Date:
September 27, 2021
12:00PM (noon) – 1:00PM

Title:
Excitatory dysfunction drives network deficits in a schizophrenia 16p11.2 duplication iPSC derived neuronal model 

Abstract:
The 16p11.2 locus is a copy number variant (CNV) strongly linked to autism spectrum disorder, intellectual disability and epilepsy, however, only duplications have been linked to schizophrenia (SCZ). Animal and post-mortem studies have isolated robust alterations in excitatory/inhibitory networks in SCZ, though dissecting the causative factors in complex neuronal tissue poses a significant challenge. However, advances in the generation of pure excitatory and GABA-ergic cortical stem cell derived neurons provides a unique approach to dissect cell-type specific dysfunction in iPSC-derived neuronal models of SCZ. Isogenic and patient 16p11.2 duplication iPSC-derived neurons were assessed by multi-electrode array, identifying reductions in electrical activity and network formation. Interestingly, these deficits were present in mono-cultured excitatory neurons, supporting primary dysfunction of glutamatergic cortical neurons. In order to identify altered molecular pathways, transcriptomics was performed revealing alterations in gene sets involved in calcium homeostasis and cellular morphology. Calcium network imaging and morphological analyses revealed disruptions to dendritic length and calcium handling that may contribute to activity and network phenotypes.  The presence of these deficits in both isogenic and patient lines suggest penetrant alterations to glutamatergic neurodevelopment that may contribute to cortical dysfunction and SCZ risk.

Registration:  https://northwestern.zoom.us/meeting/register/tJ0uf–uqzgiHtC1S3Q1goUygf6ivb2GHFBG