Leaky wiring of the brain: local cluster of coupled synapses and extracellular signal integration

The wiring scheme is key to the function of the brain. Neurons are structurally wired by synapses and most synapses in the CNS are considered sufficiently isolated to avoid cross-talk to AMPA receptors of neighboring synapses. On the contrary, we show here with optical reporter proteins that the neurotransmitter glutamate regularly spreads far into the extracellular space (>1μm) after vesicular release. Together with 2P-glutamate uncaging our data suggest that multi-vesicular release rather regularly generates crosstalk responses at AMPA receptors of ~2-4 adjacent synapses (>70 synapses for NMDA receptors). Extracellular spread of glutamate is cooperative and coincident synaptic release events show enhanced spread and cause supra-additive activation of postsynapses. Thus, synaptic wiring of the brain seems to deviate more from point-to-point communication than previously reported and involves broadcasting information to very local neighborhoods which can stabilize learning performance and allow for integration of synaptic activity within the extracellular space.