Theoretical analysis of low power optogenetic control of synaptic plasticity with subcellular expression of CapChR2 at postsynaptic spine.

Precise control of intracellular calcium ([Formula: see text]) concentration at the synaptic neuron terminal can unravel the mechanism behind computation, learning, and memory formation inside the brain. Recently, the discovery of [Formula: see text]-permeable channelrhodopsins (CapChRs) has opened the opportunity to effectively control the intracellular [Formula: see text] concentration using optogenetics. Here, we present a new theoretical model for precise optogenetic control with newly discovered CapChR2 at postsynaptic neuron. A detailed theoretical analysis of coincident stimulation of presynaptic terminal, postsynaptic spine and optogenetic activation of CapChR2-expressing postsynaptic spine shows different ways to control postsynaptic intracellular [Formula: see text] concentration. Irradiance-dependent [Formula: see text] flow is an additional advantage of this novel method. The minimum threshold of light irradiance and optimal ranges of time lag among different stimulations and stimulation frequencies have also been determined. It is shown that synaptic efficacy occurs at 20 µW/mm at coincident electrical stimulation of presynaptic terminal and postsynaptic spine with optogenetic activation of CapChR2-expressed postsynaptic spine. The analysis provides a new means of direct optogenetic control of [Formula: see text]-based synaptic plasticity, better understanding of learning and memory processes, and opens prospects for targeted therapeutic interventions to modulate synaptic function and address various neurological disorders.