Synaptic summation shapes information transfer in GABA-glutamate co-transmission

Co-transmission, the release of multiple neurotransmitters from a single neuron, is an increasingly recognized phenomenon in the nervous system. A particularly interesting combination of neurotransmitters exhibiting co-transmission is glutamate and GABA, which, when co-released from neurons, demonstrate complex biphasic activity patterns that vary depending on the time or amplitude differences from the excitatory (AMPA) or inhibitory (GABA_A) signals. Naively, the outcome signal produced by these differences can be functionally interpreted as simple mechanisms that only add or remove spikes by excitation or inhibition. However, the complex interaction of multiple time-scales and amplitudes may deliver a more complex temporal coding, which is experimentally difficult to access and interpret. In this work, we employ an extensive computational approach to distinguish these postsynaptic co-transmission patterns and how they interact with dendritic filtering and ionic currents. We specifically focus on modeling the summation patterns and their flexible dynamics that arise from the many combinations of temporal and amplitude co-transmission differences. Our results indicate a number of summation patterns that excite, inhibit, and act transiently, which have been previously attributed to the interplay between the intrinsic active and passive electrical properties of the postsynaptic dendritic membrane. Our computational framework provides an insight into the complex interplay that arises between co-transmission and dendritic filtering, allowing for a mechanistic understanding underlying the integration and processing of co-transmitted signals in neural circuits.

The online version contains supplementary material available at 10.1007/s11571-025-10383-2.