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When talking about action potentials we say that previous neurons caused an action potential in this neuron and that this neuron's action potential caused the same in further neurons.

But what is the origin of the first-ever action potential? Maybe in a living organism, there are no action potentials initially because the brain is always "on" and some part of the brain can always initiate processes in an other. If that is the case then how is the brain turned "on" initially? If not, then how does the first action potential get triggered from the "resting state"?

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The very first evoked spike is most likely triggered by spontaneous activity, as even neurons with no synaptic connections are able to fire action potentials (Luhmann et al. 2016). Later in life neurons can be excited by the external environment through sensory stimulation. At some point the central pattern generators also mature and, either by network synchronization or tuning of intrinsic neuronal properties, are able to maintain a self-sustained activity pattern.

The question is then what triggers spontaneous activity during development? It has to do with calcium signaling, both exogenous and from internal stores. The exogenous trigger is paracrine release of GABA and glutamate before the formation of synapses (Rosenberg and Spitzer 2011).

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