Abstract
In order to understand and find therapeutic strategies for neurological disorders, disease models that recapitulate the connectivity and circuitry of patients’ brain are needed. Owing to many limitations of animal disease models, in vitro neuronal models using patient-derived stem cells are currently being developed. However, prior to employing neurons as a model in a dish, they need to be evaluated for their electrophysiological properties, including both passive and active membrane properties, dynamics of neurotransmitter release, and capacity to undergo synaptic plasticity. In this review, we survey recent attempts to study these issues in human induced pluripotent stem cell-derived neurons. Although progress has been made, there are still many hurdles to overcome before human induced pluripotent stem cell-derived neurons can fully recapitulate all of the above physiological properties of adult mature neurons. Moreover, proper integration of neurons into pre-existing circuitry still needs to be achieved. Nevertheless, in vitro neuronal stem cell-derived models hold great promise for clinical application in neurological diseases in the future.
Highlights
The complexity of the human central nervous system and its inaccessibility to direct studies make its modeling necessary in order to investigate physiological and pathological processes occurring in it
AP, action potential; Cm, membrane capacitance; DIV, days in vitro; iN, induced neuronal; iPSC, induced pluripotent stem cell; NPC, neural progenitor cell; NQ, not quantified; Rin, input resistance; RMP, resting membrane potential; τ, membrane time constant; x, not measured, used or stated co-cultured with astrocytes, AP-dependent spontaneous neurotransmission is first observed 2 weeks after differentiation followed by continuous increases in frequency and amplitude over the course of 60 days [10]
Curing neurological diseases is a challenging task in experimental therapeutics
Summary
The complexity of the human central nervous system and its inaccessibility to direct studies make its modeling necessary in order to investigate physiological and pathological processes occurring in it. The activity in early developing networks differs from that of mature networks by a number of factors, including the excitatory–inhibitory shift of γ-aminobutyric acid (GABA), the occurrence of giant depolarizing potentials (GDPs) and progressively increasing frequencies of both GABAergic and glutamatergic spontaneous neurotransmission, indicative of developmental synaptogenesis [7]. The progression of synaptic neurotransmission over the course of iPSC-derived neuron differentiation has been described recently [9, 10], the excitatory–inhibitory shift of GABA and the importance of GDPs have yet to be investigated in detail It is currently unknown whether neuronal differentiation from somatic cells shares the electrophysiological characteristics of natural neuronal development. Extracellular recordings of local field potentials are used to study the collective activity of many cells by monitoring the signals in the extracellular space of the brain, in order to investigate the synaptic connectivity of neuronal circuits in specific areas.
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