Genetic strategies to investigate neuronal circuit properties using stem cell-derived neurons

Abstract

The mammalian brain is anatomically and functionally complex, and prone to diverse forms of injury and neuropathology. Scientists have long strived to develop cell replacement therapies to repair damaged and diseased nervous tissue. However, this goal has remained unrealized for various reasons, including nascent knowledge of neuronal development, the inability to track and manipulate transplanted cells within complex neuronal networks, and host graft rejection. Recent advances in embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) technology, alongside novel genetic strategies to mark and manipulate stem cell-derived neurons, now provide unprecedented opportunities to investigate complex neuronal circuits in both healthy and diseased brains. Here, we review current technologies aimed at generating and manipulating neurons derived from ESCs and iPSCs toward investigation and manipulation of complex neuronal circuits, ultimately leading to the design and development of novel cell-based therapeutic approaches.

Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

“…Although epigenetic marks are lost with reprogramming, disease signatures at the level of single induced human neurons or DG-CA3 circuits reconstructed from induced human neurons ex vivo will presumably reflect the interactions between stress and genetic risk factors of PTSD. In vitro reconstruction of the DG-CA3 circuit with human neurons and using optical imaging and optogenetic tools to probe how properties and connectivity of DGCs and CA3 neurons from PTSD patients differ from healthy controls may enable identification of pathological changes in these neuronal populations (Garcia et al, 2012b;Garcia et al, 2012a;Yu et al, 2013). Gene editing tools that enable rapid engineering of disease mutations in human DGCs and CA3 neurons will facilitate causal assessment of genetic mutations and phenotypes (Hsu et al, 2014).…”

Will Brain Cells Derived From Induced Pluripotent Stem Cells or Directly Converted From Somatic Cells (iNs) Be Useful for Schizophrenia Research?

“…Recent advances to manipulate transplanted neurons permits the investigation of these cells in preexisting brain circuits. 17 iPSCs have also been established from a schizophrenia patient with a 22q11.2 deletion, a rare deletion of moderately large effect. 13 …”

Developing stem cell-based therapies for neural repair

“…In an original research article, Yoshikawa et al (2013) examine the potential of 2 commonly used anti-convulsant drugs to improve the differentiation and survival of iPSC-derived dopaminergic neurons in vitro and in vivo , with this knowledge having implications for improved grafting approaches for treatment of Parkinson's disease. Garcia et al (2013) highlight advancement in tools and technology that enable us to more accurately assess the integration of transplanted neurons in the brain. Finally, Broughton et al (2013) provide a review on the exogenous “chaperone” benefits that stem cell grafts may provide in neural repair.…”