Intracellular calcium ( \(\:C{a}^{2+}\) ) signaling at synapses is fundamental to understanding how the brain processes information, learns and stores memories. However, achieving precise control over calcium dynamics at the level of individual synapses remains a major challenge in neuroscience. Recent advances in calcium-permeable channelrhodopsins (CapChRs) provide a promising optogenetic strategy for directly modulating postsynaptic calcium influx with high spatial and temporal precision. Here, we present a new theoretical model of synergistic sono-optogenetic control of postsynaptic \(\:C{a}^{2+}\) dynamics using CapChR1, CapChR2, C2-LC and PsCatCh2.0 expressed at the postsynaptic spine. We systematically explored multiple stimulation paradigms, including coordinated electrical activation of presynaptic and postsynaptic terminals, optogenetic excitation of CapChR-expressing spines, ultrasound (US) stimulation of pre- and postsynaptic terminals using MscL-I92L and combined synergistic sono-opto stimulation. These approaches reveal multiple tunable pathways for shaping postsynaptic calcium responses, with optical irradiance and US providing an additional degree of control over \(\:C{a}^{2+}\) influx. Our analysis identifies the minimum optical irradiance, optimal inter-stimulus timing and stimulation frequency ranges required to effectively modulate synaptic efficacy. Robust synaptic modulation is achieved at an irradiance of 7 µW/mm² when electrical stimulation of the presynaptic terminal and postsynaptic spine is combined with US and optogenetic activation of CapChR2 at the postsynaptic spine, a significant 61.11% reduction from the previously reported irradiance of 18 µW/mm² in our earlier study Dixit et al. (2025). Similarly, the required irradiance is 8 µW/mm² for CapChR1, 10 µW/mm² for C2-LC, and 34 µW/mm² for PsCatCh2.0. Collectively, these results demonstrate that integrating sonogenetics with synaptic plasticity provides a flexible and energy-efficient strategy for directly controlling \(\:C{a}^{2+}\) -dependent synaptic plasticity, substantially reducing the optical power required for effective synaptic modulation.
