CREB Signaling Is Involved in Rett Syndrome Pathogenesis.

Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the MECP2 gene. To facilitate the study of cellular mechanisms in human cells, we established several human stem cell lines: human embryonic stem cell (hESC) line carrying the common T158M mutation (MECP2T158M/T158M ), hESC line expressing no MECP2 (MECP2-KO), congenic pair of wild-type and mutant RTT patient-specific induced pluripotent stem cell (iPSC) line carrying the V247fs mutation (V247fs-WT and V247fs-MT), and iPSC line in which the V247fs mutation was corrected by CRISPR/Cas9-based genome editing (V247fs-MT-correction). Detailed analyses of forebrain neurons differentiated from these human stem cell lines revealed genotype-dependent quantitative phenotypes in neurite growth, dendritic complexity, and mitochondrial function. At the molecular level, we found a significant reduction in the level of CREB and phosphorylated CREB in forebrain neurons differentiated from MECP2T158M/T158M , MECP2-KO, and V247fs-MT stem cell lines. Importantly, overexpression of CREB or pharmacological activation of CREB signaling in those forebrain neurons rescued the phenotypes in neurite growth, dendritic complexity, and mitochondrial function. Finally, pharmacological activation of CREB in the female Mecp2 heterozygous mice rescued several behavioral defects. Together, our study establishes a robust in vitro platform for consistent quantitative evaluation of genotype-dependent RTT phenotypes, reveals a previously unappreciated role of CREB signaling in RTT pathogenesis, and identifies a potential therapeutic target for RTT.SIGNIFICANCE STATEMENT Our study establishes a robust human stem cell-based platform for consistent quantitative evaluation of genotype-dependent Rett syndrome (RTT) phenotypes at the cellular level. By providing the first evidence that enhancing cAMP response element binding protein signaling can alleviate RTT phenotypes both in vitro and in vivo, we reveal a previously unappreciated role of cAMP response element binding protein signaling in RTT pathogenesis, and identify a potential therapeutic target for RTT.

Inhibition of Lateral Prefrontal Cortex Produces Emotionally Biased First Impressions: A Transcranial Magnetic Stimulation and Electroencephalography Study.

Optimal functioning in everyday life requires the ability to override reflexive emotional responses and prevent affective spillover to situations or people unrelated to the source of emotion. In the current study, we investigated whether the lateral prefrontal cortex (lPFC) causally regulates the influence of emotional information on subsequent judgments. We disrupted left lPFC function using transcranial magnetic stimulation (TMS) and recorded electroencephalography (EEG) before and after. Subjects evaluated the likeability of novel neutral faces after a brief exposure to a happy or fearful face. We found that lPFC inhibition biased evaluations of novel faces according to the previously processed emotional expression. Greater frontal EEG alpha power, reflecting increased inhibition by TMS, predicted increased behavioral bias. TMS-induced affective misattribution was long-lasting: Emotionally biased first impressions formed during lPFC inhibition were still detectable outside of the laboratory 3 days later. These findings indicate that lPFC serves an important emotion-regulation function by preventing incidental emotional encoding from automatically biasing subsequent appraisals.