Midbrain dopaminergic inputs gate amygdala intercalated cell clusters by distinct and cooperative mechanisms in male mice

Dopaminergic signaling plays an important role in associative learning, including fear and extinction learning. Dopaminergic midbrain neurons encode prediction error-like signals when threats differ from expectations. Within the amygdala, GABAergic intercalated cell (ITC) clusters receive one of the densest dopaminergic projections, but their physiological consequences are incompletely understood. ITCs are important for fear extinction, a function thought to be supported by activation of ventromedial ITCs that inhibit central amygdala fear output. In mice, we reveal two distinct novel mechanisms by which mesencephalic dopaminergic afferents control ITCs. Firstly, they co-release GABA to mediate rapid, direct inhibition. Secondly, dopamine suppresses inhibitory interactions between distinct ITC clusters via presynaptic D1 receptors. Early extinction training augments both GABA co-release onto dorsomedial ITCs and dopamine-mediated suppression of dorso-to ventromedial inhibition between ITC clusters. These findings provide novel insights into dopaminergic mechanisms shaping the activity balance between distinct ITC clusters that could support their opposing roles in fear behavior

The CompactLight Design Study

CompactLight is a Design Study funded by the European Union under the Horizon 2020 researchand innovation funding programme, with Grant Agreement No. 777431. CompactLight was conducted byan International Collaboration of 23 international laboratories and academic institutions, three privatecompanies, and five third parties. The project, which started in January 2018 with a duration of 48months, aimed to design an innovative, compact, and cost-effective hard X-ray FEL facility complementedby a soft X-ray source to pave the road for future compact accelerator-based facilities. The result is anaccelerator that can be operated at up to 1 kHz pulse repetition rate, beyond today’s state of the art, usingthe latest concepts for high brightness electron photoinjectors, very high gradient accelerating structuresin X-band, and novel short-period undulators. In this report, we summarize the main deliverable of theproject: the CompactLight Conceptual Design Report, which overviews the current status of the designand addresses the main technological challenges

A coding-independent function of an alternative Ube3a transcript during neuronal development

The E3 ubiquitin ligase Ube3a is an important regulator of activity-dependent synapse development and plasticity. Ube3a mutations cause Angelman syndrome and have been associated with autism spectrum disorders (ASD). However, the biological significance of alternative Ube3a transcripts generated in mammalian neurons remains unknown. We report here that Ube3a1 RNA, a transcript that encodes a truncated Ube3a protein lacking catalytic activity, prevents exuberant dendrite growth and promotes spine maturation in rat hippocampal neurons. Surprisingly, Ube3a1 RNA function was independent of its coding sequence but instead required a unique 3' untranslated region and an intact microRNA pathway. Ube3a1 RNA knockdown increased activity of the plasticity-regulating miR-134, suggesting that Ube3a1 RNA acts as a dendritic competing endogenous RNA. Accordingly, the dendrite-growth-promoting effect of Ube3a1 RNA knockdown in vivo is abolished in mice lacking miR-134. Taken together, our results define a noncoding function of an alternative Ube3a transcript in dendritic protein synthesis, with potential implications for Angelman syndrome and ASD

MiRNA-135a regulates the expression of small conductance calcium-activated potassium (SK3) channels in epilepsy-like conditions

Background Excessive and hypersynchronous neuronal discharges are key characteristics in the pathophysiology of neurological disorders such as epilepsy. Owing to their ability of regulating neuronal excitability, small conductance calcium-activated potassium (SK) channels have been implicated in several diseases of the brain, and their activation provided neuroprotection in different paradigms of cell death, including oxidative stress and excitotoxicity. Objectives In our study, we investigated the function and regulation of SK channel expression in different models of epilepsy and excessive neuronal firing. Methods As a model for hypersynchronous neuronal firing in vitro, we used primary cortical neurons either challenged with glutamate or deprived of magnesium to increase neuronal firing. In addition, we used perforant pathway stimulation (PPS) to induce hippocampal seizures in vivo. We investigated neuronal firing using multielectrode array recordings, analyze SK channel expression by Western blot, and assess mitochondrial performance by evaluating mitochondrial complex activity. MicroRNA135a-dependent effects on SK3 channels were investigated using a dual-luciferase assay. Results and Conclusions In vitro, analysis of neuronal firing in magnesium deprived primary neuronal cultures revealed that SK channel activation fully blocked the increase in neuronal activity, and restored homeostatic signaling. We found reduced SK3 channel expression following glutamate-induced excitotoxicity in vitro, and following PPS in the rat hippocampus in vivo. Further, PPS in vivo impaired the performance of mitochondrial complex I. Interestingly, we identified miRNA-135a as a key regulator of SK3 channel expression in primary neurons. Thus, we provide strong evidence that SK3 channels are involved in epilepsy(-like) conditions which are characterized by enhanced neuronal firing and an impairment of mitochondrial function, and the miRNA135a-dependent regulation of SK3 channel expression was unraveled as a new regulatory mechanism

A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses

Synaptic downscaling is a homeostatic mechanism that allows neurons to reduce firing rates during chronically elevated network activity. Although synaptic downscaling is important in neural circuit development and epilepsy, the underlying mechanisms are poorly described. We performed small RNA profiling in picrotoxin (PTX)-treated hippocampal neurons, a model of synaptic downscaling. Thereby, we identified eight microRNAs (miRNAs) that were increased in response to PTX, including miR-129-5p, whose inhibition blocked synaptic downscaling in vitro and reduced epileptic seizure severity in vivo. Using transcriptome, proteome, and bioinformatic analysis, we identified the calcium pump Atp2b4 and doublecortin (Dcx) as miR-129-5p targets. Restoring Atp2b4 and Dcx expression was sufficient to prevent synaptic downscaling in PTX-treated neurons. Furthermore, we characterized a functional crosstalk between miR-129-5p and the RNA-binding protein (RBP) Rbfox1. In the absence of PTX, Rbfox1 promoted the expression of Atp2b4 and Dcx. Upon PTX treatment, Rbfox1 expression was downregulated by miR-129-5p, thereby allowing the repression of Atp2b4 and Dcx. We therefore identified a novel activitydependent miRNA/RBP crosstalk during synaptic scaling, with potential implications for neural network homeostasis and epileptogenesis