European Research Council Advanced Grant(ERC-AG 787157)
NAP3.0 National Program of the Hungarian Academy of Sciences(NKFIH K135561) Támogató:
NKFIH
Max Planck Society and by the Deutsche Forschungsgemeinschaft(DFG under CRC 1286)
Pronounced differences in neurotransmitter release from a given presynaptic neuron,
depending on the synaptic target, are among the most intriguing features of cortical
networks. Hippocampal pyramidal cells (PCs) release glutamate with low probability
to somatostatin expressing oriens-lacunosum-moleculare (O-LM) interneurons (INs),
and the postsynaptic responses show robust short-term facilitation, whereas the release
from the same presynaptic axons onto fast-spiking INs (FSINs) is ~10-fold higher and
the excitatory postsynaptic currents (EPSCs) display depression. The mechanisms underlying
these vastly different synaptic behaviors have not been conclusively identified. Here,
we applied a combined functional, pharmacological, and modeling approach to address
whether the main difference lies in the action potential-evoked fusion or else in
upstream priming processes of synaptic vesicles (SVs). A sequential two-step SV priming
model was fitted to the peak amplitudes of unitary EPSCs recorded in response to complex
trains of presynaptic stimuli in acute hippocampal slices of adult mice. At PC–FSIN
connections, the fusion probability (P fusion ) of well-primed SVs is 0.6, and 44%
of docked SVs are in a fusion-competent state. At PC–O-LM synapses, P fusion is only
40% lower (0.36), whereas the fraction of well-primed SVs is 6.5-fold smaller. Pharmacological
enhancement of fusion by 4-AP and priming by PDBU was recaptured by the model with
a selective increase of P fusion and the fraction of well-primed SVs, respectively.
Our results demonstrate that the low fidelity of transmission at PC–O-LM synapses
can be explained by a low occupancy of the release sites by well-primed SVs.
