Human-Induced Pluripotent Stem Cell (iPSC)-Derived GABAergic Neuron Differentiation in Bipolar Disorder

被引:1
|
作者
Schill, Daniel J. [1 ]
Attili, Durga [1 ]
DeLong, Cynthia J. [1 ]
McInnis, Melvin G. [2 ]
Johnson, Craig N. [1 ]
Murphy, Geoffrey G. [3 ]
O'Shea, K. Sue [1 ,2 ]
机构
[1] Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA
关键词
GABA switch; gamma-aminobutyric acid; KCC2; NKCC1; neuron; patient; skin biopsy; somatostatin; stem cell; GENOME-WIDE ASSOCIATION; GABA; BRAIN; KCC2; DYSFUNCTION; PROMOTES; CACNA1C; TARGET; DELAYS; NKCC1;
D O I
10.3390/cells13141194
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Bipolar disorder (BP) is a recurring psychiatric condition characterized by alternating episodes of low energy (depressions) followed by manias (high energy). Cortical network activity produced by GABAergic interneurons may be critical in maintaining the balance in excitatory/inhibitory activity in the brain during development. Initially, GABAergic signaling is excitatory; with maturation, these cells undergo a functional switch that converts GABAA channels from depolarizing (excitatory) to hyperpolarizing (inhibitory), which is controlled by the intracellular concentration of two chloride transporters. The earliest, NKCC1, promotes chloride entry into the cell and depolarization, while the second (KCC2) stimulates movement of chloride from the neuron, hyperpolarizing it. Perturbations in the timing or expression of NKCC1/KCC2 may affect essential morphogenetic events including cell proliferation, migration, synaptogenesis and plasticity, and thereby the structure and function of the cortex. We derived induced pluripotent stem cells (iPSC) from BP patients and undiagnosed control (C) individuals, then modified a differentiation protocol to form GABAergic interneurons, harvesting cells at sequential stages of differentiation. qRT-PCR and RNA sequencing indicated that after six weeks of differentiation, controls transiently expressed high levels of NKCC1. Using multi-electrode array (MEA) analysis, we observed that BP neurons exhibit increased firing, network bursting and decreased synchrony compared to C. Understanding GABA signaling in differentiation may identify novel approaches and new targets for treatment of neuropsychiatric disorders such as BP.
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页数:16
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