Widespread co-release of glutamate and GABA throughout the mouse brain

Several brain neuronal populations transmit both the excitatory and inhibitory neurotransmitters, glutamate, and GABA. However, it remains largely unknown whether these opposing neurotransmitters are co-released simultaneously or are independently transmitted at different times and locations. By recording from acute mouse brain slices, we observed biphasic miniature postsynaptic currents, i.e., minis with time-locked excitatory and inhibitory currents, in striatal spiny projection neurons. This observation cannot be explained by accidental coincidence of monophasic excitatory and inhibitory minis. Interestingly, these biphasic minis could either be an excitatory current leading an inhibitory current or vice versa. Deletion of dopaminergic neurons did not eliminate biphasic minis, indicating that they originate from another source. Importantly, we found that both types of biphasic minis were present in multiple striatal neuronal types and in nine out of ten other brain regions. Overall, co-release of glutamate and GABA appears to be a widespread mode of neurotransmission in the brain. Voltage clamp recording at an intermediate voltage shows that the two opposing neurotransmitters, glutamate and GABA, are co-released by a fraction of synapses in many regions throughout the brain.