Abstract Details

Title Human iPSC-derived Neurogenin-2 (NGN2) Cortical Neurons Develop Functional Connectivity and Small-world Network Topology In Vitro

Topic Child Neurology and Developmental Neurology

Presentation(s) P6 - Poster Session 6 (11:45 AM-12:45 PM)

Poster/Presentation
Number 6-017

Objective To investigate the development of functional connectivity in human induced pluripotent stem cell (iPSC)-derived neurogenin-2 (NGN2) cortical neurons and small-world network topology in vitro on microelectrode array (MEA) systems.

Background MEA recordings from human iPSC-derived neurons show disease-related phenotypes including differences in firing and burst rates.

Design/Methods To reveal microscale network activity, we investigated age-related differences in the functional connectivity and network topology. We cultured human NGN2 iPSC-derived neurons with human astrocytes on 64-electrode MEAs (n=15 cultures). We performed 10-minute recordings weekly from days-in-vitro (DIV) 14-35 and analysis with MEA-NAP (https://github.com/SAND-Lab/MEA-NAP/). We applied one-way ANOVA and the Tukey-Kramer method to adjust for multiple pairwise comparisons.

Results NGN2 cortical cultures showed a significant increase in the number of active electrodes (p=3e-7), mean firing rate (p=7e-6), and mean network burst rate (p=0.01) from DIV14-35. Significant functional connections were determined using the spike time tiling coefficient and probabilistic thresholding. Network features were compared from cultures at DIV14-35. The functional connectivity significantly increased from DIV14-35 including the network density (p=0.001) and top 10% of edge weights (p=3e-5). The number of modules significantly decreased (p=0.01) while the mean participation coefficient significantly increased (p=0.01) indicating a shift in activity from within subcommunities to network-wide. At DIV35, the mean small-worldness coefficient approached zero, indicating small-world topology, compared to more randomly connected networks at DIV14-28 (p=3e-4).

Conclusions MEA recordings revealed that NGN2 neurons develop patterns of functional connectivity and network topology also seen at larger spatial scales in the brain and, thus, could inform mechanistic and therapeutic studies of neuronal development and disease.

Authors/Disclosures
Mahsa Khayat-Khoei, MD PRESENTER	The institution of Dr. Khayat-Khoei has received research support from The National MS Society of America, for Fellowship Award.
Nazanin Ershadinia, MD (Brigham and Women's Hospital)	Dr. Ershadinia has nothing to disclose.
David Oluigbo	Mr. Oluigbo has nothing to disclose.
Timothy Sit	Dr. Sit has nothing to disclose.
Howard L. Weiner, MD (Brigham and Women'S Hospital)	Dr. Weiner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Weiner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medday Pharmaceuticals. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for vTv Therapeutics. Dr. Weiner has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Tiziana Life Sciences. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for vTv Therapeutics. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medday Pharmaceuticals. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for vTv Therapeutics. Dr. Weiner has stock in vTv Therapeutics. The institution of Dr. Weiner has received research support from National Institute of Health. The institution of Dr. Weiner has received research support from National MS Society. The institution of Dr. Weiner has received research support from Genzyme Corp. The institution of Dr. Weiner has received research support from Genentech, Inc. . The institution of Dr. Weiner has received research support from Verily Life Sciences LLC. The institution of Dr. Weiner has received research support from EMD Serono, Inc..
Susanna Mierau, MD, PhD (Brigham & Women's Hospital Neurology Department)	An immediate family member of Dr. Mierau has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers in Bioinformatics. The institution of Dr. Mierau has received research support from National Institutes of Health. The institution of Dr. Mierau has received research support from Evelyn Trust. The institution of Dr. Mierau has received research support from Novo Nordisk Foundation. The institution of an immediate family member of Dr. Mierau has received research support from Novo Nordisk Foundation. The institution of an immediate family member of Dr. Mierau has received research support from Helmsley Foundation. The institution of an immediate family member of Dr. Mierau has received research support from National Institutes of Health. The institution of an immediate family member of Dr. Mierau has received research support from Chan Zuckerberg Initiative.

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