Many protocols have been designed to differentiate human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs) into neurons. Despite the relevance of electrophysiological properties for proper neuronal function, little is known about the evolution over time of important neuronal electrophysiological parameters in iPSC-derived neurons. Yet, understanding the development of basic electrophysiological characteristics of iPSC-derived neurons is critical for evaluating their usefulness in basic and translational research. Therefore, we analyzed the basic electrophysiological parameters of forebrain neurons differentiated from human iPSCs, from day 31 to day 55 after the initiation of neuronal differentiation. We assayed the developmental progression of various properties, including resting membrane potential, action potential, sodium and potassium channel currents, somatic calcium transients and synaptic activity. During the maturation of iPSC-derived neurons, the resting membrane potential became more negative, the expression of voltage-gated sodium channels increased, the membrane became capable of generating action potentials following adequate depolarization and, at day 48–55, 50% of the cells were capable of firing action potentials in response to a prolonged depolarizing current step, of which 30% produced multiple action potentials. The percentage of cells exhibiting miniature excitatory post-synaptic currents increased over time with a significant increase in their frequency and amplitude. These changes were associated with an increase of Ca2+ transient frequency. Co-culturing iPSC-derived neurons with mouse glial cells enhanced the development of electrophysiological parameters as compared to pure iPSC-derived neuronal cultures. This study demonstrates the importance of properly evaluating the electrophysiological status of the newly generated neurons when using stem cell technology, as electrophysiological properties of iPSC-derived neurons mature over time.

On the front cover: The cover image, submitted by Mayuri Shukla et al., is from the review article "The role of melatonin in targeting cell signaling pathways in neurodegeneration," https://doi.org/10.1111/nyas.14005.The New York Academy of Sciences believes it has a responsibility to provide an open forum for discussion of scientific questions. The positions

Melatonin is involved in the physiological regulation of the β-amyloid precursor protein (βAPP)-cleaving secretases which are responsible for generation of the neurotoxic amyloid beta (Aβ) peptide, one of the hallmarks of Alzheimer's disease (AD) pathology. In this study, we aimed to determine the underlying mechanisms of this regulation under pathological conditions. We establish that melatonin prevents Aβ -induced downregulation of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) as well as upregulation of β-site APP-cleaving enzyme 1 (BACE1) and presenilin 1 (PS1) in SH-SY5Y cell cultures. We also demonstrate that the intrinsic mechanisms of the observed effects occurred via regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and glycogen synthase kinase (GSK)-3β as melatonin reversed Aβ -induced upregulation and nuclear translocation of NF-κBp65 as well as activation of GSK3β via its receptor activation. Furthermore, specific blocking of the NF-κB and GSK3β pathways partially abrogated the Aβ -induced reduction in the BACE1 and PS1 levels. In addition, GSK3β blockage affected α-secretase cleavage and modulated nuclear translocation of NF-κB. Importantly, our study for the first time shows that peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is a crucial target of melatonin. The compromised levels and/or genetic variation of Pin1 are associated with age-dependent tau and Aβ pathologies and neuronal degeneration. Interestingly, melatonin alleviated the Aβ -induced reduction of nuclear Pin1 levels and preserved the functional integrity of this isomerase. Our findings illustrate that melatonin attenuates Aβ -induced alterations of βAPP-cleaving secretases possibly via the Pin1/GSK3β/NF-κB pathway.