Javier Emperador-Melero, PhD-student at FGA, describes how regulated secretory pathways mature in mixed excitatory/inhibitory micro-networks of human iPS-cell derived neurons.
During the last years, the Functional Genomics department @ CNCR has invested in the design of simple, standardized networks of human neurons derived from re-programming of human somatic (skin) cells. Javier Emperador-Melero, PhD-student in the department, has now published the first paper on these networks that consist of 4-20 excitatory and inhibitory neurons. These networks have functional synapses, show spontaneous activity and a stable excitation/inhibition balance, just like the neural networks in our brain do. Aish Geeyarpuram Nadadhur, another PhD-student involved in this study, has recently submitted a paper characterizing these networks in more detail.
The study that Javier and his team are publishing describes how secretory pathways responsible for the secretion of signaling molecules, like neurotransmitters and neuromodulators, mature in developing micro-networks. The main finding is that the pathway that regulates secretion of neuromodulators, such as neuropeptides and trophic factors, matures much earlier than the pathway that regulates synaptic transmission.
The micro-networks described in this study are of course highly simplified models for the real human brain, but thanks to the high degree of standardization and the excellent experimental control, these networks are a powerful model system to study disorders of the human brain where synapses are suspected to malfunction. The first large scale studies on autism, intellectual disability, schizophrenia and epilepsy are already underway at CNCR (see COSYN, SUN and STXBP1 disorders).
Top left panel: nine micro-islands with human iPS-cell derived neurons, containing several excitatory and inhibitory neurons. Middle panel: zoom in of the circled island containing 5 neurons. Bottom left panel: staining for inhibitory synapses. Bottom middle panel: staining for excitatory synapses. Right panels: Patch clamp recordings of synaptic transmission in these human neurons sensitive to blockers of excitatory transmission (top) or inhibitory transmission (bottom).