Exogenous alpha-Synuclein decreases raft partitioning of Cav2.2 channels inducing dopamine release

alpha-Synuclein is thought to regulate neurotransmitter release through multiple interactions with presynaptic proteins, cytoskeletal elements, ion channels, and synaptic vesicles membrane. alpha-Synuclein is abundant in the presynaptic compartment, and its release from neurons and glia has been described as responsible for spreading of alpha-synuclein-derived pathology. alpha-Synuclein-dependent dysregulation of neurotransmitter release might occur via its action on surface-exposed calcium channels. Here, we provide electrophysiological and biochemical evidence to show that alpha-synuclein, applied to rat neurons in culture or striatal slices, selectively activates Cav2.2 channels, and said activation correlates with increased neurotransmitter release. Furthermore, in vivo perfusion of alpha-synuclein into the striatum also leads to acute dopamine release. We further demonstrate that alpha-synuclein reduces the amount of plasma membrane cholesterol and alters the partitioning of Cav2.2 channels, which move from raft to cholesterol-poor areas of the plasma membrane. We provide evidence for a novel mechanism through which alpha-synuclein acts from the extracellular milieu to modulate neurotransmitter release and propose a unifying hypothesis for the mechanism of alpha-synuclein action on multiple targets: the reorganization of plasma membrane microdomains.

Modulation of event-related desynchronization during kinematic and kinetic hand movements

Background Event-related desynchronization/synchronization (ERD/ERS) is a relative power decrease/increase of electroencephalogram (EEG) in a specific frequency band during physical motor execution and mental motor imagery, thus it is widely used for the brain-computer interface (BCI) purpose. However what the ERD really reflects and its frequency band specific role have not been agreed and are under investigation. Understanding the underlying mechanism which causes a significant ERD would be crucial to improve the reliability of the ERD-based BCI. We systematically investigated the relationship between conditions of actual repetitive hand movements and resulting ERD. Methods Eleven healthy young participants were asked to close/open their right hand repetitively at three different speeds (Hold, 1/3 Hz, and 1 Hz) and four distinct motor loads (0, 2, 10, and 15 kgf). In each condition, participants repeated 20 experimental trials, each of which consisted of rest (8–10 s), preparation (1 s) and task (6 s) periods. Under the Hold condition, participants were instructed to keep clenching their hand (i.e., isometric contraction) during the task period. Throughout the experiment, EEG signals were recorded from left and right motor areas for offline data analysis. We obtained time courses of EEG power spectrum to discuss the modulation of mu and beta-ERD/ERS due to the task conditions. Results We confirmed salient mu-ERD (8–13 Hz) and slightly weak beta-ERD (14–30 Hz) on both hemispheres during repetitive hand grasping movements. According to a 3 × 4 ANOVA (speed × motor load), both mu and beta-ERD during the task period were significantly weakened under the Hold condition, whereas no significant difference in the kinetics levels and interaction effect was observed. Conclusions This study investigates the effect of changes in kinematics and kinetics on resulting ERD during repetitive hand grasping movements. The experimental results suggest that the strength of ERD may reflect the time differentiation of hand postures in motor planning process or the variation of proprioception resulting from hand movements, rather than the motor command generated in the down stream, which recruits a group of motor neurons.

Crosstalk between oestrogen receptors and thyroid hormone receptor isoforms results in differential regulation of the preproenkephalin gene

Nuclear receptors are ligand-activated transcription factors, which have the potential to integrate internal metabolic events in an organism, with consequences for control of behaviour. Previous studies from this laboratory have shown that thyroid hormone receptor (TR) isoforms can inhibit oestrogen receptor (ER)alpha-mediated induction of preproenkephalin (PPE) gene expression in the hypothalamus. Also, thyroid hormone administration inhibits lordosis, a behaviour facilitated by PPE expression. We have examined the effect of multiple ligand-binding TR isoforms on the ER-mediated induction of the PPE gene in transient transfection assays in CV-1 cells. On a natural PPE gene promoter fragment containing two putative oestrogen response elements (EREs), both ER alpha and beta isoforms mediate a four to five-fold induction by oestrogen. Cotransfection of TR alpha 1 along with ER alpha inhibited the ER alpha transactivation of PPE by approximately 50%. However, cotransfection with either TR beta 1 or TR beta 2 expression plasmids produced no effect on the ER alpha or ER beta mediated induction of PPE. Therefore, under these experimental conditions, interactions with a single ER isoform are specific to an individual TR isoform. Transfection with a TR alpha 1 DNA-binding mutant could also inhibit ER alpha transactivation, suggesting that competition for binding on the ERE may not be the exclusive mechanism for inhibition. Data with the coactivator, SRC-1, suggested that coactivator squelching may participate in the inhibition. In dramatic contrast, when ER beta is cotransfected, TR alpha 1 stimulated ER beta-mediated transactivation of PPE by approximately eight-fold over control levels. This is the first study revealing specific interactions among nuclear receptor isoforms on a neuroendocrine promoter. These data also suggest that the combinatorics of ER and TR isoforms allow multiple forms of flexible gene regulations in the service of neuroendocrine integration.