Mitochondrial complex I activity in microglia sustains neuroinflammation.

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3.

Bilateral intracortical inhibition during unilateral motor preparation and sequence learning.

Motor sequence learning gradually quickens reaction time, suggesting that sequence learning alters motor preparation processes. Interestingly, evidence has shown that preparing sequence movements decreases short intracortical inhibition (SICI) in the contralateral motor cortex (M1), but also that sequence learning alters motor preparation processes in both the contralateral and ipsilateral M1s. Therefore, one possibility is that sequence learning alters the SICI decreases occurring during motor preparation in bilateral M1s. To examine this, two novel hypotheses were tested: unilateral sequence preparation would decrease SICI in bilateral M1s, and sequence learning would alter such bilateral SICI responses. Paired-pulse transcranial magnetic stimulation was delivered over the contralateral and ipsilateral M1s to assess SICI in an index finger muscle during the preparation of sequences initiated by either the right index or little finger. In the absence of sequence learning, SICI decreased in both the contralateral and ipsilateral M1s during the preparation of sequences initiated by the right index finger, suggesting that SICI decreases in bilateral M1s during unilateral motor preparation. As sequence learning progressed, SICI decreased in the contralateral M1 whilst it increased in the ipsilateral M1. Moreover, these bilateral SICI responses were observed at the onset of motor preparation, suggesting that sequence learning altered baseline SICI levels rather than the SICI decreases occurring during motor preparation per se. Altogether, these results suggest that SICI responses in bilateral M1s reflect two motor processes: an acute decrease of inhibition during motor preparation, and a cooperative but bidirectional shift of baseline inhibition levels as sequence learning progresses.

Mitochondrial reverse electron transport in myeloid cells perpetuates neuroinflammation.

Sustained smouldering, or low grade, activation of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis (MS) 1 . Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells 2 . However, how these metabolic features act to perpetuate neuroinflammation is currently unknown. Using a multiomics approach, we identified a new molecular signature that perpetuates the activation of myeloid cells through mitochondrial complex II (CII) and I (CI) activity driving reverse electron transport (RET) and the production of reactive oxygen species (ROS). Blocking RET in pro-inflammatory myeloid cells protected the central nervous system (CNS) against neurotoxic damage and improved functional outcomes in animal disease models in vivo . Our data show that RET in myeloid cells is a potential new therapeutic target to foster neuroprotection in smouldering inflammatory CNS disorders 3 .

Actualización sobre receptores dopaminérgicos centrales / Current concepts of central dopaminergic receptors

El presente trabajo tiene como objetivo revisar los avances en el estudio de la dopamina, como neurotransmisor a nivel del sistema nervioso central y su posible relación funcional con diversos desórdenes, en especial las esquizofrenias. Se revisan los conocimientos del sistema dopaminérgico central, en lo que respecta a anatomía de las vías dopaminérgicas y a la bioquímica de la transmisión, desde su síntesis hasta su inactivación enzimática. Se analisan los diversos métodos y estudios, tanto in vivo como in vitro, que se emplean para reconocer los diversos tipos de receptores dopaminérgicos centrales. Así, desde que se reconoce un adenil ciclasa sensible a dopamina, se obtienen 2 tipos de receptores dopaminérgicos, el D-1 que aumenta el AMPc y el D-2, que no están asociados a la enzima. Posteriormente, usando técnicas de radioligandos, se logra reconocer a 3 subtipos de receptores dopaminérgicos con localización y características bien definidas. Un mayor estudio de la dopamina y en especial de los receptores dopaminérgicos centrales, permitirá comprender las bases neurofisiológicas y farmacológicas de algunos desórdenes tales com las esquizofrenias, la enfermedad de Parkinson, el corea de Huntington, entre otras, permitiendo el desarrollo de medicamentos más selectivos y con mayor acción