Artificial grammar learning in zebra finches and human adults: XYX versus XXY.

Abstracting syntactic rules is critical to human language learning. It is debated whether this ability, already present in young infants, is human- and language specific or can also be found in non-human animals, indicating it may arise from more general cognitive mechanisms. Current studies are often ambiguous and few have directly compared rule learning by humans and non-human animals. In a series of discrimination experiments, we presented zebra finches and human adults with comparable training and tests with the same artificial stimuli consisting of XYX and XXY structures, in which X and Y were zebra finch song elements. Zebra finches readily discriminated the training stimuli. Some birds also discriminated novel stimuli when these were composed of familiar element types, but none of the birds generalized the discrimination to novel element types. We conclude that zebra finches show evidence of simple rule abstraction related to positional learning, suggesting stimulus-bound generalization, but found no evidence for a more abstract rule generalization. This differed from the human adults, who categorized novel stimuli consisting of novel element types into different groups according to their structure. The limited abilities for rule abstraction in zebra finches may indicate what the precursors of more complex abstraction as found in humans may have been like.

Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome.

Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the MeCP2 gene for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circular RNA (circRNA) and transcribed-ultraconserved region (T-UCR) populations in a mouse model of the disease reveals widespread dysregulation and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of hippocampal samples from affected individuals confirms abnormal levels of several cytoskeleton-related proteins together with key alterations in neurotransmission. Importantly, the glutamate receptor GRIA3 gene displays altered biogenesis in affected individuals and in vitro human cells and is influenced by expression of two ultraconserved RNAs. We also describe post-transcriptional regulation of SIRT2 by circRNAs, which modulates acetylation and total protein levels of GluR-1. As a consequence, both regulatory mechanisms converge on the biogenesis of AMPA receptors, with an effect on neuronal differentiation. In both cases, the noncoding RNAs antagonize MeCP2-directed regulation. Our findings indicate that noncoding transcripts may contribute to key alterations in Rett syndrome and are not only useful tools for revealing dysregulated processes but also molecules of biomarker value.

Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology.

Mesial temporal lobe epilepsy (mTLE) is a chronic disease characterized by recurrent seizures that originate in the temporal lobes of the brain. Anti-epileptic drugs (AEDs) are the standard treatment for managing seizures in mTLE patients, but are frequently ineffective. Resective surgery is an option for some patients, but does not guarantee a postoperative seizure-free period. Therefore, further insight is needed into the pathogenesis of mTLE to enable the design of new therapeutic strategies. Circular RNAs (circRNAs) have been identified as important regulators of neuronal function and have been implicated in epilepsy. However, the mechanisms through which circRNAs contribute to epileptogenesis remain unknown. Here, we determine the circRNA transcriptome of the hippocampus and cortex of mTLE patients by using RNA-seq. We report 333 differentially expressed (DE) circRNAs between healthy individuals and mTLE patients, of which 23 circRNAs displayed significant adjusted p-values following multiple testing correction. Interestingly, hippocampal expression of circ_Satb1, a circRNA derived from special AT-rich sequence binding protein 1 (SATB1), is decreased in both mTLE patients and in experimental epilepsy. Our work shows that circ_Satb1 displays dynamic patterns of neuronal expression in vitro and in vivo. Further, circ_Satb1-specific knockdown using CRISPR/CasRx approaches in hippocampal cultures leads to defects in dendritic spine morphology, a cellular hallmark of mTLE. Overall, our results identify a novel epilepsy-associated circRNA with disease-specific expression and previously unidentified cellular effects that are relevant for epileptogenesis.

Circular RNAs: Novel Regulators of Neuronal Development.

Circular RNAs (circRNAs) are highly stable, circularized long non-coding RNAs. circRNAs are conserved across species and appear to be specifically enriched in the nervous system. Recent studies show that many circRNAs are expressed in a tissue- and developmental-stage-specific manner, reveal a striking regulation of circRNAs during neuronal development, and detect their presence at synaptic sites. The exact functions of circRNAs remain poorly understood, but evidence from analysis of some circRNA molecules suggests that they could substantially contribute to the regulation of gene expression, particularly in architecturally complex and polarized cells such as neurons. Emerging evidence also indicates that circRNAs are involved in the development and progression of various neurological disorders. In this review, we summarize the molecular characteristics of circRNAs and discuss their proposed functions and mechanism-of-action in developing neurons.