Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • Introduction Neurotransmitters are critical for nervous syst

    2018-10-24

    Introduction Neurotransmitters are critical for nervous system control of behaviors and physiological functions (Kandel et al., 2000; Holz and Fisher, 2012). The challenge in gaining insight into regulation of neurotransmitter secretion in human ach receptors disorders has been the lack of human neuronal models from individual clinical cases. The human-induced pluripotent stem cell (hiPSC) neuronal approach has the capability to assess human brain cellular properties and may potentially be able to ach receptors address the fundamental property of activity-dependent secretion of neurotransmitters required for chemical neurotransmission. We therefore asked whether neurons differentiated from hiPSCs (Brennand et al., 2011; Peitz et al., 2013) possess the ability to secrete neurotransmitters in an activity-dependent manner, and whether biosynthetic enzymes for neurotransmitters are expressed. Further, to determine whether hiPSC neurons can be utilized to study neurotransmitter secretion related to a psychiatric brain disorder, we tested schizophrenia (SZ) hiPSC-derived neurons to answer the question of whether alterations in secreted neurotransmitters are recapitulated, including dopamine, which plays a role in SZ (Seeman, 1987; Coyle and Konopask, 2012; Eyles et al., 2012).
    Results
    Discussion It is important to clarify that increased catecholamine release does not necessarily indicate increased production in SZ hiPSC neurons but may instead imply a difference in the overall activity of one or more neuronal subtypes (Yu et al., 2014) and/or a change in the composition of neuronal populations (Robicsek et al., 2013) throughout the differentiation of these heterogeneous SZ hiPSC neuronal cultures. Indeed, an increased percentage of TH-positive neurons was observed in the SZ hiPSC neurons relative to controls, which likely accounts for the elevated catecholamines detected. A number of possible explanations might account for the increased number of TH-positive neurons observed, including, but not limited to, different rates of TH specification, maturation, or survival relative to other neurons in the culture. Given that our previously reported microarray comparisons of SZ and control hiPSC neural progenitor cells (NPCs) (Brennand et al., 2014) and neurons (Brennand et al., 2011) failed to detect increased patterning of DA and catecholamine fate, we posit that the differences observed more likely reflect differential survival of TH neurons rather than increased specification. Because changes in TH staining were not reflected in gene expression differences, this increase might instead indicate graded levels of protein, changing protein stability, and/or changes in protein translation. It is also possible that aberrant regulation of reuptake and metabolism of catecholamines in SZ hiPSC neurons may occur. We further speculate that the increased oxidative stress that we (Brennand et al., 2014) and others (Paulsen et al., 2012; Robicsek et al., 2013) have reported in SZ hiPSC neurons may be contributing to our observed results, and note that increased TH staining is generally reflected in neurons derived from higher passage NPCs, which might have been exposed to increasing amounts of stress with increased time in culture. Finally, because the observed increase in TH-positive neurons was heavily skewed by results in two of three SZ patients, we predict that in future studies of larger cohorts, hiPSC neurons derived from some but not all SZ patients may show this effect. Thus, the variability between patient-derived neurons in vitro may reflect real variance between SZ patients and could underlie, in part, the differences in drug responsiveness among patients. The molecular and cellular mechanisms contributing to these differences remain to be elucidated. The increase in the portion of TH-positive (relative to βIII-TUBULIN-positive) neurons in SZ hiPSC neurons is consistent with the upregulation of neuroregulin in SZ (Kato et al., 2011), which is thought to upregulate the expression of TH, resulting in increased DA and a hyperdopaminergic state (Kato et al., 2011). Alternately, it may be consistent with increased oxidative stress in SZ brain tissue causing preferential loss of non-catecholamine-producing neurons (Behrens et al., 2007). Though a recent postmortem study of SZ patients assessed TH protein levels in the substantia nigra/ventral tegmental brain area, great variability was observed among SZ brain samples compared to controls (Perez-Costas et al., 2012); another study found decreased TH-immunoreactive axons, but it is not known whether the data indicated fewer axons from individual neurons or fewer TH neurons (Akil et al., 2000). Nonetheless, these findings, when combined with our results, point to the importance of TH levels in SZ.