Abstract Details

Title 15q11.2 Deletion Results in Altered Excitability and Connectivity in Human Induced Pluripotent Stem Cell Derived Neurons

Topic Child Neurology and Developmental Neurology

Presentation(s) S51 - Child Neurology: Bench to Bedside: Progress in Treating Genetic Disorders (4:58 PM-5:09 PM)

Poster/Presentation
Number 009

Background Copy number variation at the 15q11.2 locus has been implicated in schizophrenia, intellectual disability and autism and it is deleted in 1.4% of patients with idiopathic generalized epilepsy. It is also deleted in the more severe forms of Prader Willie and Angelman syndrome, emphasizing its importance in neural development and the pathogenesis of neural developmental disorders. However, it is unclear how deletion of 15q11.2 results in altered neuronal excitability.

Objective

To determine the effect of 15q11.2 deletion on neuronal development and network excitability in an in vitro model of neural developmental disorders.

Design/Methods We developed an in vitro culture system comprised predominantly of glutamatergic neurons derived from induced pluripotent stem cells from 15q11.2 deleted and control patients. Using immunofluorescence we assessed cultures for markers of maturity and synaptic development, which were evident by 60 days in vitro (DIV). We assessed neurons within the cultures at weekly intervals beginning at 35-40 days DIV for evidence of functionality, excitability, and connectivity using multielectrode arrays.

Results Although both control and 15q11.2 deleted lines demonstrated functional neuronal spiking by 40 DIV, 15q11.2 deleted lines exhibited developmental delay. They were slower to acquire mature neuronal markers and exhibited lower bursting activity. Most striking, however, was a marked difference in the development of synchronized periodic spike bursts. Control cultures demonstrated highly synchronized trains of bursts with intervening periods of decreased spiking as early as 60 DIV, while the 15q11.2 deleted cultures had significantly decreased levels of synchronization and more uniform burst rates over a similar time-frame.

Conclusions

These data suggest that 15q11.2 deletion alters neuronal maturation and impairs their functional connectivity. As these changes were observed in human neurons in vitro, they suggest that 15q11.2 deletion causes cell autonomous changes in neurons, which may contribute to alterations in network excitability and synaptic maturation in patients.

Authors/Disclosures
Christa Habela, MD (Johns Hopkins University) PRESENTER	The institution of Dr. Habela has received research support from NINDS. Dr. Habela has received publishing royalties from a publication relating to health care.
Arens Taga, MD (Johns Hopkins University)	Dr. Taga has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Carl E. Stafstrom, MD, PhD (Johns Hopkins Hospital - Pediatric Neurology)	No disclosure on file
	No disclosure on file
Hongjun Song, PhD	No disclosure on file
Nicholas J. Maragakis, MD, FAAN (Johns Hopkins University School of Medicine)	Dr. Maragakis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UptoDate. Dr. Maragakis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Apellis Pharmaceuticals. Dr. Maragakis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx. An immediate family member of Dr. Maragakis has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for National Basketball Association. Dr. Maragakis has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Akava. An immediate family member of Dr. Maragakis has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Johns Hopkins Howard County Medical Center. Dr. Maragakis has stock in Akava. The institution of Dr. Maragakis has received research support from NIH/NINDS. The institution of Dr. Maragakis has received research support from Department of Defense. The institution of Dr. Maragakis has received research support from Maryland Stem Cell Research Fund. Dr. Maragakis has received intellectual property interests from a discovery or technology relating to health care.

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