A Combined Optogenetic-Knockdown Strategy Reveals a Major Role of Tomosyn in Mossy Fiber Synaptic Plasticity

•MF-CA3 synaptic plasticity can be reliably assessed using optogenetics•Combined KD-optogenetic strategy enables selective activation of manipulated neurons•MF-CA3 short-term plasticity is drastically reduced in tomosyn-deficient synapses•Increased basal Pr at tomosyn-deficient synapses occludes MF-CA3 LTP

SummaryNeurotransmitter release probability (Pr) largely determines the dynamic properties of synapses. While much is known about the role of presynaptic proteins in transmitter release, their specific contribution to synaptic plasticity is unclear. One such protein, tomosyn, is believed to reduce Pr by interfering with the SNARE complex formation. Tomosyn is enriched at hippocampal mossy fiber-to-CA3 pyramidal cell synapses (MF-CA3), which characteristically exhibit low Pr, strong synaptic facilitation, and pre-synaptic protein kinase A (PKA)-dependent long-term potentiation (LTP). To evaluate tomosyn’s role in MF-CA3 function, we used a combined knockdown (KD)-optogenetic strategy whereby presynaptic neurons with reduced tomosyn levels were selectively activated by light. Using this approach in mouse hippocampal slices, we found that facilitation, LTP, and PKA-induced potentiation were significantly impaired at tomosyn-deficient synapses. These findings not only indicate that tomosyn is a key regulator of MF-CA3 plasticity but also highlight the power of a combined KD-optogenetic approach to determine the role of presynaptic proteins.

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