The amount of regulatory RNA encoded in the genome and the extent of RNA editing by the post-transcriptional deamination of adenosine to inosine (A-I) have increased with developmental complexity and may be an important factor in the cognitive evolution of animals. The newest member of the A-I editing family of ADAR proteins, the vertebrate-specific ADAR3, is highly expressed in the brain, but its functional significance is unknown. In vitro studies have suggested that ADAR3 acts as a negative regulator of A-I RNA editing but the scope and underlying mechanisms are also unknown. Meta-analysis of published data indicates that mouse Adar3 expression is highest in the hippocampus, thalamus, amygdala and olfactory region. Consistent with this, we show that mice lacking exon 3 of Adar3 (which encodes two double stranded RNA binding domains) have increased levels of anxiety and deficits in hippocampus-dependent short- and long-term memory formation. RNA sequencing revealed a dysregulation of genes involved in synaptic function in the hippocampi of Adar3-deficient mice. We also show that ADAR3 transiently translocates from the cytoplasm to the nucleus upon KCl-mediated activation in SH-SY5Y cells. These results indicate that ADAR3 contributes to cognitive processes in mammals.

Amyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-β peptide (Aβ) component of pathognomonic extracellular plaques of AD. Additional early cortical changes in AD include neuroinflammation and elevated iron levels. Activation of the innate immune system in the brain is a neuroprotective response to infection; however, persistent neuroinflammation is linked to AD neuropathology by uncertain mechanisms. Non-parametric machine learning analysis on transcriptomic data from a large neuropathologically characterised patient cohort revealed the acute phase protein lactoferrin (Lf) as the key predictor of amyloid pathology. In vitro studies showed that an interaction between APP and the iron-bound form of Lf secreted from activated microglia diverted neuronal APP endocytosis from the canonical clathrin-dependent pathway to one requiring ADP ribosylation factor 6 trafficking. By rerouting APP recycling to the Rab11-positive compartment for amyloidogenic processing, Lf dramatically increased neuronal Aβ production. Lf emerges as a novel pharmacological target for AD that not only modulates APP processing but provides a link between Aβ production, neuroinflammation and iron dysregulation.

Genetic studies have implicated numerous risk variants for schizophrenia.^1-7 One of the next challenges is to further understand the biological mechanisms of the large number and diversity of genes that are associated with schizophrenia. To do that, we need to generate functional data capturing molecular pathways that are relevant to schizophrenia and examine the involvement of multiple candidate genes. Such strategy holds the potential to advance our understanding of the underlying molecular basis of schizophrenia and a way to develop novel treatments.