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Kikuta, K.

Publications and source records attributed to Kikuta, K..

2 recordsLinked to original sources

Synaptic input architecture of visual cortical neurons revealed by large-scale synapse imaging without backpropagating action potentials

How neurons integrate thousands of synaptic inputs to compute sharply tuned outputs is a critical question in sensory information processing. To answer this question, it is essential to record the location and activity of synaptic inputs in vivo. However, back-propagating action potential (BAP) calcium signals invade dendrites and spines, making accurate recording of spine responses difficult. In this study, we first developed a new method to record spine calcium responses without BAP signals. Using this method, we performed large-scale imaging of visually evoked spine activity from layer 2/3 pyramidal neurons and revealed three patterns of dendritic functional architectures of synaptic inputs: dendrites with clusters of spines of similar responses, dendrites with spines of diverse responses, and dendrites with spines where the majority of them show no visual response. Our model suggests that only a small fraction of spines on dendrites of clustered architectures are sufficient to generate sharply tuned output.

neuroscience↗

Discovery and characterization of stereodefined PMO-gapmers targeting tau

Antisense oligonucleotides (ASOs) are an important class of therapeutics to treat genetic diseases, and expansion of this modality to neurodegenerative disorders has been an active area of research. To realize chronic administration of ASO therapeutics to treat neurogenerative diseases, new chemical modifications improving activity and safety profile are still needed. Furthermore, it is highly desirable to develop a single stereopure ASO with defined activity and safety profile to avoid any efficacy and safety concerns due to the batch-to-batch variation in the composition of diastereomers. Herein, a stereopure PMO-gapmer was developed as a new construct to improve safety and stability by installing charge-neutral PMOs at the wing region and by fully controlling phosphorus stereochemistries. The developed stereopure PMO-gapmer construct was applied to the discovery of ASO candidates for the reduction of microtubule-associated protein tau (MAPT, tau). Sequence screening targeting MAPT followed by screening of optimal phosphorus stereochemistry identified stereopure development candidates. While evaluating the stereopure PMO-gapmers, we observed a dramatic difference in safety profile among stereoisomers in which only one phosphorus stereochemistry differs. These results further highlight the benefits of developing stereopure ASOs as safe and well-characterized candidates for clinical studies.

neuroscience↗