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Fibroblast growth factor 2 regulates activity and gene expression of human post‐mitotic excitatory neurons
Author(s) -
Gupta Shweta,
MRedmond Tanya,
Meng Fan,
Tidball Andrew,
Akil Huda,
Watson Stanley,
Parent Jack M.,
Uhler Michael
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14255
Subject(s) - excitatory postsynaptic potential , mitosis , gene expression , microbiology and biotechnology , biology , fibroblast growth factor , neuroscience , gene , inhibitory postsynaptic potential , genetics , receptor
Abstract Many neuropsychiatric disorders are thought to result from subtle changes in neural circuit formation. We used human embryonic stem cells and induced pluripotent stem cells (hi PSC s) to model mature, post‐mitotic excitatory neurons and examine effects of fibroblast growth factor 2 ( FGF 2). FGF 2 gene expression is known to be altered in brain regions of major depressive disorder ( MDD ) patients and FGF 2 has anti‐depressive effects in animal models of depression. We generated stable inducible neurons (siNeurons) conditionally expressing human neurogenin‐2 ( NEUROG 2) to generate a homogenous population of post‐mitotic excitatory neurons and study the functional as well as the transcriptional effects of FGF 2. Upon induction of NEUROG 2 with doxycycline, the vast majority of cells are post‐mitotic, and the gene expression profile recapitulates that of excitatory neurons within 6 days. Using hES cell lines that inducibly express NEUROG 2 as well as GC a MP 6f, we were able to characterize spontaneous calcium activity in these neurons and show that calcium transients increase in the presence of FGF 2. The FGF 2‐responsive genes were determined by RNA ‐Seq. FGF 2‐regulated genes previously identified in non‐neuronal cell types were up‐regulated ( EGR 1, ETV 4, SPRY 4, and DUSP 6) as a result of chronic FGF 2 treatment of siNeurons. Novel neuron‐specific genes were also identified that may mediate FGF 2‐dependent increases in synaptic efficacy including NRXN 3, SYT 2, and GALR 1. Since several of these genes have been implicated in MDD previously, these results will provide the basis for more mechanistic studies of the role of FGF 2 in MDD.