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Effects of Ethanol on Cellular Composition and Network Excitability of Human Pluripotent Stem Cell‐Derived Neurons
Author(s) -
Larsen Zoe H.,
Chander Praveen,
Joyner Jason A.,
Floruta Crina M.,
Demeter Tess L.,
Weick Jason P.
Publication year - 2016
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13218
Subject(s) - glutamatergic , excitatory postsynaptic potential , neuroscience , gabaergic , inhibitory postsynaptic potential , neocortex , induced pluripotent stem cell , biology , forebrain , premovement neuronal activity , glutamate receptor , central nervous system , receptor , embryonic stem cell , biochemistry , gene
Background Prenatal alcohol exposure ( PAE ) in animal models results in excitatory–inhibitory (E/I) imbalance in neocortex due to alterations in the GABA ergic interneuron ( IN ) differentiation and migration. Thus, E/I imbalance is a potential cause for intellectual disability in individuals with fetal alcohol spectrum disorder ( FASD ), but whether ethanol (Et OH ) changes glutamatergic and GABA ergic IN specification during human development remains unknown. Here, we created a human cellular model of PAE / FASD and tested the hypothesis that Et OH exposure during differentiation of human pluripotent stem cell‐derived neurons ( hPSN s) would cause the aberrant production of glutamatergic and GABA ergic neurons, resulting in E/I imbalance. Methods We applied 50 mM Et OH daily to differentiating hPSN s for 50 days to model chronic first‐trimester exposure. We used quantitative polymerase chain reaction, immunocytochemical, and electrophysiological analysis to examine the effects of Et OH on hPSN specification and functional E/I balance. Results We found that Et OH did not alter neural induction nor general forebrain patterning and had no effect on the expression of markers of excitatory cortical pyramidal neurons. In contrast, our data revealed highly significant changes to levels of transcripts involved with IN precursor development (e.g., GSX 2 , DLX 1 / 2 / 5 / 6 , NR 2F2 ) as well as mature IN specification (e.g., SST , NPY ). Interestingly, Et OH did not affect the number of GABA ergic neurons generated nor the frequency or amplitude of miniature excitatory and inhibitory postsynaptic currents. Conclusions Similar to in vivo rodent studies, Et OH significantly and specifically altered the expression of genes involved with IN specification from hPSN s, but did not cause imbalances of synaptic excitation–inhibition. Thus, our findings corroborate previous studies pointing to aberrant neuronal differentiation as an underlying mechanism of intellectual disability in FASD . However, in contrast to rodent binge models, our chronic exposure model suggests possible compensatory mechanisms that may cause more subtle defects of network processing rather than gross alterations in total E/I balance.