Astrocytic α4-containing nAChR signaling in the hippocampus governs the formation of temporal association memory.

Everyday episodic memories involve linking together related events that are temporally separated. However, the mechanisms of forming this temporal association have remained unclear. Here, using astrocyte-specific manipulations, we show that potentiating astrocyte Ca2+ signaling in the hippocampal cornu ammonis 1 (CA1) enhances the strength of such temporal association, in parallel with long-term potentiation (LTP) enhancement of temporoammonic pathway to CA1, whereas attenuation of astrocyte Ca2+ signaling has the opposite effect. Moreover, we identify that these effects are mediated by astrocytic α4 subunit-containing nicotinic acetylcholine receptors (α4-nAChRs) via mechanisms involving NMDAR co-agonist supply. Finally, astrocytic α4-nAChRs underlie the cognitive enhancer nicotine's physiological effects. Together, these findings highlight the importance of astrocyte Ca2+ signaling in cognitive behavior and reveal a mechanism in governing the temporal association of episodic memory formation that operates through α4-nAChRs on hippocampal astrocytes.

Computer-Aided Directed Evolution Generates Novel AAV Variants with High Transduction Efficiency.

Adeno-associated viruses (AAVs) have become safe and effective tools for therapeutic in vivo gene drug delivery. Among many AAV serotypes, AAV2 is the most well-characterized. Although many studies have been carried out on the engineering of the capsid VR-VIII region, few attempts have been made in the VR-IV region. Here, we targeted amino acid positions 442-469 of the VR-IV region and established an engineering paradigm of computer-aided directed evolution, based on training samples from previous datasets, to obtain a viral vector library with high diversity (~95,089). We further examined two variants selected from the library. The transduction efficiency of these two novel AAV variants, AAV2.A1 and AAV2.A2, in the central nervous system was 10-15 times higher than that of AAV2. This finding provides new vehicles for delivering gene drugs to the brain.