TRPC channels regulate Ca(2+)-signaling and short-term plasticity of fast glutamatergic synapses

Transient receptor potential (TRP) proteins form Ca(2+)-permeable, nonselective cation channels, but their role in neuronal Ca(2+) homeostasis is elusive. In the present paper, we show that TRPC channels potently regulate synaptic plasticity by changing the presynaptic Ca(2+)-homeostasis of hippocampal neurons. Specifically, loss of TRPC1/C4/C5 channels decreases basal-evoked secretion, reduces the pool size of readily releasable vesicles, and accelerates synaptic depression during high-frequency stimulation (HFS). In contrast, primary TRPC5 channel-expressing neurons, identified by a novel TRPC5–τ-green fluorescent protein (τGFP) knockin mouse line, show strong short-term enhancement (STE) of synaptic signaling during HFS, indicating a key role of TRPC5 in short-term plasticity. Lentiviral expression of either TRPC1 or TRPC5 turns classic synaptic depression of wild-type neurons into STE, demonstrating that TRPCs are instrumental in regulating synaptic plasticity. Presynaptic Ca(2+) imaging shows that TRPC activity strongly boosts synaptic Ca(2+) dynamics, showing that TRPC channels provide an additional presynaptic Ca(2+) entry pathway, which efficiently regulates synaptic strength and plasticity.