Complexity and graded regulation of neuronal cell-type-specific alternative splicing revealed by single-cell RNA sequencing.

The enormous cellular diversity in the mammalian brain, which is highly prototypical and organized in a hierarchical manner, is dictated by cell-type-specific gene-regulatory programs at the molecular level. Although prevalent in the brain, the contribution of alternative splicing (AS) to the molecular diversity across neuronal cell types is just starting to emerge. Here, we systematically investigated AS regulation across over 100 transcriptomically defined neuronal types of the adult mouse cortex using deep single-cell RNA-sequencing data. We found distinct splicing programs between glutamatergic and GABAergic neurons and between subclasses within each neuronal class. These programs consist of overlapping sets of alternative exons showing differential splicing at multiple hierarchical levels. Using an integrative approach, our analysis suggests that RNA-binding proteins (RBPs) Celf1/2, Mbnl2, and Khdrbs3 are preferentially expressed and more active in glutamatergic neurons, while Elavl2 and Qk are preferentially expressed and more active in GABAergic neurons. Importantly, these and additional RBPs also contribute to differential splicing between neuronal subclasses at multiple hierarchical levels, and some RBPs contribute to splicing dynamics that do not conform to the hierarchical structure defined by the transcriptional profiles. Thus, our results suggest graded regulation of AS across neuronal cell types, which may provide a molecular mechanism to specify neuronal identity and function that are orthogonal to established classifications based on transcriptional regulation.

Brain Translation: A Feather Tips the Scale.

In this issue of Molecular Cell, Gonatopoulos-Pournatzis et al. (2020) report a neuron-specific microexon in eIF4G translation initiation factors that dampens synaptic protein translation. Autism-associated disruption of this exon results in increased protein production, likely through reduced coalescence with cytoplasmic ribonucleoprotein granule components, including FMRP.

Non-canonical Wnt Signaling through Ryk Regulates the Generation of Somatostatin- and Parvalbumin-Expressing Cortical Interneurons.

GABAergic interneurons have many important functions in cortical circuitry, a reflection of their cell diversity. The developmental origins of this diversity are poorly understood. Here, we identify rostral-caudal regionality in Wnt exposure within the interneuron progenitor zone delineating the specification of the two main interneuron subclasses. Caudally situated medial ganglionic eminence (MGE) progenitors receive high levels of Wnt signaling and give rise to somatostatin (SST)-expressing cortical interneurons. By contrast, parvalbumin (PV)-expressing basket cells originate mostly from the rostral MGE, where Wnt signaling is attenuated. Interestingly, rather than canonical signaling through ß-catenin, signaling via the non-canonical Wnt receptor Ryk regulates interneuron cell-fate specification in vivo and in vitro. Indeed, gain of function of Ryk intracellular domain signaling regulates SST and PV fate in a dose-dependent manner, suggesting that Ryk signaling acts in a graded fashion. These data reveal an important role for non-canonical Wnt-Ryk signaling in establishing the correct ratios of cortical interneuron subtypes.

Unique Associations Among Emotion Dysregulation Dimensions and Aggressive Tendencies: A Multisite Study.

Although problems with emotion regulation (ER) have long been associated with internalizing symptoms, only recently has an ER framework been applied to the study of aggression. Therefore, little is known about the unique and independent associations between specific domains of the ER construct and different kinds of aggressive tendencies. We sought to explore these associations in two independent samples of young adults. Furthermore, we tested whether gender moderated the proposed emotion dysregulation-aggression link. Our results corroborated the association between emotion dysregulation and aggression in both samples. Specifically, the inability to control impulsive behavior when upset (i.e., negative urgency) was uniquely related to physical aggression, verbal aggression, anger, and hostility. Limited access to ER strategies was also significantly associated with overall aggression and hostility. The effect of negative urgency on physical and verbal aggression was stronger among males than females, although only in one sample.

Tolerability of the dexamethasone-corticotropin releasing hormone test in major depressive disorder.

BACKGROUND: The dexamethasone-corticotropin releasing hormone (Dex-CRH) test may differentially predict which depressed patients will respond to antidepressant medication. However, a comprehensive analysis of the safety of this test in psychiatric patients has not previously been performed. METHODS: We conducted a pooled analysis of depressed patients in four clinical studies. Observed and subjectively reported side-effects in 454 patients were collected for 90 minutes following CRH administration. Pre-test electrocardiograms were available in 250 patients to assess cardiac safety. Descriptive statistics were performed to evaluate these safety data. RESULTS: Eight-six (18.9%) subjects experienced no side-effects from the procedure. The mean number of side-effects per subject was 1.4±1.0. The most frequent adverse events were: flushing (n=216, 47.6%), feeling of warmth (144, 31.7%), hyperpnea/tachypnea (108, 23.8%), palpitations (37, 8.1%), and tachycardia (28, 6.2%). Side-effects were consistently mild and brief in duration. There were no serious adverse events. CONCLUSION: The Dex-CRH test produces a mild, predictable side-effect profile, characterized by flushing, feelings of warmth, hyperpnea/tachypnea, palpitations, and tachycardia. These results provide reassurance that the Dex-CRH test is well tolerated in psychiatric patients.