favorable prognosis of the liver disease, whereas others report an increased mortality in patients with PBC and SSc compared to patients with PBC alone. This paper discusses the features of patients with PBC-associated SSc. Our aims are to clarify some of the pathogenetic, diagnostic, and clinical challenges that are currently faced in the routine management of these patients. We also intend to provide some practical hints for practitioners that will assist in the early identification of patients with PBC-associated SSc

Is shoulder involvement in clinically suspect arthralgia an early feature of rheumatoid arthritis? A longitudinal ultrasound study

Pathophysiology and treatment of rheumatic disease

Mammalian Target of Rapamycin: Is It Relevant to COPD Pathogenesis or Treatment?

The mammalian target of rapamycin (mTOR) signalling pathway regulates fundamental metabolic processes such as inflammation, autophagy and apoptosis, all of which influence cell fate. Recent experimental data suggest that mTOR signalling is involved in many diseases, including lung diseases, but with contrasting data. Overexpression of mTOR and its signalling proteins have been linked to lung cell senescence and development of emphysema, pulmonary hypertension and inflammation. On the other hand, mTOR inhibitors, as rapamycin and/or its derivatives, restore corticosteroid sensitivity in peripheral blood mononuclear cells from chronic obstructive pulmonary disease (COPD) patients, and overexpression of mTOR suppresses cigarette smoke-induced inflammation and emphysema, suggesting that induction of mTOR expression/activity might be useful to treat COPD. This apparent discrepancy is due to complex and heterogenic enzymatic pathway of mTOR. Translation of pre-clinical positive data on the use of mTOR inhibitors to COPD therapy needs a more in-depth knowledge of mTOR signalling